Amino acid transport system A is involved in inflammatory nociception in rats.
Previous studies have indicated that central sensitization is a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation and astrocytes play an important role in the central sensitization. The current study investigated the role of amino acid transport system A in central sensitization and hyperalgesia induced by intraplantar injection of formalin in rats. Formalin (5%, 50μl) injected subcutaneously into the unilateral hindpaw pad induced typical biphase nociceptive behaviors, including licking/biting and flinching of the injected paw and an increase of glial fibrillary acid protein (GFAP, an activated astrocyte marker) expression in spinal dorsal horn, and these effects could be attenuated by intrathecal injection of the competitive inhibitor of amino acid system A transporter, methylaminoisobutyric acid (MeAIB, 0.1, 0.3, 0.5, and 0.7mmol), in a dose-dependent manner. Intrathecal injection of vehicle (PBS) had no effect on the formalin-induced nociceptive behaviors and increase of the GFAP. These findings suggest that amino acid transport system A is involved in inflammation-induced nociception, and inhibition of this transporter system results in inhibition of the central sensitization and hyperalgesia.


Tissue engineered pre-vascularized buccal mucosa equivalents utilizing a primary triculture of epithelial cells, endothelial cells and fibroblasts.
Artificial generated buccal mucosa equivalents are a promising approach for the reconstruction of urethral defects. Limiting in this approach is a poor blood vessel supply after transplantation, resulting in increased morbidity and necrosis. We generated a pre-vascularized buccal mucosa equivalent in a tri-culture of primary buccal epithelial cells, fibroblasts and microvascular endothelial cells, using a native collagen membrane as a scaffold. A successful pre-vascularization and dense formation of capillary-like structures at superficial areas was demonstrated. The lumen size of pre-formed blood vessels corresponded to the capillary size in vivo (10-30 μm). Comparing native with a highly cross-linked collagen membrane we found a distinct higher formation of capillary-like structures on the native membrane, apparently caused by higher secretion of angiogenic factors such as PDGF, IL-8 and angiopoietin by the cells. These capillary-like structures became functional blood vessels through anastomosis with the host vasculature after implantation in nude mice. This in vitro method should result in an accelerated blood supply to the biomaterial with cells after transplantation and increase the succes rates of the implant material.


Biosocial aspects of domestic violence.
Domestic violence, defined as acts of verbal abuse and physical violence performed against women by current intimate main partners, was surveyed by means of the Conflict Tactics Scale. We examined the relationships between a biological variable (testosterone level), social variables (demographics, social integration), and behaviour (substance use) and self-reported domestic violence. Forced-entry OLS regression models allowed us to study how social and behavioural variables modified the effects of testosterone on this specific violent behaviour. The sample consisted of 54 men who had a main sexual partner and who identified themselves as Black, White, or Hispanic. The men were recruited from various social-service-agency sites in the area of Miami, Florida, on the basis of their risk factors for HIV/AIDS. The sample can best be described as culturally diverse men of low socioeconomic status who had a main sexual partner. A high percentage of participants reported some level of both verbal and physical aggression towards their partners. Testosterone levels were significantly associated with levels of both verbal aggression and physical violence self-reported by the men. Testosterone level, demographic characteristics, and alcohol consumption contributed to explaining the variance in self-reported verbal and physical abuse. The high heritability of testosterone level and its association with violent behaviour warrant the inclusion of this variable in studies of antisocial and criminal behaviour including domestic violence.


Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function.
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association. We used repeated measures analysis to compare the association between cumulative lead biomarkers-bone lead measured using K-shell X-Ray Fluorescence-and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses. A 15μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead. Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.


Dynamic agent of an injectable and self-healing drug-loaded hydrogel for embolization therapy.
Embolic agents are crucial for trans-catheter arterial embolization (TAE) in the treatment of various unresectable malignant tumors. Although solid particles, liquid oils, and some polymeric hydrogels have proved their capacities for embolic therapies, the low efficiency, time sensitivity, and cytotoxicity are still considered as challenges. In this study, we developed a three-component dynamic self-healing hydrogel to overcome these limitations. With the help of the Schiff-base bonding, both glycol-chitosan and carbazochrome, containing amine groups, react with dibenzaldehyde-terminated poly(ethylene-glycol) (DF-PEG), forming the dynamic self-healing hydrogels under a mild condition within 200 s. 1H NMR and rheology test were used to characterize the Schiff-base formation and mechanical strength. Controlled-release of carbazochrome from different gelator concentrations of DF-PEG was also studied. Furthermore, in vivo evaluation of the embolization on rats showed the superior embolic effects of the injectable and self-healing hydrogel. Therefore, this new dynamic agent demonstrated the potential for application as a simple, inexpensive, and tunable embolic agent for cancer treatment and drug delivery system.


Radiation pressure measurement using a macroscopic oscillator in an ambient environment.
In contrast to current efforts to quantify the radiation pressure of light using nano-micromechanical resonators in cryogenic conditions, we proposed and experimentally demonstrated the radiation pressure measurement in ambient conditions by utilizing a macroscopic mechanical longitudinal oscillator with an effective mass of the order of 20 g. The light pressure on a mirror attached to the oscillator was recorded in a Michelson interferometer and results showed, within the experimental accuracy of 3.9%, a good agreement with the harmonic oscillator model without free parameters.


Liver Transplantation Using Right Lobe Graft With Focal Nodular Hyperplasia: Report of 2 Cases.
We described 2 cases of adult-to-adult liver transplantation using right lobe grafts donated by 2 patients suffering from focal nodular hyperplasia, the volumes of which were 360 cm3 and 220 cm3. This study was performed in compliance with the Declaration of the Helsinki. For preparation of the graft, back-table hepatic venous outflow reconstruction, including replacement of the retrohepatic inferior vena cava and bridging of hepatic segment V5/V8, was performed by using prosthetic vessel grafts. The liver grafts after subtracting the weight of focal nodular hyperplasia functioned well without serious small-for-size syndrome or graft dysfunction in spite of graft-to-recipient weight ratio less than 0.8%. This suggested the functioning of hepatocyte within focal nodular hyperplasia, which avoided graft deficiency. These 2 recipients were given not only conventional immunosuppressants (tacrolimus and mycophenolate sodium) but also anticoagulants (low molecular weight heparin and warfarin). Thrombosis of the prosthetic inferior vena cava 1 month after transplant in recipient 1 was treated by placement of intravascular stent. Biliary duct anastomotic stricture 2 weeks after transplant in recipient 2 was treated by placement of biliary stent. These 2 recipients remain well at more than 2 years post-transplant. These successful explorative cases highlight the safe use of a graft containing focal nodular hyperplasia. The partial liver resection grafts with focal nodular hyperplasia could be applied to the patients on the waiting list for liver transplantation.


Work disability among women with rheumatoid arthritis. The relative importance of disease, social, work, and family factors.
Yelin and others have shown social work factors to be more important than disease factors in predicting work disability among arthritis patients; however, the effects of family factors on work role functioning have not been considered in previous explanatory models. In this study, we use Yelin's model to explain work disability among 122 women with rheumatoid arthritis and to incorporate family factors into the model. Using logistic regression, we found, as with previous studies, that work autonomy, social factors, and disease factors are important predictors of work disability. In the logistic regression model, self-assessed health status seemed to be more important than work factors in predicting work status. Further, family factors significantly contributed to the explanatory model, in that having more home responsibilities was associated with lower risk of work disability.


Description of the anterior cerebral artery and its cortical branches: Variation in presence, origin, and size.
Certain aspects of the anterior cerebral artery (ACA) cortical branches tend to vary, including absent or additional arteries, variation in origin, and changes to diameter and length. Knowledge of these factors can be crucial in aneurysm and arteriovenous malformation surgery. Few studies report on these aspects and a South African study have not been completed. Therefore, the aim of this study is to report absent or additional arteries, the origin, diameter and length of ACA cortical branches in a Western Cape population. A coloured silicone was injected into the ACA of 121 hemispheres (60 right, 61 left), consisting of 83 males and 38 females. Specimens were divided in groups younger than 34 (n=36), between 35 and 48 (n=35), older than 49 (n=40), and unknown (n=10). There were three population groups; coloured (n=72), black (n=37), white (n=10), and unknown (n=2). Any absent or additional arteries were noted, as well as the origins. External diameter and lengths were measured using a digital micrometre, string and a ruler. The diameter and lengths indicated significant differences between right and left, sex, age and population groups. Most commonly absent (callosomarginal artery) and additional (paracentral lobule artery) arteries were noted. Origins were similar to the literature; however, previously unreported origins and common trunks were also observed. The aspects reported have been neglected in previous work and neurosurgeons should be aware of these variations and anomalies to avoid complications. Studies should continue to assess the cerebral vasculature since undocumented variations are still being reported.


Cyclosporine monitoring with 2-hour postdose levels in heart transplant recipients.
Cyclosporine therapeutic drug monitoring based on 2-hour postdose concentration (C2) compared with conventional trough concentration (C0) can improve clinical outcomes for de novo renal and liver transplant patients. However, in heart transplant patients, published studies are limited. To determine the clinical significance of C2 compared with C0 following orthotopic heart transplantation, the authors measured CsA at C0 and C2 and estimated CsA area under the curve (AUC) using Bayesian estimation and 4 sparse sample algorithms in a cross section of 31 adult patients receiving triple-drug immunosuppression with CsA, mycophenolate mofetil (MMF), and prednisone. CsA was measured using a validated HPLC method. Endomyocardial biopsies were graded based on the ISHLT system. Mean +/- SD values for CsA dose, C0, and C2 were 4.8 +/- 1.4 mg/kg/d, 240 +/- 62 microg/L, and 1319 +/- 469 microg/L, respectively. Correlation with AUC, using different estimation algorithms, was better for C2 (r(2) = 0.79-0.99) than for C0 (r(2)= 0.11-0.52). The mean +/- SD values for C0 (microg/L) and C2 (microg/L) for rejectors (n = 3) were 215 +/- 68 and 949 +/- 204 versus 242 +/- 62 and 1359 +/- 474 for the nonrejectors (P = 0.66 and 0.12, respectively). Fisher exact test P values using the median as threshold value for C0 and C2 (234 microg/L and 1251 microg/L, respectively) were 0.6 and 0.1. Analysis of the data revealed that C0 values in rejectors have wider variability than C2. There were no rejectors among the 16 patients exceeding the C2 median value; for C0, however, there was not an easily identifiable threshold value. There is a trend for a significant relationship between C2 and the incidence of rejection, but the number of rejectors was too small to reach statistical significance. A prospective concentration-control de novo study design is recommended as the most appropriate way to fully evaluate the potential utility of C2 monitoring in heart transplant patients.


Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.
Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.


Potent inhibition of CYP1A2 by Frutinone A, an active ingredient of the broad spectrum antimicrobial herbal extract from P. fruticosa.
1. Frutinone is an active ingredient extracted from the lipophilic fraction of the Polygala Fruticosa demonstrating various antibacterial and fungal properties. The aim of this study was to characterize its metabolism in an effort to understand metabolism based drug-herb interactions. 2. In vitro metabolic clearance and metabolite identification studies were done using cryopreserved hepatocytes. Reaction phenotyping and inhibition studies were done using human liver microsomes and recombinant cytochrome P450s (CYPs). Frutinone A-CYP1A2 interactions were rationalized using docking simulations. 3. Hepatic clearance was predicted to be low (7.17 mL/min/kg), with reaction phenotyping studies indicating no clearance by the enzymes tested. Frutinone was identified as a potent inhibitor of CYP1A2 with moderate effects on CYP2C19, 2C9, 2D6 and 3A4. CYP1A2 inhibition was reversible and characterised by an IC(50) of 0.56 µM. Inhibition was differential showing mixed (K(i) = 0.48 µM) and competitive (K(i) = 0.31 µM) inhibition with 3-cyano-7-ethoxycoumarin and ethoxyresorufin, respectively. Two binding sites, one for inhibitors and the other for substrates were identified in silico. 4. The potent CYP1A2 inhibition by Frutinone A could be predictive of the potential drug-herb interaction risk in the use of herbal extracts from P. fruticosa. The data suggest future pharmacological research on this chromocoumarin should take metabolic properties into account.


[Mastoid eosinophilic granuloma: a case report].
Langerhans cell histiocytosis is a proliferating cell disease that may take various forms characterised by bone, skin lymph nodes and visceral lesions. Eosinophilic granuloma is a localised form of histiocytosis X, or Langerhans' cells histiocytosis, a benign form with unknown aetiology. At the head and neck level, it is usually located on the temporal, and usually occur in association with multifocal disease; however, isolated lesions may occur in the mastoid bone alone. The author's present a case of a patient with unifocal eosinophilic granuloma limited to the mastoid treated in ENT and radiotherapy departments. CT scan demonstrated an osteolytic lesion of the mastoid. The biopsy and immunohistochemical study confirmed the diagnosis. A surgery followed by a radiotherapy (20 Gy) have stabilised the situation. There is no recurrency after one year. Unifocal eosinophilic granuloma of the temporal bone is a benign lesion of langerhans' cell histiocytosis. Its diagnosis is difficult when the disease remains isolated. Its treatment depend on its extension and its risks. The excellent prognosis does not dispense on regulary follow up.


An outbreak of spinal neuronopathy of goat kids in Fiji.
A newly recognised caprine neuropathy is described in which goat kids developed rapidly progressive neurologic signs in association with widespread demyelination, spinal cord neuronal degeneration and active demyelination.


Functional activity of neutrophils in diabetes mellitus and coronary heart disease: role of myeloperoxidase in the development of oxidative stress.
We performed a comparative analysis of functional activity of neutrophils in patients with type 2 diabetes mellitus with and without symptoms of CHD. Enhanced H2O2 production by neutrophils in response to N-formyl-Met-Leu-Phe (fMLP) was found in patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus associated with CHD, fMLP-induced release of myeloperoxidase from azurophilic granules of neutrophils was reduced and plasma myeloperoxidase level was elevated. Increased peroxidase activity of myeloperoxidase, reduced plasma catalase activity, and increased levels of TBA-reactive lipid peroxidation products and oxidized glutathione were detected in patients of both groups. Since myeloperoxidase is an important neutrophilic mediator of oxidative stress, its increased activity in the blood can be an additional marker of oxidative stress and cardiovascular risk in patients with diabetes mellitus.


Beta-adrenergic receptor subtypes in stress-induced behavioral depression.
The purpose of this study was to examine the role of beta-adrenergic receptors in an animal model of stress-induced behavioral depression. beta-Adrenergic receptors in several brain regions and leukocytes of rats were determined by receptor binding techniques using 125I-cyanopindolol (cyp) as ligand and propranolol as displacer for total beta-adrenergic receptors, and ICI 86,406 for beta 1- and ICI 118,551 for beta 2-adrenergic receptors. We observed that the maximum number of binding sites (Bmax) and the apparent dissociation constant (Kd) of 125I-cyp binding to total beta-adrenergic receptors were increased in hippocampus of stressed rats with escape deficits (48 h after training) as compared to control rats. This increase was due to an increase in Bmax and Kd of 125I-cyp binding to beta 1-adrenergic receptors but not to beta 2-adrenergic receptors. There was no significant difference in beta 1-adrenergic receptors in cortex and cerebellum or beta 2-adrenergic receptors in hippocampus, cortex, cerebellum, or leukocytes of stressed (48 h after training) rats with escape deficits as compared to control rats. Interestingly, it was observed that beta 1- and beta 2-adrenergic receptors in various brain regions (cortex, cerebellum, and hippocampus) and beta 2-adrenergic receptors in leukocytes of stressed rats (10 days after training) were not significantly different from control rats, although escape deficits were still present. These results suggest that abnormalities in adrenergic neurotransmission are associated with an upregulation of beta 1-adrenergic receptors, which in turn may be involved in the early stages of behavioral deficits caused by uncontrollable shock.


Anti-inflammatory effects of lithium gluconate on keratinocytes: a possible explanation for efficiency in seborrhoeic dermatitis.
Topical lithium (Li) gluconate has a beneficial effect on seborrhoeic dermatitis (SD), unlike oral lithium (Li) used in psychiatry. SD is an inflammatory dermatitis associated, in most of cases, with colonization by lipophilic yeasts of the genus Malassezia. However, the exact mechanism of action of Li gluconate in SD still remains unknown. The aim of our study was to investigate the effect of topical Li on cytokine secretion and innate immunity. For this purpose, we investigated first the modulatory effect of Li on two pro-inflammatory and two anti-inflammatory cytokine secretion and second, the modulatory effect of Li on Toll-like receptor (TLR) 2 and 4 expression by unstimulated and stimulated keratinocytes. Two different skin models were used: keratinocytes in monolayer and skin explants. In some of them, inflammation was induced with LPS (1 mug/ml) or zymosan (2 mg/ml). Then the skin models were incubated with Li gluconate (Labcatal*, Montrouge, France) at three different concentrations (1.6, 3, 5 mM) determined according to viability MTT test. Expression of TNFalpha, IL6, IL10, TGFbeta1, TLR2 and TLR4 was detected by immunohistochemistry (IHC). Cytokines were quantified by ELISA methods. Our results showed that the effect of Li on keratinocytes is dose-dependent. At low concentration (1.6 mM), Li enhanced TNFalpha secretion, whereas, at higher concentration (5 mM), Li significantly enhanced IL10 expression and secretion. However, there was no significant modulation of Li on IL6 and TGFbeta1 secretion. Moreover, Li at 5 mM significantly decreased TLR2 and TLR4 expressions by differentiated keratinocytes. As Li concentration during topical treatment is probably closer to 5 mM than to 1 mM, the therapeutic effect of Li gluconate in DS may be explained by two anti-inflammatory actions: an increased expression and secretion of IL10 and a decreased expression of TLR2 and TLR4 by keratinocytes. The diminution of TLR2 expression by Li may not allow MF to trigger inflammation response in lesional skin.


Incorporating spirituality into home care at the end of life.
The home health clinician may be aware that the patient has spiritual needs, but may be unable to respond to these needs. This may be due to inadequate education or the assumption that spiritual needs should be addressed by chaplains, clergy, or other "spiritual" care providers. In reality, clinicians in the home are in the best position to offer spiritual support when caring for patients in their homes at the end of life.


Steroid hormone 20-hydroxyecdysone disturbs fat body lipid metabolism and negatively regulates gluconeogenesis in Hyphantria cunea larvae.
The steroid hormone 20-hydroxyecdysone (20E) has been described to regulate fat body lipid metabolism in insects, but its accurate regulatory mechanism, especially the crosstalk between 20E-induced lipid metabolism and gluconeogenesis remains largely unclear. Here, we specially investigated the effect of 20E on lipid metabolism and gluconeogenesis in the fat body of Hyphantria cunea larvae, a notorious pest in forestry. Lipidomics analysis showed that a total of 1 907 lipid species were identified in the fat body of H. cunea larvae assigned to 6 groups and 48 lipid classes. The differentially abundant lipids analysis showed a significant difference between 20E-treated and control samples, indicating that 20E caused a remarkable alteration of lipidomics profiles in the fat body of H. cunea larvae. Further studies demonstrated that 20E accelerated fatty acid β-oxidation, inhibited lipid synthesis, and promoted lipolysis. Meanwhile, the activities of pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase were dramatically suppressed by 20E in the fat body of H. cunea larvae. As well, the transcriptions of genes encoding these 4 rate-limiting gluconeogenic enzymes were significantly downregulated in the fat body of H. cunea larvae after treatment with 20E. Taken together, our results revealed that 20E disturbed fat body lipid homeostasis, accelerated fatty acid β-oxidation and promoted lipolysis, but negatively regulated gluconeogenesis in H. cunea larvae. The findings might provide a new insight into hormonal regulation of glucose and lipid metabolism in insect fat body.


Actions of neomycin on neuronal L-, N-, and non-L/non-N-type voltage-sensitive calcium channel responses.
The effects of neomycin on neuronal voltage-sensitive calcium channel (VSCC) responses were investigated by evaluating its effects on calcium-dependent neuronal responses that are sensitive and insensitive to the N-type voltage-sensitive calcium channel antagonist omega-conotoxin GVIA and the L-type VSCC antagonist nitrendipine. Chick synaptosomal 45Ca2+ influx and K(+)-evoked release of [3H]norepinephrine from chick cortical brain slices were omega-conotoxin GVIA sensitive and nitrendipine insensitive, suggesting that these responses are mediated predominantly by N-type VSCC. The K(+)-evoked increase of intracellular calcium in cortical neurons and the K(+)-evoked release of [3H]norepinephrine from rat brain cortical slices was partially sensitive to omega-conotoxin GVIA and nitrendipine, suggesting that these responses are mediated by N-, L- and non-L/non-N-type VSCC. Rat synaptosomal 45Ca2+ influx and the K(+)-evoked release of [3H]D-aspartate from rat hippocampal slices were completely insensitive to omega-conotoxin GVIA and nitrendipine, suggesting that these responses were mediated predominantly by non-L/non-N-type VSCC. Neomycin caused a concentration-dependent and virtually complete inhibition of all response parameters, with IC50 values ranging from 90 to 400 microM. The results suggest that neomycin is a nonselective inhibitor of neuronal responses mediated by L-, N-, and non-L/non-N-type VSCC.


The free fatty acid receptor G protein-coupled receptor 40 (GPR40) protects from bone loss through inhibition of osteoclast differentiation.
The mechanisms linking fat intake to bone loss remain unclear. By demonstrating the expression of the free fatty acid receptor G-coupled protein receptor 40 (GPR40) in bone cells, we hypothesized that this receptor may play a role in mediating the effects of fatty acids on bone remodeling. Using micro-CT analysis, we showed that GPR40(-/-) mice exhibit osteoporotic features suggesting a positive role of GPR40 on bone density. In primary cultures of bone marrow, we showed that GW9508, a GRP40 agonist, abolished bone-resorbing cell differentiation. This alteration of the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation occurred via the inhibition of the nuclear factor κB (NF-κB) signaling pathway as demonstrated by decrease in gene reporter activity, inhibitor of κB kinase (IKKα/β) activation, inhibitor of κB (IkBα) phosphorylation, and nuclear factor of activated T cells 1 (NFATc1) expression. The GPR40-dependent effect of GW9508 was confirmed using shRNA interference in osteoclast precursors and GPR40(-/-) primary cell cultures. In addition, in vivo administration of GW9508 counteracted ovariectomy-induced bone loss in wild-type but not GPR40(-/-) mice, enlightening the obligatory role of the GPR40 receptor. Then, in a context of growing prevalence of metabolic and age-related bone disorders, our results demonstrate for the first time in translational approaches that GPR40 is a relevant target for the design of new nutritional and therapeutic strategies to counter bone complications.


Poly(ethylene glycol) doubly and singly cationized by different alkali metal ions: relative cation affinities and cation-dependent resolution in a quadrupole ion trap mass spectrometer.
Structural information of gas phase complexes of poly(ethylene glycol) (PEG) cationized by one or two different alkali metal ions is inferred from MS and MS/MS experiments performed with an electrospray quadrupole ion trap mass spectrometer. The rationale for selecting PEG was that its sites for cation binding are non-selective with respect to the repeating monomeric unit of the polymer, but there is selectivity with respect to the formation of an inner coordination sphere specific to each metal ion. The dissociation of [M1+ M2+ (EO23)], where EO23 = linear polymer of ethylene oxide, 23 units in length, resulted in loss of one of the alkali metal ions, with preference for loss of the larger cation, with no fragmentation of the PEG backbone for Na, K, Rb, and Cs. Li was not examined in this portion of the study. The selectivity for loss of the larger alkali metal ion was [Na+ K+ (EO23)] to [Na+ (EO23)] + K+ at 100%; [K+ Rb+ (EO23)] to [K+ (EO23)] + Rb+ at 93%; and [Rb+ Cs+ (EO23)] to [Rb+ (Eo23)] + Cs+ at 99%. The resolution of [M+ (EOx)] for x = 20-30 was dependent on the alkali metal ion, with the highest resolution observed for Cs+ and the lowest for Na+. These results are discussed with respect to the packing of the oxygen atoms on PEG (M.W.(avg) = 1000) around an alkali metal ion of different radius, and how this packing leads to an ensemble of unique structures, and therefore mobilities for [M+ (EOx)].


Efficient separation of He/CH4 mixture by functionalized graphenylene membranes: A theoretical study.
In this work, we prepared two types of functionalized pore on pristine graphenylene membrane to study and compare the He/CH4 separation performance employing molecular dynamics (MD) simulation. The gas molecules transport through the membranes was monitored during the simulations. The results indicated that methane molecules cannot pass through the membranes under applied conditions, while helium molecules simply penetrate through, which verifies the ultrahigh selectivity of helium over methane molecules. The maximum helium permeance of about 1 × 107 GPU was obtained through the functionalized graphenylene membrane at room temperature, which is much higher than graphenylene membrane. As a consequence, the functionalized graphenylene membrane can supply both high permeance and selectivity for helium separation. The van der Waals (vdW) interactions between gas molecules and the surface of the membrane was also investigated. We further conducted the potential of mean force (PMF) calculations to study the permeation of gas molecules across the membrane. Although methane molecules, due to more powerful interactions between them and the surface of the membrane, adsorb on the membrane surface, face higher energy barrier near the membrane nanopore. In reality, adsorption prefers methane molecules on the membrane surface, while diffusion favors helium over methane molecules through the nanopores. The functionalized graphenylene membrane is expected to be able to be employed as a promising membrane for a highly efficient helium purification system.


A mitochondrial division inhibitor, Mdivi-1, inhibits mitochondrial fragmentation and attenuates kainic acid-induced hippocampal cell death.
Kainic acid (KA)-induced excitotoxicity promotes cytoplasmic calcium accumulation, oxidative stress, and apoptotic signaling, leading to hippocampal neuronal death. Mitochondria play a critical role in neuroinflammation and the oxidative stress response. Mitochondrial morphology is disrupted during KA-induced seizures; however, it is not clear whether mitochondrial fission or fusion factors are involved in KA-induced neuronal death. We investigated the effect of Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, on mitochondrial morphology and function in KA-injected mice. Mdivi-1 pretreatment significantly reduced seizure activity and increased survival rates of KA-treated mice. Mdivi-1 was protective against mitochondrial morphological disruption, and it reduced levels of phosphorylated Drp1 (Ser616) and Parkin recruitment to mitochondria. By contrast, levels of mitochondrial fusion factors did not change. Mdivi-1 also reduced KA-induced neuroinflammation and glial activation. We conclude that inhibition of mitochondrial fission attenuates Parkin-mediated mitochondrial degradation and protects from KA-induced hippocampal neuronal cell death.


Segmented approach to simultaneous intrusion and space closure: biomechanics of the three-piece base arch appliance.
Deep overbite correction and space closure in patients with flared incisors are mechanically difficult to achieve with conventional orthodontic treatment. The purpose of this article is to present an appliance design that allows simultaneous intrusion and retraction of anterior teeth as well as correction of their axial inclinations. A three-piece base arch was used to achieve simultaneous intrusion and space closure. Various clinical situations are discussed and analyzed from a biomechanical standpoint. Sequences of treatment, appliance design, and management of side effects are described in detail. The segmented approach to simultaneous intrusion and space closure is useful for achieving precise control of tooth movements in the anteroposterior and vertical dimensions.


Cryotherapy protocols for metastatic breast cancer after failure of radical surgery.
To retrospectively assess the effect of cryotherapy in patients with metastatic breast cancer (MBC) but without local recurrence after resection of the primary lesion, we divided 120 MBC patients into cryotherapy (91 patients) and chemotherapy (29 patients) groups. In the cryotherapy group, 37 patients with tumor recurrence received multiple cryoablations, while 54 patients received only a single cryoablation. Moreover, 62 cryotherapy-group patients underwent cryoablation immediately after the detection of metastases (timely cryotherapy); 35 patients received simultaneous immunotherapy (cryo-immunotherapy), and 29 patients underwent cryoablation in our hospital 3 months after receiving chemotherapy in other centers (chemo-cryotherapy and delayed cryotherapy). Overall survival (OS) after the diagnosis of MBC was assessed after a 10-year follow-up. The median OS was higher in the cryotherapy group (55 months) than in the chemotherapy group (27 months; P<0.0001). In the cryotherapy group, longer median OS was associated with multiple (76 months) rather than single cryoablations (48 months; P=0.0005) and with timely (67 months) rather than delayed cryoablation (48 months; P=0.0012). The median OS was higher after cryo-immunotherapy (83 months) than after chemo-cryotherapy (48 months) or cryotherapy alone (43 months; P<0.0001 for both). In conclusion, timely and multiple cryoablations, especially when combined with immunotherapy, offer significant advantages over chemotherapy in extending the OS of MBC patients.


How accurate is cytological diagnosis of cervical glandular lesions?
Gynecological cytology has some inaccurate morphological categorization and poor interobserver reproducibility especially for glandular lesions. Liquid-based cytology (LBC) preparations are presumed to reduce artifacts that interfere in diagnosis performance, but its value to correctly identify glandular alterations has not been sufficiently reported. The objective of this study was to compare the diagnostic performance and interobserver agreement of LBC and conventional Pap smear to identify histologically confirmed glandular lesions according to five cytologists. Sensitivity ranged from 55.8 to 73.1% and 32.7 to 48.1% for Pap smear and LBC, respectively. Specificity ranged from 66.1 to 87.1% and 69.4 to 94.4%, respectively. In general, agreement between pairs of cytologists was poor with kappa-values around 0.45. In conclusion, relying entirely on cervical cytology to rule out glandular lesions may be risky. The use of HPV DNA test alone or combined to screening glandular lesions may contribute to minimize the limitations of both conventional and LBC preparations to diagnose glandular abnormalities.


EANM guideline on quality risk management for radiopharmaceuticals.
This document is intended as a supplement to the EANM "Guidelines on current Good Radiopharmacy Practice (cGRPP)" issued by the Radiopharmacy Committee of the EANM (Gillings et al. in EJNMMI Radiopharm Chem. 6:8, 2021). The aim of the EANM Radiopharmacy Committee is to provide a document that describes how to manage risks associated with small-scale "in-house" preparation of radiopharmaceuticals, not intended for commercial purposes or distribution.


Effect of anterior capsule contraction on visual function after cataract surgery.
To examine the effect of contraction of the anterior capsule opening after cataract surgery on visual acuity and contrast sensitivity. Hayashi Eye Hospital, Fukuoka, Japan. Thirty-two eyes of 32 consecutive patients who showed marked contraction of the anterior capsule opening after implantation of an intraocular lens were recruited. The area of the anterior capsule opening was measured by Scheimpflug videophotography before and after neodymium:YAG (Nd:YAG) laser anterior capsulotomy and was correlated with visual acuity and contrast sensitivity. After Nd:YAG laser anterior capsulotomy, the mean area of the anterior capsule opening increased significantly from 8.2 mm(2) to 18.0 mm(2) (P<.0001). Contrast sensitivity at most visual angles also improved significantly after Nd:YAG anterior capsulotomy, although visual acuity did not. The area of the anterior capsule opening before anterior capsulotomy was correlated significantly with contrast sensitivity but not with visual acuity, whereas there was no correlation between the opening area after anterior capsulotomy and visual acuity or contrast sensitivity. Contraction of the anterior capsule opening after cataract surgery significantly diminished contrast sensitivity in proportion to the opening area but did not markedly worsen visual acuity. Neodymium:YAG laser anterior capsulotomy improved contrast sensitivity.


Meta-analysis of self-reported substance use compared with laboratory substance assay in general adult mental health settings.
An accurate assessment of substance use is necessary to make a correct psychiatric diagnosis and to provide appropriate treatment. This study uses meta-analysis to establish the strength of the association between self-reported substance use and the results of laboratory substance assay including the testing for specific substances and screening for any substance use in psychiatric hospitals and in community mental health settings. A systematic search for published studies was supplemented by additional data required for meta-analysis provided by several researchers in this field. Using random-effects meta-analysis, we calculated the pooled estimate of the odds ratio of a positive substance assay in patients reporting use or non-use of substances and estimated the sensitivity, specificity, positive predictive value and negative predictive value. Twenty-six studies met the inclusion criteria. Very strong associations were found between self-reported use and positive tests for cannabis [N = 11 studies, odds ratio (OR) = 22.3; 95% confidence interval (CI) = 10.1-49.1], amphetamines (N = 8, OR = 26.6; 95% CI = 7.9-88.9), cocaine (N = 8, OR = 39.7; 95% CI = 16.2-97.2) and opiates (N = 7, OR = 83.5; 95% CI = 26.7-260.7). Strong associations were found between self-reported use of any substance and positive substance screening (N = 15, OR = 7.2, 95% CI = 3.6-14.1) and tests for alcohol use (N = 5, OR = 8.5; 95% CI = 2.5-28.4). Screening for any substance use had a sensitivity of 61% and a specificity of 66%. Testing for individual substances was specific but lacked sensitivity. Screening has the potential to detect clinically relevant substances that would not be reported by the patient, whereas testing for a specific substance has little advantage over self-report. The sensitivity of the substance assay might be improved by obtaining a sample at the earliest opportunity. Consideration should be given to the increased use of substance screening in general adult mental health settings because it could improve the accuracy of psychiatric diagnosis and increase the likelihood of patients receiving treatment for substance use disorders.


Type-3 ryanodine receptor involved in Ca2+-induced Ca2+ release and transmitter exocytosis at frog motor nerve terminals.
Ca(2+)-induced Ca2+ release (CICR) occurs in frog motor nerve terminals after ryanodine receptors (RyRs) are primed for activation by conditioning large Ca2+ entry. We studied which type of RyR exists, whether CICR occurs without conditioning Ca2+ entry and how RyRs are primed. Immunohistochemistry revealed the existence of RyR3 in motor nerve terminals and axons and both RyR1 and RyR3 in muscle fibers. A blocker of RyR, 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) slightly decreased rises in intracellular Ca2+ ([Ca2+]i) induced by a short tetanus (50 Hz, 1-2s), but not after treatment with ryanodine. Repetitive tetani (50 Hz for 15s every 20s) produced repetitive rises in [Ca2+]i, whose amplitude overall waxed and waned. TMB-8 blocked the waxing and waning components. Ryanodine suppressed a slow increase in end-plate potentials (EPPs) induced by stimuli (33.3 Hz, 15s) in a low Ca2+, high Mg2+ solution. KN-62, a blocker of Ca(2+)/calmoduline-activated protein kinase II (CaMKII), slightly reduced short tetanus-induced rises in [Ca2+]i, but markedly the slow waxing and waning rises produced by repetitive tetani in both normal and low Ca2+, high Mg2+ solutions. Likewise, KN-62, but not KN-04, an inactive analog, suppressed slow increases in EPP amplitude and miniature EPP frequency during long tetanus. Thus, CICR normally occurs weakly via RyR3 activation by single impulse-induced Ca2+ entry in frog motor nerve terminals and greatly after the priming of RyR via CaMKII activation by conditioning Ca2+ entry, thus, facilitating transmitter exocytosis and its plasticity.


Radiographic measurement of intestinal length among children with short bowel syndrome: Retrospective determination remains problematic.
Small bowel length is the most reliable predictor of enteral independence in pediatric short bowel syndrome. Retrospectively measured bowel lengths on upper GI with small bowel follow-through (UGI/SBFT) were compared to operative measurements. A pediatric radiologist and surgical trainees blinded to operative measurements retrospectively analyzed UGI/SBFT studies using the digital radiography curved measurement tool. Children with SBS and severe intestinal failure (parenteral nutrition >90days) at a multidisciplinary intestinal failure program 2002-2015 were included. Data were expressed as median (Q1, Q3). Thirty-six children aged 0.8 (0.4, 3.7) years were analyzed. Fifty-six percent had intestinal malrotation, and 58% had prior serial transverse enteroplasty. Studies were conducted within 10 (7, 20) days of surgery. Intraoperative bowel length was 90cm (45, 142), while UGI/SBFT measurement by radiologist was 45cm (28, 63), with a mean difference of 47cm (SD 58cm, p<0.001) and a mean percent error of 50%. Radiographic assessment underestimated intestinal length in 83% of patients. Bowel length measured retrospectively from upper GI with small bowel follow-through studies usually underestimated intraoperative bowel length. The limits of agreement were too wide for this technique to be clinically useful. Operative measurement remains necessary to assess intestinal length and rehabilitation potential. Study of Diagnostic Test. Level III.


Nicotine regulates DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) phosphorylation at multiple sites in neostriatal neurons.
Nicotinic acetylcholine receptors (nAChRs) regulate dopaminergic signaling in the striatum by modulating the release of neurotransmitters. We have recently reported that nicotine stimulates the release of dopamine via alpha4beta2(*) nAChRs and/or alpha7 nAChRs, leading to the regulation of DARPP-32 at Thr34, the site involved in regulation of protein phosphatase-1 (PP-1). In this study, we investigated the regulation of DARPP-32 phosphorylation at its other sites, Thr75 [cyclin-dependent kinase-5 (Cdk5) site], Ser97 (CK2 site), and Ser130 (CK1 site), that serve to modulate Thr34 phosphorylation and dephosphorylation. In neostriatal slices, nicotine (100 microM) increased phosphorylation of DARPP-32 at Ser97 and Ser130 at an early time point (30 s) and decreased phosphorylation of DARPP-32 at Thr75 at a late time point (3 min). The increase in Ser97 and Ser130 phosphorylation was mediated through the release of dopamine via activation of alpha4beta2(*) nAChRs and alpha7 nAChRs and the subsequent activation of dopamine D1 and D2 receptors. The decrease in Thr75 phosphorylation was mediated through the release of dopamine via activation of alpha4beta2(*) nAChRs and the subsequent activation of dopamine D1 receptors. These various actions of nicotine on modulatory sites of phosphorylation would be predicted to result in a synergistic increase in the state of phosphorylation of DARPP-32 at Thr34 and thus would contribute to increased dopamine D1 receptor/DARPP-32 Thr34/PP-1 signaling.


Enhancement of terminal B lymphocyte differentiation in vitro by fibroblast-like stromal cells from human spleen.
Stromal elements are major components of lymphoid tissues contributing to both tissue architecture and function. In this study we report on the phenotype and function of fibroblast-like stromal cells obtained from human spleen. These cells express high levels of CD44 and ICAM-1 and moderate levels of VLA-4, VCAM, CD40 and CD21. They fail to express endothelial, epithelial, lymphocyte and monocyte/macrophage markers. We show that these cells interact with B cell blasts induced in vitro by anti-CD40 and anti-mu stimulation. As a result of these interactions both IL-6 and IgG secretion into culture medium is increased. The enhanced secretion of IgG is partly inhibited by abolishing B cell blaststromal cell contact or by anti-IL-6, anti-VCAM or anti-CD49d antibodies. Our studies also suggest that the ability of stromal cells to promote B cell survival is most likely the underlying mechanism of the enhanced immunoglobulin secretion. Comparison of stromal cells from different lymphoid and non-lymphoid organs revealed that bone marrow- and spleen-derived stromal cells are the most effective in promoting B cell blast differentiation.


Mitotic recombination: a genotoxic effect of the antidepressant citalopram in Aspergillus nidulans.
This report evaluates the potential of the antidepressant drug citalopram to induce homozygotization of genes previously present in a heterozygous condition, by homologous recombination. In order to address this question, a heterozygous diploid strain of the filamentous fungus Aspergillus nidulans and the homozygotization assay were utilized. Non-cytotoxic concentrations of citalopram (50, 75 and 100 μmol/L) showed a strong recombinogenic effect in A. nidulans, inducing homozygosis of the diploid strain's nutritional markers. The genetic markers exhibited homozygotization index (HI) rates higher than 2.0 and significantly different from HI control ones. Since citalopram has been previously characterized as a DNA synthesis inhibitor, the recombinogenic potential of this antidepressant in A. nidulans may be associated with the recombinational repair of citalopram-induced DNA strand breaks.


Assessing and prioritizing biogas barriers to alleviate energy poverty in Pakistan: an integrated AHP and G-TOPSIS model.
Biogas is a promising renewable technology to alleviate energy poverty. Pakistan has a capacity of 5 million bio digesters that can be installed in different farming areas. However, this target has never been achieved because many barriers hamper the biogas industry development. In previous studies, some researchers have indicated these barriers in different geographical contexts: however, these barriers are rarely examined in Pakistan. To fulfill the research gap, this study prioritizes potential barriers. Using a literature review and a modified Delphi technique, we identify 25 sub-barriers and catalog them into 5 main categories. The analytical hierarchy process (AHP) prioritizes the main barriers and sub-barriers based on potential. Grey Technique for Order Preference by Similarity to Ideal Solution (G-TOPSIS) ranks the practical alternatives to combat these barriers. The study findings specify that the "financial barrier" is the top-ranked barrier among the main categories, followed by technical, socio-cultural, institutional and administrative, and environmental barriers. The overall ranking shows that the "high starting price tag" is ranked first among all sub-barriers in all categories. It has been proposed that "appropriate financial incentives" and "promotion of customized technology" would be feasible alternative solutions to combat the issues. Based on the research findings, some policy recommendations were suggested for biogas uptake in Pakistan. This study may assist policymakers, stakeholders, and government institutions in accelerating the potential of biogas energy to alleviate energy poverty in rural areas of Pakistan.


Sudden, unexpected death due to undiagnosed frontal glioblastoma in a schizophrenic patient.
The incidence of sudden death due to undiagnosed primary intracranial tumor is low in forensic autopsy. We report a case of a 48-year-old white male, known to be a schizophrenic patient for several years, and in whom a medico-legal autopsy disclosed a large, previously undiagnosed, bilateral frontal glioblastoma infiltrating the genu of corpus callosum. We emphasize the importance of performing complete autopsy, including a thorough neuropathological examination, in all cases of sudden unexpected death, especially in those cases in which no extracerebral cause of death had been established and whose clinical history was primarily of a psychiatric nature.


Microexplosion cystolithotripsy in 105 cases.
We treated 105 consecutive patients with bladder calculi by microexplosion lithotripsy, with a success rate of 100 per cent. The weight of the removed calculi averaged 18 gm., with a range of 2 to 305 gm. For the procedure spinal anesthesia was used in 78 patients, while general anesthesia was used in 24. Minor extraperitoneal bladder perforation occurred only once and it resolved spontaneously several days later. Presently, we consider microexplosion lithotripsy to be the treatment of first choice for bladder calculi.


Central Nervous System Germ Cell Tumors.
Germ cells tumors most commonly affect children and adolescents, and occasionally arise in the central nervous system. Except for mature teratomas, they are all malignant. Pure germinomas are exquisitely sensitive to treatment and are highly curable with craniospinal radiation therapy. Surgery plays no role other than to establish the histologic diagnosis. Diagnostic confirmation includes normal levels of serum and cerebrospinal fluid alpha-fetoprotein and at most only minor elevations in beta human chorionic gonadotrophin (beta-hCG). Although it has become quite common to use chemotherapy to reduce the dose and field of radiation in the treatment of germinomas, longer follow-up in these patients is revealing a significant number of subarachnoid and ventricular recurrences. A recent follow-up study in patients treated for intracranial germinomas showed no significant difference in the psychosocial functioning of those treated with chemotherapy and radiation compared with those treated with chemotherapy alone, which raises further questions about the rationale for modifying a proven successful treatment. Malignant non-germinomatous germ cell tumors are much more resistant to treatment and difficult to cure. Surgical resection appears to have prognostic significance, although the predilection for midline structures makes complete resection difficult if not impossible at times. The best results have been obtained with platinum-based chemotherapy and full-dose craniospinal radiation therapy. Pure teratomas are not typically responsive to chemotherapy or radiation therapy and surgery is the only proven treatment modality.


A randomized controlled trial of brain and heart health manager-led mHealth secondary stroke prevention.
This study explores the effect of brain and heart health manager (BHHM)-led stroke secondary prevention on blood pressure, and in improving the self-management ability of stroke patients. The BHHM has not been reported. A total of 200 stroke patients, who were discharged from our hospital, were randomized into two groups at a 1:1 ratio: intervention group and control group. Patients in the control group were followed up for six months via telephone, while patients in the experimental group were followed up for six months using the BHHM-led mHealth follow-up. The primary outcomes were systolic blood pressure (BP) and self-management ability at 3, 6, 9 and 12 months, while the secondary outcomes included medication adherence, the body mass index (BMI), and blood low-density lipoprotein. The systolic BP between these two groups at four time points (Ftime =8.734, Fgroup =172.075, and Finteraction =11.363) was statistically significant (P<0.05). The self-health management ability at four time points during follow-up period (Ftime =115.09, Fgroup =1,185.50, and Finteraction =108.22) was also significantly different between these two groups. Furthermore, there was a statistically significant difference in compliance with medication at six months (χ2=37.616, P=0.000). However, after one year, there were no significant differences in BMI (t=0.214, P=0.644), total cholesterol (t=0.56, P=0.837), and low-density lipoprotein (t=0.042, P=0.455). The BHHM-led mHealth follow-up is an effective method for managing BP and improving the self-care ability. Furthermore, this approach has no obvious effect on the management of BMI and blood low-density lipoprotein. A potential signal of efficacy with the intervention was observed.


The 1-min sit-to-stand test--A simple functional capacity test in cystic fibrosis?
We aimed to assess the measurement properties and the minimal important difference (MID) of the 1-min sit-to-stand (STS) test in cystic fibrosis (CF). Patients with CF were tested during a pulmonary rehabilitation program. Five STS tests were performed during the program; two tests at the beginning (STS0 and STS1) and three tests at the end (STS2a-2c). Exercise capacity, pulmonary function, and health-related quality of life (HRQoL) and patient-reported health status were measured at the beginning and end of the program. We calculated overall mean, standard deviation, coefficient of variation (CV), and intraclass correlation coefficient (ICC) of the STS test. The MID was calculated using anchor-based and distributional methods. Fourteen participants (8 female, mean age 30.4±6.1years) were included. STS test performance increased significantly from STS0 to STS1 indicative of a learning effect. Test-retest reliability for the subsequent STS2a-2c tests was excellent (ICC 0.98, 95% CI 0.96-0.99). The estimated MID for the STS test was 5 repetitions. STS test performance was responsive to change (effect size of 0.97) and correlated with exercise capacity (r=0.63-0.73) and with the physical functioning HRQoL scale (r=0.72). The 1-min STS test appears to be a reliable, valid, and feasible test to measure functional capacity in patients with CF.


Cholecystectomy with drainage. Factors influencing wound infection in 1,000 elective cases.
A retrospective review of 1,000 elective cholecystectomies was undertaken to identify factors associated with wound infection. The technic of wound drainage appears to influence the incidence of infectious wound complications to a significant degree.


Flow cytometry analysis of CD11c-positive peripheral blood mononuclear cells in horses.
Horses have played a prominent role in shaping our modern world, with important effects on health. Unfortunately, better characterization of the horse immune system is still needed. In this report, using flow cytometry techniques, four monoclonal antibodies against horse CD11c integrin were characterized and described for their ability to provide a positive recognition signal in peripheral blood mononuclear cells. Further immune cell phenotype experiments were performed using MHC-II, CD14, TLR4 and the specific anti-horse CD11c monoclonal antibody (1C4). With this staining panel, it was possible to detect a cell population defined by CD11c+MHC-II+TLR4+CD14low, which could be considered as putative dendritic cells. This manuscript shows that a new monoclonal antibody (1C4) can be used for the characterization of dendritic cells and their different lineages, opening the possibility of better understanding the mechanisms of immunity in horses.


Altered heart and kidney phospholipid fatty acid composition are associated with cardiac hypertrophy in hypertensive rats.
We examined the association of cardiac hypertrophy or fibrosis with the phospholipid fatty acid (FA) composition of heart and kidney in hypertensive rats. Eight-week-old spontaneously hypertensive rats (SHRs) (n=8) and Wistar Kyoto rats (WKYs, n=8) as a normotensive control, were fed ad libitum for 6 weeks with regular AIN-76 diet. Phospholipid FA compositions in the left ventricle and kidney were measured and histological analyses were performed. Compared with WKYs, SHRs had lower proportions of γ-linolenic acid, α-linolenic acid, eicosadienoic acid, eicosatrienoic acid, dihomo-γ-linoleic acid, docosadienoic acid and nervonic acid in heart, and stearic acid (SA), γ-linolenic acid, and eicosapentaenoic acid (EPA) in kidney. After adjusting for food intake, SHRs still maintained higher proportions of SA, and total saturated FAs in the heart and a lower proportion of eicosapentaenoic acid in the kidney. Additionally, compared with WKYs, SHRs showed larger cardiomyocyte diameters in the left ventricles, indicating cardiac hypertrophy and interstitial fibrosis. Cardiomyocyte diameters also positively correlated with cardiac SA (r=0.550, p<0.05) and negatively with kidney EPA (r=-0.575, p<0.05). Tissue FA compositions were associated with cardiac hypertrophy in a hypertensive setting, implicating the pathogenic role of tissue FAs in hypertension and related complications.


Effectiveness of canalicular laceration repair using monocanalicular intubation with Monoka tubes.
This study aimed to evaluate the clinical efficacy of canalicular laceration repair using monocanalicular intubation with Monoka tubes. A total of 36 single lacerated canaliculi were repaired using monocanalicular intubation with Monoka tubes, without mucosal anastomosis of the canaliculi, and were retrospectively reviewed. Demographic information, injury locations, associated ocular injuries, complications and outcomes were analysed. Mean patient age was 34 years (range 1-64 years). Tubes were removed at a mean of 4.2 months (range 3-6 months). There were 26 lower canalicular lacerations (72%) and 10 upper canalicular lacerations (28%). Overall, 34 of 36 cases (92%) showed improvement in symptoms and exhibited positivity on the dye disappearance test at 4-12 months after the procedure (mean 7.8 months). In total, 21 patients (58%) achieved complete success, 13 patients (36%) achieved partial success and two patients (6%) suffered surgical failure. Complications were seen in five cases and included two early tube protrusions, two punctal slits and one punctal granuloma. Monocanalicular intubation with Monoka tubes leads to successful outcomes without significant complications and offers an alternative to bicanalicular intubation in the treatment of monocanalicular lacerations.


Animal models for the study of the effects of spaceflight on the immune system.
Animal models have been used to determine the effects of spaceflight on the immune system. Rats and rhesus monkeys have been the primary animals used for actual space flight studies, but mice have also been utilized for studies in ground-based models. The primary ground based model used has been hindlimb unloading of rodents, which is similar to the chronic bed-rest model for humans. A variety of immune responses have been shown to be modified when animals are hindlimb unloaded. These results parallel those observed when animals are flown in space. In general, immune responses are depressed in animals maintained in the hindlimb unloading model or flown in space. These results raise the possibility that spaceflight could result in decreased resistance to infection in animals.


Sequence and genome organization of papaya meleira virus infecting papaya in Brazil.
Papaya sticky disease ('meleira') was first observed in Brazil at the beginning of the 1980s. The disease is characterized by intense latex exudation from the fruit surface that becomes dark as it oxidizes, which makes it difficult to sell. The causal agent, which has been called papaya meleira virus (PMeV), has been identified as an isometric virus particle, approximately 50 nm in diameter, with a double-stranded RNA genome. Here, we report the first complete sequence and organization of the 8.7-kb viral dsRNA genome. Two ORFs coding for a putative coat protein and RNA-dependent RNA polymerase (RdRp) were predicted. In silico analysis revealed that the translated ORF2 contains the conserved domains characteristic of an RdRp protein (pfam02123:RdRP 4), which is a family that includes RdRps from members of the genera Luteovirus, Totivirus and Rotavirus. Evolutionary analysis with amino acid sequences with the RdRps from members of the family Totiviridae and some dsRNA viruses showed that PMeV RdRp did not root itself in any genus.


Are amorphous aggregates of actin formed at the initial stage of polymerization?
Amorphous aggregates of actin of various sizes were observed under an electron microscope, when actin polymerization was inhibited or retarded by EDTA or by low salt concentration. It was first thought that these aggregates could be intermediate complexes of actin in the process of polymerization. These aggregates were, however, present in usual G-actin solution as well as column-chromatographed or highly clarified samples. In the samples prefixed with glutaraldehyde, the aggregates were also observed. Moreover, similar aggregates were seen in denatured actin samples. Hence it is concluded that these aggregates of actin are artefact products due to the treatment with uranyl acetate used for negative staining.


In-situ arsenic remediation by aquifer iron coating: Field trial in the Datong basin, China.
An aquifer Fe-coating technology was evaluated for in-situ As remediation. The groundwater in the aimed aquifer has low dissolved Fe(II) concentration and high As(III) concentration, which has a low affinity toward Fe-oxides/hydroxides. To overcome these challenges, dissolved Fe(II) (5.0 mM) and NaClO (2.6 mM) were injected into the studied aquifer to promote the formation of Fe oxides/hydroxides and to oxidize As(III) into As(V), thus removing aqueous As via adsorption and/or co-precipitation. During field experiment, As concentration in groundwater from the pumping well significantly decreased. Fe and As speciation calculations indicate that incorporation of negatively charged As(V) into goethite was the probable mechanism for As removal. Both chemical sequential extraction results and spectroscopic data also support that alternating injection of Fe(II) and NaClO can achieve aquifer Fe coating and immobilize As via adsorption onto Fe oxides/hydroxides. Geochemical modelling further confirms that although competition for sorption sites between As and other dissolved species is expected in the natural groundwater system, high surface area of the Fe oxides/hydroxides can provide sufficient sites for As retention. The ability to effectively decrease As concentration of in-situ aquifer Fe-coating technology indicates that this approach should have extensive applicability to similar high As groundwater occurred worldwide.


Prediction of mortality risk of health checkup participants using machine learning-based models: the J-SHC study.
Early detection and treatment of diseases through health checkups are effective in improving life expectancy. In this study, we compared the predictive ability for 5-year mortality between two machine learning-based models (gradient boosting decision tree [XGBoost] and neural network) and a conventional logistic regression model in 116,749 health checkup participants. We built prediction models using a training dataset consisting of 85,361 participants in 2008 and evaluated the models using a test dataset consisting of 31,388 participants from 2009 to 2014. The predictive ability was evaluated by the values of the area under the receiver operating characteristic curve (AUC) in the test dataset. The AUC values were 0.811 for XGBoost, 0.774 for neural network, and 0.772 for logistic regression models, indicating that the predictive ability of XGBoost was the highest. The importance rating of each explanatory variable was evaluated using the SHapley Additive exPlanations (SHAP) values, which were similar among these models. This study showed that the machine learning-based model has a higher predictive ability than the conventional logistic regression model and may be useful for risk assessment and health guidance for health checkup participants.


Background, an important factor in visual search.
The ability to detect an object depends on the contrast between the object and its background. Despite this, many models of visual search rely solely on the properties of target and distractors, and do not take the background into account. Yet, both target and distractors have their individual contrasts with the background. These contrasts generally differ, because the target and distractors are different in at least one feature. Therefore, background is likely to play an important role in visual search. In three experiments we manipulated the properties of the background (luminance, orientation and spatial frequency, respectively) while keeping the target and distractors constant. In the first experiment, in which target and distractors had a different luminance, changing the background luminance had an extensive effect on search times. When background luminance was in between that of the target and distractors, search times were always short. Interestingly, when the background was darker than both the target and the distractors, search times were much longer than when the background was lighter. Manipulating orientation and spatial frequency of the background, on the other hand, resulted in search times that were longest for small target-background differences. Thus, background plays an important role in search. This role depends on the individual contrast of both target and distractors with the background and the type of feature contrast (luminance, orientation or spatial frequency).


Integration of aerobic granular sludge and mesh filter membrane bioreactor for cost-effective wastewater treatment.
Conventional MBR has been mostly based on floc sludge and the use of costly microfiltration membranes. Here, a novel aerobic granule (AG)-mesh filter MBR (MMBR) process was developed for cost-effective wastewater treatment. During 32-day continuous operation, a predominance of granules was maintained in the system, and good filtration performance was achieved at a low trans-membrane pressure (TMP) of below 0.025 m. The granules showed a lower fouling propensity than sludge flocs, attributed to the formation of more porous biocake layer at mesh surface. A low-flux and low-TMP filtration favored a stable system operation. In addition, the reactor had high pollutant removal efficiencies, with a 91.4% chemical oxygen demand removal, 95.7% NH(4)(+) removal, and a low effluent turbidity of 4.1 NTU at the stable stage. This AG-MMBR process offers a promising technology for low-cost and efficient treatment of wastewaters.


Cell-free synthesis of preuteroglobin and processing to uteroglobin by polysomes from rabbit endometrium.
Polysomes from rabbit endometrium, incubated in a cell-free system in the presence of [35S]methionine, completed polypeptide chains pre-initiated in vivo. Polypeptide chains were analyzed by SDS-gel electrophoresis after immunoprecipitation with anti-uteroglobin. Endometrial polysomes, freed of membranes by detergent treatment, synthesized both mature uteroglobin and preuteroglobin not yet cleaved in vivo. Membrane-bound polysomes synthesized exclusively mature uteroglobin, indicating the processing of preuteroglobin by the membranes bound to the ribosomes.


Evaluating the relationship between cannabis use and IQ in youth and young adults at clinical high risk of psychosis.
Among people with psychosis, those with a history of cannabis use show better cognitive performance than those who are cannabis naïve. It is unknown whether this pattern is present in youth at clinical high risk (CHR) of psychosis. We evaluated relationships between IQ and cannabis use while controlling for use of other substances known to impact cognition in 678 CHR and 263 healthy control (HC) participants. IQ was estimated using the Vocabulary and Block Design subtests of the Wechsler Abbreviated Scale of Intelligence. Drug and alcohol use severity and frequency were assessed with the Alcohol and Drug Use Scale, and we inquired participants' age at first use. CHR were further separated into early and late age at onset of cannabis use sub-groups, and low-, moderate- and high-frequency sub-groups. No significant differences in IQ emerged between CHR or HC cannabis users vs. non-users, or between use frequency groups. CHR late-onset users showed significantly higher IQ than CHR early-onset users. Age at onset of cannabis use was significantly and positively correlated with IQ in CHR only. Results suggest that age at onset of cannabis may be a more important factor for IQ than use current use or use frequency in CHR.


Emergency endovascular repair for ruptured abdominal aortic aneurysms: feasibility and comparison of early results with conventional open repair.
To assess the feasibility of endovascular aortic repair (EVAR) on patients presenting with a ruptured abdominal aortic aneurysm (AAA) in a teaching hospital, and to compare there post-operative outcomes with contemporaneous patients treated with open repair (OR). A series of consecutive of patients presenting ruptured AAA with retro/intraperitoneal haematoma were included in the study. EVAR was attempted whenever possible. In all other cases (severe haemodynamic instability, adverse anatomy, device unavailability), ruptured AAA were treated by OR. Thirty-seven patients were enrolled between January 2001 and July 2004. Seventeen (46%) patients were treated using adapted designed aortoiliac endografts (eight bifurcated, eight aorto-uniiliac, one iliac extension). Twenty (54%) patients unfit for EVAR because of severe haemodynamic instability (n=8), adverse anatomical configuration (n=7), or unavailability of an appropriate endograft (n=5) were treated by OR. Twenty-seven (73%) had a retrospective suitable anatomy for EVAR. Three early conversions from EVAR to OR were performed. Blood loss, operating time, and intensive care stay were significantly decreased in EVAR patients (respectively: 156 min+/-60, 1520 ml+/-1175, 3 days for EVAR; vs. 222 min+/-82, 3075 ml+/-1750, 13 days for OS; P<.01). The 30-day mortality rate was 23.5% for EVAR vs. 50% for OR (P=0.09). EVAR of ruptured AAA is feasible for selected patients based on haemodynamic and morphologic criteria, and should be associated with improved immediate outcomes as compared with OR. These results should be tempered by the fact that these patients have heavy comorbidities which explains the absence of difference in mid-term mortality rates between the two groups, but should also encourage surgical institutions that are managing such life-threatening emergencies to introduce EVAR as part of their therapeutic arsenal for ruptured AAA.


On the spectral formulation of Granger causality.
Spectral measures of causality are used to explore the role of different rhythms in the causal connectivity between brain regions. We study several spectral measures related to Granger causality, comprising the bivariate and conditional Geweke measures, the directed transfer function, and the partial directed coherence. We derive the formulation of dependence and causality in the spectral domain from the more general formulation in the information-theory framework. We argue that the transfer entropy, the most general measure derived from the concept of Granger causality, lacks a spectral representation in terms of only the processes associated with the recorded signals. For all the spectral measures we show how they are related to mutual information rates when explicitly considering the parametric autoregressive representation of the processes. In this way we express the conditional Geweke spectral measure in terms of a multiple coherence involving innovation variables inherent to the autoregressive representation. We also link partial directed coherence with Sims' criterion of causality. Given our results, we discuss the causal interpretation of the spectral measures related to Granger causality and stress the necessity to explicitly consider their specific formulation based on modeling the signals as linear Gaussian stationary autoregressive processes.


Air GunPellet Embolization to common femoral vein: A case report and literature review.
Intraluminal migration of pellet has a wide range of manifestations. It can be asymptomatic or present with devastating outcomes such as ischemia, sepsis, or pulmonary embolism. We present a case of 57-year-old male who had a shot from air gun to his thigh, with antegrade migration to left proximal common femoral vein. He was taken to operating room for open exploration and retrieval of the pellet. In summary, this case emphasizes the significance of stepwise approach in diagnosing and management of intra-vascular missiles. After establishing the diagnosis counselling for the patient in details for the risk and benefit of intervention is needed to choose either retrieval of the pellet or more of a conservative approach.


Complementary clinical effects of red complex bacteria on generalized periodontitis in a caucasian population.
To relate five periodontopathogenic bacteria, including the red complex, to the severity, extent, and inflammation of the periodontal lesion in Caucasian patients with generalized aggressive and chronic periodontitis and to explore whether tobacco use is associated with a specific bacterial profile. A cross-sectional and analytic study was conducted in patients with aggressive and chronic periodontitis. Data were gathered on socio-demographic and periodontal variables, and RH-PCR was used to determine subgingival bacterial profile. Linear and logistic regression analyses were performed. The study included 60 patients with aggressive and 123 with chronic periodontitis. Total red complex bacteria count was higher in aggressive periodontitis, mainly due to T. denticola (P = 0.015). In both periodontitis types, models showed an association between T. forsythia count and probing depth (B = 0.157, P = 0.030) and between T. denticola count and higher bleeding scores (B = 2.371, P = 0.027). Smoking did not affect the red complex bacteria count in either disease. The prevalence of red complex bacteria was similar between aggressive and chronic periodontitis, but their count was higher in the former. In both diseases, T. forsythia was associated with greater severity and T. denticola with more severe bleeding. Tobacco smoking was not associated with the presence of red complex bacteria in either disease.


Effects of polyamines on mitochondrial Ca(2+) transport.
Mammalian mitochondria are able to enhance Ca(2+) accumulation in the presence of polyamines by activating the saturable systems of Ca(2+) inward transport and buffering extramitochondrial Ca(2+) concentrations to levels similar to those in the cytosol of resting cells. This effect renders them responsive to regulate free Ca(2+) concentrations in the physioloical range. The mechanism involved is due to a rise in the affinity of the Ca(2+) transport system, induced by polyamines, most probably exhibiting allosteric behaviour. The regulatory site of this mechanism is the so-called S(1) binding site of polyamines, which operates in physiological conditions and is located in the energy well between the two peaks present in the energy profile of mitochondrial spermine transport. Spermine is bidirectionally transported across teh inner membrane by cycling, in which influx and efflux are driven by electrical and pH gradients, respectively. Most probably, polyamine affects the Ca(2+) transport system when it acts from the outside-that is, in the direction of its uniporter channel, in order to reach the S(1) site. Important physiological functions are related to activation of Ca(2+) transport systems by polyamines and their interactions with the S(1) site. These functions include a rise in the metabolic rate for energy supply and modulation of mitochondrial permeability transition induction, with consequent effects on the triggering of the apoptotic pathway.


Bulk segregant analysis coupled with transcriptomics and metabolomics revealed key regulators of bacterial leaf blight resistance in rice.
Bacterial leaf blight (BLB) is a highly destructive disease, causing significant yield losses in rice (Oryza sativa). Genetic variation is contemplated as the most effective measure for inducing resistance in plants. The mutant line T1247 derived from R3550 (BLB susceptible) was highly resistant to BLB. Therefore, by utilizing this valuable source, we employed bulk segregant analysis (BSA) and transcriptome profiling to identify the genetic basis of BLB resistance in T1247. The differential subtraction method in BSA identified a quantitative trait locus (QTL) on chromosome 11 spanning a 27-27.45 Mb region with 33 genes and 4 differentially expressed genes (DEGs). Four DEGs (P < 0.01) with three putative candidate genes, OsR498G1120557200, OsR498G1120555700, and OsR498G1120563600,0.01 in the QTL region were identified with specific regulation as a response to BLB inoculation. Moreover, transcriptome profiling identified 37 resistance analogs genes displaying differential regulation. Our study provides a substantial addition to the available information regarding QTLs associated with BLB, and further functional verification of identified candidate genes can broaden the scope of understanding the BLB resistance mechanism in rice.


The juxta-oral organ of Chievitz (organum yuxtaorale) updated: Embryology, anatomy, function and pathology.
The Chievitz's organ or juxta-oral organ is a mysterious bilateral structure, phylogenetically preserved, which develops from the mouth epithelium as an invagination that loses connection to it in the prenatal period. It is located laterally to the walls of the oral cavity in an imprecise anatomical location and receives abundant innervation from the buccal nerve. Structurally it consists of non-keratinizing squamous-like neuroepithelial cells surrounded by two layers of connective tissue with nerve fibers and different morphotypes of sensory corpuscles. Its function is completely unknown although based on its rich innervation it is assumed that works as a mechanoreceptor. We have performed immunohistochemistry for axonal and Schwann cells, and the putative mechanoproteins ASIC2, TRPV4 and Piezo2 in sections of fetal juxta-oral organ. Intraparenchymatous nerve fibers and sensory corpuscles were observed as well as immunoreactivity for Piezo2 in both nerve fibers and epithelial parenchymatous cells. We add indirect evidence that the juxtaoral organ is a mechanoreceptor because in addition to its dense innervation, the epithelial cells and sensory nerve fibers display immunoreactivity for the mechanogated ion channel Piezo2. Based on current knowledge, the functional and clinical importance of the juxta-oral organ should be further investigated.


Primary lipofilling as an adjunct in transverse upper gracilis flap breast reconstruction.
In many centres, the myocutaneous transverse upper gracilis (TUG) flap represents an alternative choice in autologous breast reconstruction when abdominal tissue is unavailable. However, a single TUG flap may be volume deficient, particularly in the upper pole. We describe the application of simultaneous lipofilling to the pectoralis major muscle at the index procedure and present our decision-making algorithm, technique and outcomes. A retrospective review of all TUG flaps between January 2011 and May 2021 was conducted. Patient demographics, volume of primary and any subsequent fat grafting and complications were recorded. A total of 183 patients (242 TUG flaps) were included in this study. Of these; 130 patients were reconstructed with single TUG flaps, 16 patients received a single TUG flap with immediate lipofilling, and 37 patients underwent stacked, double TUG flap reconstructions. Of the 242 flaps, there were 2 flap losses (<1%), neither of which occurred in the immediate lipofilling cohort. Among the 130 single TUG patients, 28 (21.5%) required a cumulative total of 40, and a mean of 1.4, secondary lipofilling procedures. The immediate lipofilling patients were injected with a mean of 42 ml fat (range: 20-80 ml). In this group, only 2 of 16 patients required secondary lipofilling. The mean follow-up was 67 months (17-141). Primary lipofilling may reduce the need for secondary revisional procedures and appears safe at the index operation, adds little operative time and has negligible donor site morbidity. In patients where a second (stacked) flap would add unnecessary volume and complexity, it can be considered a useful adjunct.


The correlation of leukocyte-specific protein 1 (LSP1) rs3817198(T>C) polymorphism with breast cancer: A meta-analysis.
Multiple studies have investigated the correlation of single nucleotide polymorphisms (SNPs) in leukocyte-specific protein 1 (LSP1) with susceptibility to breast cancer (BC) and have yielded inconsistent conclusions, particularly rs3817198(T > C). Consequently, we performed a meta-analysis to estimate this relationship more comprehensively. Four databases were utilized to locate eligible publications: PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. This meta-analysis included 14 studies, including 22 reports of 33194 cases and 36661 controls. The relationship of rs3817198 polymorphism with breast cancer was estimated using odds ratios (ORs) with 95% confidence intervals (CIs). The LSP1 co-expression network was constructed by STRING, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVIDE. Download TCGA breast cancer mRNA-seq data and analyze the relationship between LSP1 expression and breast cancer chemotherapy sensitivity. The results indicated that rs3817198(T > C) was positively correlated to with breast malignancy (dominant model: OR = 1.11, 95%CI = 1.06-1.17; recessive model: OR = 1.10, 95%CI = 1.04-1.15; heterozygous model: OR = 1.09, 95%CI = 1.04-1.15; homozygous model: OR = 1.18, 95%CI = 1.09-1.28; additive model: OR = 1.09, 95%CI = 1.05-1.13), among Caucasians and Asians. However, rs3817198(T > C) may reduce the risk of breast carcinoma in Africans. Rs3817198(T > C) might result in breast carcinoma in individuals with BRCA1 and BRCA2 variants and can contribute to estrogen receptor (ER)-positive breast carcinoma. The expression of LSP1 was inversely correlated with the IC50 of doxorubicin (P = 8.91e-15, Cor = -0.23), 5-fluorouracil (P = 1.18e-22, Cor = -0.29), and cisplatin (P = 1.35e-42, Cor = -0.40). Our study identified that LSP1 rs3817198 polymorphism might result in breast malignancy, particularly among Caucasians and Asians, but lower breast cancer susceptibility in African populations. The expression of LSP1 was negatively correlated with the IC50 of doxorubicin, 5-fluorouracil, and cisplatin.


The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts.
To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity score (PS) matching to account for confounding factors. We retrospectively identified consecutive patients with stage I-IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes. Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio [HR], 1.01; 95% CI, 0.72-1.42) and PFS (HR, 1.01; 95% CI, 0.60-1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57-1.85; PFS HR, 1.14; 95% CI, 0.49-2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30-1.23; PFS HR, 1.06; 95% CI, 0.34-3.30). When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients.


Depressive symptoms are associated with fatigue, poorer functional status and less engagement in sports in axSpA and PsA: an analysis from the RABBIT-SpA cohort.
In patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA), concomitant depression might have a negative impact on the course of disease and treatment outcomes. The aims of this analysis are to determine the prevalence of depressive symptoms in axSpA and PsA patients in a real-world cohort study and to identify sociodemographic and clinical associated factors for moderate or severe depressive symptoms in both diseases. Patients from the RABBIT-SpA cohort with an axSpA or PsA diagnosis and a valid WHO-5 Well-Being Index score at baseline were included. A descriptive analysis of baseline and outcome parameters by category of depressive symptoms was performed and factors associated with the presence of depressive symptoms (moderate or severe) were examined in a logistic regression. Two thousand four hundred seventy patients (1,245 axSpA; 1,225 PsA) were included in the analysis. In both diagnoses, the proportion of patients with moderate depressive symptoms was 8% and 21% with severe symptoms. Patients with moderate or severe depressive symptoms were less likely to engage in sports than those with no or mild depressive symptoms, had more comorbidities and higher scores for disease activity, functional limitations, fatigue, and pain and took more analgesics. In axSpA, patients with a higher disease activity, a greater functional impairment and more severe fatigue were more likely to experience depressive symptoms, while patients with more years in education and engaging in sports for at least 1 h/week were less likely to experience depressive symptoms. PsA patients with a greater functional impairment and more severe fatigue were more likely to experience depressive symptoms while those engaging in sports for at least 1 h/week were less likely to experience depressive symptoms. We confirmed a high prevalence of depressive symptoms in both PsA and axSpA. Factors negatively associated with the presence of depressive symptoms were fatigue, not engaging in sports, and greater functional limitations. Depressive symptoms may affect the perception of disease activity / severity by patients. Thus, depressive symptoms are an important condition in axSpA and PsA that should be considered when evaluating disease activity and treatment outcomes.


Midesophageal carcinoma metastatic to the stomach: its unusual appearance on an upper gastrointestinal series.
We report a case of midesophageal carcinoma with metastases to the gastric fundus. The gastric metastases were detected on a standard upper gastrointestinal series before other studies. Gastric metastases from esophageal carcinoma have rarely been described in the radiologic literature and in this case had atypical features which prompted this report.


A randomized double-blind study comparing intradermal anesthetic tolerability, efficacy, and cost-effectiveness of lidocaine, buffered lidocaine, and bacteriostatic normal saline for peripheral intravenous insertion.
In this double-blind study, 256 surgical patients meeting eligibility criteria were randomized in a 1:1:1 ratio to 1 of the 3 intradermal injection groups prior to intravenous (IV) line insertion (Group 1=1% lidocaine, Group 2=1% buffered lidocaine, and Group 3=bacteriostatic normal saline with a benzyl alcohol preservative). The most tolerable solution, as measured by the average level of pain from an intradermal insertion, was buffered lidocaine (Group 2). The most efficacious, as measured by average level of pain at IV cannulation, were Groups 1 and 2. Group 3 was the most cost-effective.


[Pulmonary manifestations induced by osimertinib].
The third-generation tyrosine kinase inhibitor (TKI) osimertinib is recommended as a first-line treatment in advanced non-small cell lung cancer harboring an activating mutation of Epidermal Growth Factor Receptor (EGFR). Adverse pulmonary events related to osimertinib exposure have been reported, primarily in Japanese patients. They rarely occur in the Caucasian population. Herein we report two clinical cases of osimertinib-induced lung toxicities in patients diagnosed with advanced lung adenocarcinoma harboring an EGFR mutation. In the first case, interstitial pneumonia was asymptomatic and evolved favorably after osimertinib discontinuation. The second patient presented a more extensive form of lung injuries and despite systemic corticosteroid therapy, the evolution was fatal. Osimertinib-related lung toxicities remain exceptional. While most forms are mild, consideration of TKI treatment discontinuation may be necessitated. Introduction of another TKI or rechallenge with osimertinib might be considered along with corticosteroid therapy if necessary. Diffuse alveolar damage is a pejorative prognostic factor.


Ratiometric fluorescent detection of total phosphates in frozen shrimp samples using catalytic active Zr(IV) modified gold nanoclusters.
Phosphate salts are important food additives in a variety of foods. In this study, the Zr(IV) modified gold nanoclusters (Au NCs) were prepared for ratiometric fluorescent sensing of phosphate additives in seafood samples. Compared with bare Au NCs, the synthesized Zr(IV)/Au NCs showed stronger orange fluorescence at 610 nm. On the other hand, the Zr(IV)/Au NCs retained the phosphatase-like activity of Zr(IV) ions and could catalyze the hydrolysis of fluorescent substrate 4-methylumbelliferyl phosphate to produce blue emission at 450 nm. The addition of phosphate salts could effectively inhibit the catalytic activity of Zr(IV)/Au NCs, resulting the fluorescence decrease at 450 nm. However, the fluorescence at 610 nm almost unchanged upon the addition of phosphates. Based on this finding, the ratiometric detection of phosphates using the fluorescence intensity ratio (I450/I610) was demonstrated. The method has been further applied for sensing total phosphates in frozen shrimp samples with satisfactory results.


Endogenous metabolism in endothelial and immune cells generates most of the tissue vitamin B3 (nicotinamide).
In mammals, nicotinamide (NAM) is the primary NAD precursor available in circulation, a signaling molecule, and a precursor for methyl-nicotinamide (M-NAM) synthesis. However, our knowledge about how the body regulates tissue NAM levels is still limited. Here we demonstrate that dietary vitamin B3 partially regulates plasma NAM and NAM-derived metabolites, but not their tissue levels. We found that NAD de novo synthesis from tryptophan contributes to plasma and tissue NAM, likely by providing substrates for NAD-degrading enzymes. We also demonstrate that tissue NAM is mainly generated by endogenous metabolism and that the NADase CD38 is the main enzyme that produces tissue NAM. Tissue-specific CD38-floxed mice revealed that CD38 activity on endothelial and immune cells is the major contributor to tissue steady-state levels of NAM in tissues like spleen and heart. Our findings uncover the presence of different pools of NAM in the body and a central role for CD38 in regulating tissue NAM levels.


Psychosocial conditions do not affect short-term outcome of multidisciplinary rehabilitation in chronic obstructive pulmonary disease.
To characterize patients referred for pulmonary rehabilitation on a large number of psychologic and sociodemographic variables and to determine the contribution of these variables on the response to rehabilitation. Cross-sectional, explorative. University hospital and outpatient clinic. Eighty-one consecutive patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 second, 40%+/-16% of predicted) were included in outpatient pulmonary rehabilitation. Multidisciplinary rehabilitation program. Pulmonary function, exercise capacity (Wmax, 6-minute walk test [6MWT]), Chronic Respiratory Disease Questionnaire (CRDQ), Modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]) were assessed before and after 3 months rehabilitation. In addition, psychosocial adjustment, social support, marital status, mode of transportation, education, employment, and smoking status were assessed at the start of the rehabilitation. Rehabilitation improved exercise performance (Wmax, 6+/-12W; P<.01; 6MWT, 41+/-72 m; P<.001), quality of life (CRDQ score, 12+/-13 points; P<.001), functional status (PFSDQ-M activity score, -8+/-11 points; PFSDQ-M dyspnea score, -6+/-12 points; PFSDQ-M fatigue score, -4+/-8 points; all P<.01), HADS anxiety score (-2+/-3 points, P<.01), and HADS depression score (-3+/-3 points, P<.001). In single regression analysis, only baseline depression was weakly negatively correlated with the change in maximal workload. No other relations of initial psychologic or sociodemographic variables with outcome were observed. The effects of rehabilitation are not affected by baseline psychosocial factors. Patients with less favorable psychologic or sociodemographic conditions can also benefit from pulmonary rehabilitation. The multidisciplinary approach of the rehabilitation program might have contributed to this improvement.