Enzymatic remodeling of heparan sulfate proteoglycans within the tumor microenvironment: growth regulation and the prospect of new cancer therapies.
Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expression-related changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii) removal of sulfates from the 6-O position of heparan sulfate chains by extracellular sulfatases. Assessing or monitoring the remodeling of HSPGs has important implications for tumor diagnosis and patient prognosis while therapeutic manipulation of the remodeling process represents an exciting new possibility for treating cancer.


Carboxylesterase-Cleavable Biotinylated Nanoparticle for Tumor-Dual Targeted Imaging.
Near-infrared (NIR) nanoprobes with fluorescence "Turn-On" property are advantageous in cancer diagnosis but, to the best of our knowledge, "smart" nanoprobe that simultaneously targets both biotin receptor and carboxylesterase (CES) for HepG2 tumor-dual targeted imaging has not been reported. Methods: Using CBT-Cys click condensation reaction, we rationally designed a "smart" NIR fluorescence probe H2N-Cys(StBu)-Lys(Biotin)-Ser(Cy5.5)-CBT (NIR-CBT) and used it to facilely prepare the fluorescence-quenched nanoparticle NIR-CBT-NP. Results: In vitro results indicated that, after NIR-CBT-NP was incubated with CES for 6 h, its fluorescence was turned "On" by 69 folds. Cell experiments verified that NIR-CBT-NP was uptaken by HepG2 cells via biotin receptor-assisted endocytosis and its fluorescence was turned "On" by intracellular CES hydrolysis. Moreover, NIR-CBT-NP was successfully applied to image both biotin receptor- and CES-overexpressing HepG2 tumors. Conclusion: Fluorescence-quenched nanoparticle NIR-CBT-NP was facilely prepared to actively target biotin receptor-overexpressing HepG2 cancer cells and turn the fluorescence "On" by intracellular CES hydrolysis for tumor-dual targeted imaging. We anticipate that our fluorescence "Turn-On" nanoparticle could be applied for liver cancer diagnosis in clinic in the near future.


Memantine does not show intracellular block of the NMDA receptor channel.
Mg2+ is known to gain access to the NMDA receptor channel from both the extra- and intracellular compartments. Memantine, being an amphiphilic substance, reaches intracellular concentrations of approximately 30 microM, which are much higher than therapeutic extracellular concentrations ( approximately 1 microM). We therefore investigated whether memantine can also block the NMDA receptor channel from the intracellular compartment. NR1a/NR2A receptors were expressed in Xenopus oocytes and in classical two electrode voltage-clamp recordings, voltage-ramps from -100 to +100 mV confirmed moderate inward rectification of NR1a/NR2A receptor control responses at positive membrane potentials above +40 mV. Patch clamp recordings from these same cells (applying 100 microM glutamate and 1 mM Mg2+) revealed similar rectification at positive potentials in cell-attached mode which disappeared after pulling an inside-out patch. Application of 1 mM Mg2+ to the intracellular side of the receptor re-introduced the rectification seen in cell-attached mode, and 5 mM Mg2+ produced much more pronounced block. In contrast, 30 microM memantine was completely unable to block the NMDA receptor from the intracellular compartment. In conclusion, intracellular block of the NMDA receptor, as reported for Mg2+, is not of significance for the therapeutic effects of memantine.


Generation of an induced pluripotent stem cell line, ZIPi021-A, from fibroblasts of a Prader-Willi syndrome patient with maternal uniparental disomy (mUPD).
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of paternal expression of imprinted genes on chromosome 15q11-q13. We established a human induced pluripotent stem cell line (hiPSC), ZIPi021-A, from fibroblasts of a 4-year-old female PWS patient with the subtype of maternal uniparental disomy (mUPD). The generated hiPSC line was transgene-free, expressed pluripotency markers and showed the ability to differentiate into all three germ layers in vitro. The ZIPi021-A hiPSC line could be used as a cellular model for PWS in humans.


Exopolysaccharide from Trichoderma pseudokoningii induces macrophage activation.
In this study, we evaluated the immunomodulatory activity of an exopolysaccharide (EPS) derived from Trichoderma pseudokoningii and investigated the molecular mechanism of EPS-mediated activation of macrophages. Results revealed that EPS could significantly induce the production of nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β and enhance phagocytic activity in RAW 264.7 cells. Immunofluorescence staining indicated that EPS promoted the nuclear translocation of nuclear factor (NF)-κB p65 subunit. Western blot analysis showed that EPS increased the expression of inducible nitric oxide synthase (iNOS) protein, the degradation of IκB-α and the phosphorylation of mitogen-activated protein kinases (MAPKs). Furthermore, pretreatment of RAW 264.7 cells with specific inhibitors of NF-κB and MAPKs significantly attenuated EPS-induced TNF-α and IL-1β production. EPS also induced the inhibition of cytokine secretion by special antibodies against Toll-like receptor-4 (TLR4) and Dectin-1. These data suggest that EPS from Trichoderma pseudokoningii activates RAW 264.7 cells through NF-κB and MAPKs signaling pathways via TLR4 and Dectin-1.


Design and participant characteristics for a randomized effectiveness trial of an intensive lifestyle intervention to reduce cardiovascular risk in adults with type 2 diabetes: The I-D-HEALTH study.
Intervening in Diabetes with Healthy Eating, Activity and Linkages To Healthcare (I-D-HEALTH) is a community-based randomized trial evaluating the effectiveness of a group-based adaption of the Look AHEAD intensive lifestyle intervention. Most potentially eligible patients were identified through electronic medical record queries or referral to a diabetes resource hub. Trial enrollees had a usual source of primary care, elevated body mass index (BMI) and type 2 diabetes. I-D-HEALTH participants were randomized to either standard care alone or standard care plus free-of-charge access to a group-based lifestyle intervention (GLI) offered by the YMCA. GLI participation was encouraged, but not required, for the latter group. The primary outcome is percent weight change over 6, 12 and 24months. Secondary outcomes include direct intervention costs and direct medical and non-medical expenditures, as well as changes in systolic blood pressure, hemoglobin A1c and cholesterol. Among 331 I-D-HEALTH participants, 167 were randomized to standard care and 164 to GLI. The mean age (±standard deviation) in each group was 57.1years (±12.2) and 57.6years (±10.5), respectively. Mean BMI was 34.9kg/m(2) (±7.3) among standard care participants and 36.2kg/m(2) (±7.8) among GLI participants. In both groups, approximately one third of participants were non-Hispanic Whites. We detected no significant differences between groups in mean systolic blood pressure, hemoglobin A1c or total cholesterol (P >0.05 for all characteristics above). The I-D-HEALTH study enrolled a diverse sample of adults with diabetes and offers a unique opportunity to evaluate the effectiveness of offering a community-based intensive lifestyle intervention.


Effect of a BLT receptor antagonist in a model of severe ischemia and reperfusion injury in the rat.
Pharmacological strategies which limit neutrophil recruitment may also limit the damage induced by the reperfusion of an ischemic vascular territory. In the present study, we have investigated the effects of the BLT receptor antagonist, CP-105,696 ((+)-1-(3S,4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl]-cyclopentane carboxylic acid), on the local, remote and systemic inflammatory changes observed during severe intestinal ischemia (120 min) and reperfusion (120 min) injury. The post-ischemic treatment with CP-105,696 (3 mg/kg) virtually abolished the increase in vascular permeability, but not neutrophil accumulation, in the intestine and lungs. CP-105,696 partially inhibited the reperfusion-induced neutropenia, but failed to affect intestinal haemorrhage or lethality. CP-105,696 had no inhibitory effect on the local and systemic increases in the concentrations of tumour necrosis factor (TNF-alpha), interleukin-1 beta and interleukin-10, but markedly suppressed interleukin-6. Overall, our results show that activation of BLT receptor plays a minor role in the local, remote and systemic injuries following severe ischemia and reperfusion in rats.


Anatomic response of occult choroidal neovascularization to intravitreal ranibizumab: a study by indocyanine green angiography.
To investigate changes in indocyanine green angiography (ICGA) features of occult choroidal neovascularization (CNV) after intravitreal ranibizumab injections. We reviewed the charts of all consecutive patients with newly diagnosed occult CNV secondary to age-related macular degeneration (AMD) treated by intravitreal ranibizumab. In all patients, optical coherence tomography (OCT) and ICGA were performed at baseline, after 3 months and 12 months. Fifty-one eyes of 44 patients (ten males, 34 females, mean age 77.8 ± 7.3 years) were included. Mean follow-up was 20.3 ± 6.2 months. During the first 12 months, patients received 5.5 ± 2.7 intravitreal ranibizumab injections. When compared with baseline, best-corrected visual acuity (BCVA) significantly improved at the 3-month follow-up visit (60.5 ±22.0 vs 50.9 ±20.7 letters, p = 0.04), and stabilized at 12-month visit (55.7 ±18.2 letters; p = 0.05). Central macular thickness (CMT) significantly improved during follow-up (229.0 ±54.7 μm vs 281.0 ±61.3 μm at baseline, p = 0.003). An overall stabilization was observed on ICGA in both the lesion area (5.27 ± 3.9 mm(2) at baseline vs 4.60 ± 3.5 mm(2) at month 12, p = 0.4), and greatest linear dimension (GLD 2.66 ± 1.2 mm at baseline vs 2.55 ± 1.0 mm at month 12, p = 0.3). Eight eyes (15.7%) showed CNV growth on ICGA (lesion area 3.98 ± 3.2 mm2 at baseline vs 4.3 ± 2.7 mm2 at month-12, p = 0.6; GLD 2.11 ± 1.0 mm at baseline vs 2.70 ± 0.8 mm at month-12, p = 0.05). ICGA suggests that functional outcomes after intravitreal ranibizumab is related to CMT reduction rather than CNV regression.


Season of birth and eating disorders: patterns across diagnoses in a specialized eating disorders service.
In view of inconsistent findings from previous studies, the aim was to investigate possible seasonal variation in month of birth in patients with anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified. We examined the month of birth in a cohort of 1,305 adult patients with a DSM-IV eating disorder diagnosis at first presentation to a specialized eating disorders service. When compared to general population data, we found no evidence of significant variation in month or season of birth in anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified. The authors question whether people who develop eating disorders differ from the general population in their season of birth. Caution is expressed about further speculation regarding the etiological significance of season of birth in eating disorders.


A BODIPY-derived fluorescent probe for cellular pH measurements.
In this study, BODIPY-appended calix[4]arene was chosen as a fluorescent probe for intracellular pH. The compound with cell permeability can monitor the minor pH change near neutrality inside the cell and is the first BODIPY-derived probe reported for cytosolic pH. Owing to a high level of cell retention and minor cytotoxicity of the probe, stable fluorescence is provided in the cells for 24h, facilitating the precise observation of intracellular pH. A model of cell apoptosis was designed by exposure of the cells to a low concentration of hydrogen peroxide. An increase in the fluorescence of the cells confirmed that BODIPY-appended calix[4]arene sensed the fluctuation of the cellular pH during early cell apoptosis. The developed fluorescent pH probe will be useful for the study of cell apoptosis.


Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss.
Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.


Influence of gender and sexual hormones on outcomes after pituitary surgery: a systematic review and meta-analysis.
Although there is an increasing body of evidence showing gender differences in various medical domains as well as presentation and biology of pituitary adenoma (PA), gender differences regarding outcome of patients who underwent transsphenoidal resection of PA are poorly understood. The aim of this study was to identify gender differences in PA surgery. The PubMed/MEDLINE database was searched up to April 2023 to identify eligible articles. Quality appraisal and extraction were performed in duplicate. A total of 40 studies including 4989 patients were included in this systematic review and meta-analysis. Our analysis showed odds ratio of postoperative biochemical remission in males vs. females of 0.83 (95% CI 0.59-1.15, P = 0.26), odds ratio of gross total resection in male vs. female patients of 0.68 (95% CI 0.34-1.39, P = 0.30), odds ratio of postoperative diabetes insipidus in male vs. female patients of 0.40 (95% CI 0.26-0.64, P < 0.0001), and a mean difference of preoperative level of prolactin in male vs. female patients of 11.62 (95% CI - 119.04-142.27, P = 0.86). There was a significantly higher rate of postoperative DI in female patients after endoscopic or microscopic transsphenoidal PA surgery, and although there was some data in isolated studies suggesting influence of gender on postoperative biochemical remission, rate of GTR, and preoperative prolactin levels, these findings could not be confirmed in this meta-analysis and demonstrated no statistically significant effect. Further research is needed and future studies concerning PA surgery should report their data by gender or sexual hormones and ideally further assess their impact on PA surgery.


Spatio-temporal distribution of the adherens junction-associated molecules vinculin and talin in the early avian embryo.
To gain an insight into the possible involvement of the cytoskeletal components and cellular junctions in morphogenetic processes during development, we have studied the spatio-temporal distribution of two major adherens-junction-associated molecules, vinculin and talin, during avian embryogenesis, using immunofluorescence microscopy and immunoblotting. Both molecules were detected at very early stages during morphogenesis and were found in a wide variety of tissues deriving from the three primary germ layers. A number of tissues, including smooth and striated muscles, endothelia, and some hemopoietic precursors, expressed vinculin and talin at especially high levels either transiently or permanently. Conversely, only a few cell types, e.g., circulating erythrocytes and neurones in the central nervous system lacked or expressed them at very low levels. In addition, expression of vinculin and talin was in some cases modulated in connection with morphological rearrangements of tissues. In particular, they were transiently enhanced in restricted areas of the ectoderm and endoderm undergoing extensive foldings. However, other morphogenetic events such as local disruptions of epithelia were not accompanied by extensive modifications in their expression. Finally, it appeared that, in most cases, vinculin and talin overlapped in their distribution, and the level of their expression was regulated coincidently with the notable exceptions of the primordium of the central nervous system, the nephron, and the liver where each molecule followed independent regulatory patterns. It appears from this study that the spatio-temporal distribution of vinculin and talin correlates frequently with that of the adhesion molecules A-CAM (or N-cadherin), L-CAM, and of integrin receptors. Thus, vinculin and talin, in association with the membrane components of adherens junctions, may actively participate both in the control of cellular interactions during early embryonic development and in cell differentiation.


Thapsigargin-induced activation of Ca(2+)-CaMKII-ERK in brainstem contributes to substance P release and induction of emesis in the least shrew.
Cytoplasmic calcium (Ca(2+)) mobilization has been proposed to be an important factor in the induction of emesis. The selective sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, is known to deplete intracellular Ca(2+) stores, which consequently evokes extracellular Ca(2+) entry through cell membrane-associated channels, accompanied by a prominent rise in cytosolic Ca(2+). A pro-drug form of thapsigargin is currently under clinical trial as a targeted cancer chemotherapeutic. We envisioned that the intracellular effects of thapsigargin could cause emesis and planned to investigate its mechanisms of emetic action. Indeed, thapsigargin did induce vomiting in the least shrew in a dose-dependent and bell-shaped manner, with maximal efficacy (100%) at 0.5 mg/kg (i.p.). Thapsigargin (0.5 mg/kg) also caused increases in c-Fos immunoreactivity in the brainstem emetic nuclei including the area postrema (AP), nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNX), as well as enhancement of substance P (SP) immunoreactivity in DMNX. In addition, thapsigargin (0.5 mg/kg, i.p.) led to vomit-associated and time-dependent increases in phosphorylation of Ca(2+)/calmodulin kinase IIα (CaMKIIα) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) in the brainstem. We then explored the suppressive potential of diverse chemicals against thapsigargin-evoked emesis including antagonists of: i) neurokinin-1 receptors (netupitant), ii) the type 3 serotonin receptors (palonosetron), iii) store-operated Ca(2+) entry (YM-58483), iv) L-type Ca(2+) channels (nifedipine), and v) SER Ca(2+)-release channels inositol trisphosphate (IP3Rs) (2-APB)-, and ryanodine (RyRs) (dantrolene)-receptors. In addition, the antiemetic potential of inhibitors of CaMKII (KN93) and ERK1/2 (PD98059) were investigated. All tested antagonists/blockers attenuated emetic parameters to varying degrees except palonosetron, however a combination of non-effective doses of netupitant and palonosetron exhibited additive antiemetic efficacy. A low-dose combination of nifedipine and 2-APB plus dantrolene mixture completely abolished thapsigargin-evoked vomiting, CaMKII-ERK1/2 activation and SP elevation. In addition, pretreatment with KN93 or PD98059 suppressed thapsigargin-induced increases in SP and ERK1/2 activation. Intracerebroventricular injection of netupitant suppressed vomiting caused by thapsigargin which suggests that the principal site of evoked emesis is the brainstem. In sum, this is the first study to demonstrate that thapsigargin causes vomiting via the activation of the Ca(2+)-CaMKII-ERK1/2 cascade, which is associated with an increase in the brainstem tissue content of SP, and the evoked emesis occurs through SP-induced activation of neurokinin-1 receptors.


The impact of iodinated X-ray contrast agents on formation and toxicity of disinfection by-products in drinking water.
The presence of iodinated X-ray contrast media (ICM) in source waters is of high concern to public health because of their potential to generate highly toxic disinfection by-products (DBPs). The objective of this study was to determine the impact of ICM in source waters and the type of disinfectant on the overall toxicity of DBP mixtures and to determine which ICM and reaction conditions give rise to toxic by-products. Source waters collected from Akron, OH were treated with five different ICMs, including iopamidol, iopromide, iohexol, diatrizoate and iomeprol, with or without chlorine or chloramine disinfection. The reaction product mixtures were concentrated with XAD resins and the mammalian cell cytotoxicity and genotoxicity of the reaction mixture concentrates was measured. Water containing iopamidol generated an enhanced level of mammalian cell cytotoxicity and genotoxicity after disinfection. While chlorine disinfection with iopamidol resulted in the highest cytotoxicity overall, the relative iopamidol-mediated increase in toxicity was greater when chloramine was used as the disinfectant compared with chlorine. Four other ICMs (iopromide, iohexol, diatrizoate, and iomeprol) expressed some cytotoxicity over the control without any disinfection, and induced higher cytotoxicity when chlorinated. Only iohexol enhanced genotoxicity compared to the chlorinated source water.


Intra-fraction and Inter-fraction analysis of a dedicated immobilization device for intracranial radiation treatment.
Immobilization devices are crucial to minimize patient positioning uncertainties in radiotherapy (RT) treatments. Accurate inter and intra-fraction motions is particularly important for intracranial and stereotactic radiation treatment which require high precision in dose delivery. Recently, a new immobilization device has been developed specifically for the radiation treatment of intracranial malignancies. To date, no data are available on the use of this device in daily clinical practice. The aim of this study is to investigate the intra and inter-fraction variations, patient comfort and radiographer confidence of the immobilization system from two distinct institutions: HagaZiekenhuis, Den Haag, Netherlands and IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Italy. Sixteen patients (10 diagnosed with brain metastases and 6 with primary central nervous systemic tumor) from IRCCS Ospedale Sacro Cuore Don Calabria and 17 patients (all diagnosed with brain metastases tumor) from HagaZiekenhuis were included in this study. The median target volume was 436 cc (range 3.2-1628 cc) and 4.58 cc (range 0.4-27.19 cc) for IRCCS and Haga, respectively. For patients treated in IRCCS Sacro Cuore Don Calabria, the median dose prescription was 30 Gy (range 27-60 Gy) and median number of fractions 10 (range 3-30). In Haga the median dose prescription was 21 Gy (range 8-21 Gy) and the median number of fraction was 1 (range 1-3). The immobilization device was assembled during CT simulation. A short interview to the patient regarding the device's comfort level was conducted at the end of the simulation procedure. Additionally, simulation setup time and radiographer (RTT) procedures (i.e. mask preparation) were evaluated. Prior to radiation treatment delivery, an automatic rigid match on the cranial bones between cone beam computed tomography (CBCT) and planning-CT was performed. A couch shift was performed subsequently. An extra post-treatment CBCT was acquire after the treatment delivery. This post-treatment CBCT was matched with pre-treatment CBCT to identify any possible intra-fraction motion. All online matches were validated by experienced radiation oncologist or RTT. A total of 126 CBCT's were analyzed offline by radiation oncologist/medical physicist. The data of the pre-treatment CBCT match was used to quantify inter-fraction motion. The post-treatment CBCT was matched with pre-treatment CBCT to identify any possible intra-fraction motion. During the molding of the mask, all patients responded positive to the comfort. Median time required by the RTTs to assemble the immobilization system was 9 min (range 6-12 min). In terms of comfort, all patients reported a good-to high level of satisfaction. The RTTs also respond positively towards the use of the locking mechanism and clips. Results of positioning uncertainties were comparable between the two institutes. The mean inter-fraction motion for all translational and rotational directions were < 2 mm (SD < 4 mm) and < 0.5°(SD < 1.5°), respectively, while the mean intra-fraction motions were < 0.4 mm (SD < 0.6 mm) and 0.3° (SD < 0.5°). This study demonstrates the efficacy and feasibility of the immobilization device in the intracranial radiation treatment. Both patient comfort and preparation time by RTTs are considered adequate. In combination with online daily imaging procedure, this device can achieve submillimeter accuracy required for intracranial and stereotactic treatments.


Staphylococcus aureus bacteremia and endocarditis: the Grady Memorial Hospital experience with methicillin-sensitive S aureus and methicillin-resistant S aureus bacteremia.
Staphylococcus aureus has become the leading cause of endocarditis in most published series, and nosocomial acquisition is becoming more frequent. Previous studies involved community acquired methicillin-sensitive S aureus (MSSA), but recently, methicillin-resistant S aureus(MRSA) infection has increased. This may reflect the growing presence of this microorganism in clinical practice. Few data exist comparing the relative rates of endocarditis with MSSA and MRSA bacteremia. The purpose of this study was to compare these rates in a bacteremic population referred for diagnostic echocardiography. Since July 1999, the demographic and clinical information of 104 consecutive patients with at least 2 blood cultures with positive results for S aureus who were referred for echocardiography to be evaluated for endocarditis at Grady Memorial Hospital (Atlanta, Ga) have been entered into a database. This database has further been restricted to patients who have undergone either a transesophageal echocardiogram or a transthoracic echocardiogram. Of the 104 patients with S aureus bacteremia, 53 had an infection of MSSA and 51 had an infection of MRSA. There were 33 patients (31.7%) with echocardiographically confirmed endocarditis, 23 patients (43.4%) in the MSSA group versus 10 patients (19.6%) in the MRSA group (P <.009). Community-acquired MSSA bacteremia was the cause of most of the community-acquired S aureus endocarditis (20 patients [87%] vs 3 patients [30%], P =.004), and the nosocomial-acquired MRSA bacteremia was the cause of most of the nosocomial-acquired S aureus endocarditis (3 patients [13%] vs 7 patients [70%], P =.0001). Our study confirms that S aureus bacteremia is associated with high rates of endocarditis. MSSA bacteremia is associated with higher rates of endocarditis than MRSA. Community MSSA is the cause of most of the community endocarditis, whereas nosocomial MRSA is the cause of most of the MRSA endocarditis. Patients with S aureus bacteremia should be aggressively evaluated for endocarditis.


Clinical ramifications of the MHC family Fc receptor FcRn.
Knowledge that antibodies of the IgG isotype have remarkably extended persistence in circulation and are able to pass through cell barriers has substantial implications. While it is well established that so-called neonatal Fc receptor, FcRn, acts throughout life to confer these unusual properties, its ramifications on clinical medicine and therapeutic uses are not broadly appreciated. Here we discuss basic principles and gaps in understanding of FcRn, including its management of IgG antibodies and along with albumin, its impact on use and design of antibody-based therapeutics, and its genetics.


Structure, antioxidant and immunomodulatory activity of a polysaccharide extracted from Sacha inchi seeds.
In this study, a novel water-soluble polysaccharide (PVLP-1) was extracted and purified from Sacha inchi (Plukenetia volubilis L.) seeds and the structure, antioxidant and immunomodulatory activity of PVLP-1 were investigated. PVLP-1 (144 kDa) consisted of glucose (69.76%), mannose (14.86%), arabinose (10.53%), galactose (2.42%), ribose (1.23%), rhamnose (0.27%) and xylose (0.93%). PVLP-1 displayed characteristic polysaccharide bands in Fourier transform NMR spectra and infrared. The primary structure of PVLP-1 was a heteropolysaccharide with a backbone of (1 → 6)-linked glucose, sidechains of (1 → 4)-linked mannose, (1 → 4)-linked glucose and (1 → 3, 6)-linked mannose and a residue unit of →1)-linked arabinose as revealed the methylation analysis. PVLP-1 possessed good water-holding capacity (WHC), oil-holding capacity (OHC) and antioxidant capacities. Besides, PVLP-1 induced the proliferation of RAW264.7 cell and enhanced the expression of inflammatory cytokines IL-6, TNF-alpha(TNF-α) and IL-1 beta (IL-1β). The present study indicated that PVLP-1 possessed immune-enhancing bioactivities and could be functional food or adjuvant drug to improve biological immunity of immunodeficiency diseases and hypoimmunity.


False recall with the drmrs ("drummers") procedure: a quantitative summary and review.
In the Deese-Roediger-McDermott-Read-Solso (DRMRS) procedure, which has recently enjoyed widespread use, participants try to remember lists of items constructed around critical themes that are not presented. The purpose of this quantitative review was to estimate the extent to which these themes are falsely recalled (Critical Intrusions) and to compare this error rate with Correct Recall and with false recall of other words that were not presented (Noncritical Intrusions). Based on 111 estimates, the mean rate of Critical Intrusions was .374 (95% confidence interval of .344 to .403), which was a very large effect (d=2.40). Critical Intrusions were less frequent than Correct Recall (.572) but more frequent than Noncritical Intrusions (.078). Critical Intrusions were lower (.318) for people told to be confident (not to guess) than for people not so cautioned (.428), a medium to large effect size (d=0.69). Effects of other variables are summarized, and the theoretical and applied implications of these results are discussed.


Mucoid degeneration of the anterior cruciate ligament with erosion of the lateral femoral condyle.
We report a case of a mucoid degeneration of the anterior cruciate ligament (ACL) that produced osseous erosion of the medial aspect of the lateral femoral condyle. The MRI findings and differential diagnosis are discussed.


Palladium-facilitated electrolytic dechlorination of 2-chlorobiphenyl using a granular-graphite electrode.
Palladium-assisted electrocatalytic dechlorination of 2-chlorobiphenyl (2-Cl BP) in aqueous solutions was conducted in a membrane-separated electrochemical reactor with granular-graphite packed electrodes. The dechlorination took place at a granular-graphite cathode while Pd was electro-deposited from the K2PdCl6 in the solution and at a Pd-deposited granular-graphite electrode. Using the Pd-deposited graphite cathode in the membrane reactor for a sequence of experiments, each was conducted under a lower current than in the previous one, and the rate of dechlorination became slower in each consecutive experiment. At the end of this sequence, a duplicate experiment showed a loss of activity of the Pd-deposited granular-graphite cathode. In the experiments of dechlorination while Pd was deposited at the granular-graphite electrode, the rate of dechlorination increased with increases of the initial K2PdCl6 concentration and of the applied cathode potential. In each experiment, the dechlorination of 2-Cl BP was relatively fast at the beginning, as demonstrated in an experiment in which 66.4% of 2-Cl BP was dechlorinated within 4h, but the rate of dechlorination decreased over the time. This decrease can be described with two stages of exponential decrease. The values of the rate constant in the first stage varies with the applied potential and the initial K2PdCl6 concentration, but the values of the rate constant in the second stage do not show any dependence on the potential and the K2PdCl6 concentration. The current efficiency of dechlorination was improved by applying part-time current to the electrodes.


Beyond Microsystem Fixes: Targeting National Drivers of Low-Value Care Comment on "Key Factors that Promote Low-Value Care: Views of Experts From the United States, Canada, and the Netherlands".
Low-value care drivers and interventions are often focused on a microsystem (eg, clinic or inpatient ward) or within a health system. Identification of national drivers such as payment structure and medical culture of overuse can help identify regional approaches to reducing low-value care. However, these approaches in isolation are insufficient and require additional strategies. These can include policy and payment changes and adopting shared decision-making (SDM). SDM has the potential to move medical culture away from the 'more is better' paternalistic and physician-centric culture to one that actively engages patients as full partners in managing their care.


Safety of the methylene blue plus chloroquine combination in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso [ISRCTN27290841].
Safe, effective and affordable drug combinations against falciparum malaria are urgently needed for the poor populations in malaria endemic countries. Methylene blue (MB) combined with chloroquine (CQ) has been considered as one promising new regimen. The primary objective of this study was to evaluate the safety of CQ-MB in African children with uncomplicated falciparum malaria. Secondary objectives were to assess the efficacy and the acceptance of CQ-MB in a rural population of West Africa. In this hospital-based randomized controlled trial, 226 children (6-59 months) with uncomplicated falciparum malaria were treated in Burkina Faso. The children were 4:1 randomized to CQ-MB (n = 181; 25 mg/kg CQ and 12 mg/kg MB over three days) or CQ (n = 45; 25 mg/kg over three days) respectively. The primary outcome was the incidence of severe haemolysis or other serious adverse events (SAEs). Efficacy outcomes were defined according to the WHO 2003 classification system. Patients were hospitalized for four days and followed up until day 14. No differences in the incidence of SAEs and other adverse events were observed between children treated with CQ-MB (including 24 cases of G6PD deficiency) compared to children treated with CQ. There was no case of severe haemolysis and also no significant difference in mean haemoglobin between study groups. Treatment failure rates were 53.7% (95% CI [37.4%; 69.3%]) in the CQ group compared to 44.0% (95% CI [36.3%; 51.9%]) in the CQ-MB group. MB is safe for the treatment of uncomplicated falciparum malaria, even in G6PD deficient African children. However, the efficacy of the CQ-MB combination has not been sufficient at the MB dose used in this study. Future studies need to assess the efficacy of MB at higher doses and in combination with appropriate partner drugs.


Facilitation of lordosis behavior by clonidine in female guinea pigs.
Lordosis behavior was induced in previously unreceptive, ovariectomized estrogen-primed female guinea pigs by administration of the noradrenergic agonist clonidine. Clonidine also enhanced lordosis responding in females that were weakly receptive after estrogen priming. Unlike progesterone, the lordosis-facilitating effect of clonidine was not accompanied by a subsequent refractory period. Clonidine had a weak lordosis facilitatory effect when administered during the decline in receptivity to estrogen plus progesterone-primed animals and failed to induce lordosis when administered during the refractory period.


Chasing the elusive Euryarchaeota class WSA2: genomes reveal a uniquely fastidious methyl-reducing methanogen.
The ecophysiology of one candidate methanogen class WSA2 (or Arc I) remains largely uncharacterized, despite the long history of research on Euryarchaeota methanogenesis. To expand our understanding of methanogen diversity and evolution, we metagenomically recover eight draft genomes for four WSA2 populations. Taxonomic analyses indicate that WSA2 is a distinct class from other Euryarchaeota. None of genomes harbor pathways for CO2-reducing and aceticlastic methanogenesis, but all possess H2 and CO oxidation and energy conservation through H2-oxidizing electron confurcation and internal H2 cycling. As the only discernible methanogenic outlet, they consistently encode a methylated thiol coenzyme M methyltransferase. Although incomplete, all draft genomes point to the proposition that WSA2 is the first discovered methanogen restricted to methanogenesis through methylated thiol reduction. In addition, the genomes lack pathways for carbon fixation, nitrogen fixation and biosynthesis of many amino acids. Acetate, malonate and propionate may serve as carbon sources. Using methylated thiol reduction, WSA2 may not only bridge the carbon and sulfur cycles in eutrophic methanogenic environments, but also potentially compete with CO2-reducing methanogens and even sulfate reducers. These findings reveal a remarkably unique methanogen 'Candidatus Methanofastidiosum methylthiophilus' as the first insight into the sixth class of methanogens 'Candidatus Methanofastidiosa'.


Organ at risk dose calculation for left sided breast cancer treatments using intraoperative electron radiotherapy: A Monte Carlo-based feasibility study.
The present study aims to calculate the received dose by lungs and heart, as organs at risk (OAR), during intraoperative electron radiotherapy (IOERT) of left breast cancer at the presence and absence of shielding disk using Monte Carlo (MC) simulation. LIAC 12, a dedicated IOERT Linac, and an anthropomorphic phantom were considered in this study to simulate particle tracks of 6, 8, 10, and 12 MeV nominal electron energies using EGSnrc MC particle transport simulation code. The results showed that for increasing electron beam energies in the absence of shielding disk, left lung and heart dose would also be increasing so that, maximum left lung and heart dose respectively increases from 0.512 to 9.920 Gy and from 0 to 0.506 Gy with increment of electron energy from 6 to 12 MeV. Employing the shielding disk in 6 and 8 MeV energy can reduce the heart and left lung maximum dose to zero. On the other hand, this dose reduction at 10 and 12 MeV energy was respectively about 99% and 93.5% for heart and 99.9% and 92.9% for left lung. Right lung did not receive a remarkable dose both in presence and absence of shielding disk. From the results, it can be concluded that employing the shielding disk can effectively reduce the received dose to OARs.


Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.
Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption.


Analysis and design of second-order sliding-mode algorithms for quadrotor roll and pitch estimation.
The problem addressed in this paper is that of quadrotor roll and pitch estimation without any assumption about the knowledge of perturbation bounds when Inertial Measurement Units (IMU) data or position measurements are available. A Smooth Sliding Mode (SSM) algorithm is first designed to provide reliable estimation under a smooth disturbance assumption. This assumption is next relaxed with the second proposed Adaptive Sliding Mode (ASM) algorithm that deals with disturbances of unknown bounds. In addition, the analysis of the observers are extended to the case where measurements are corrupted by bias and noise. The gains of the proposed algorithms were deduced from the Lyapunov function. Furthermore, some useful guidelines are provided for the selection of the observer turning parameters. The performance of these two approaches is evaluated using a nonlinear simulation model and considering either accelerometer or position measurements. The simulation results demonstrate the benefits of the proposed solutions.


Alterations in the limbic/paralimbic cortices of Parkinson's disease patients with hyposmia under resting-state functional MRI by regional homogeneity and functional connectivity analysis.
Hyposmia is a cardinal early symptom of Parkinson's disease (PD), but the pathophysiological mechanisms underlying it remain unclear. Resting-state functional MRI (RS-fMRI) demonstrates spontaneous neuronal activity. We hypothesized that there would be alterations in the olfaction-related regions of the limbic/paralimbic cortices in PD patients with obvious hyposmia by RS-fMRI. We used the "Five Odors for Olfactory Detection Arrays" to test the threshold of olfactory detection (TOD) for 54 PD patients and 22 age-matched controls. Using the mean TOD of the control group, patients were subdivided into two groups: PD with obvious hyposmia (OH-PD, n = 38) and PD with none/less obvious hyposmia (NOH-PD, n = 16). The regional brain activity of all subjects was investigated using RS-fMRI, in combination with regional homogeneity (ReHo) and functional connectivity (FC) analysis. There were different ReHo values in the limbic/paralimbic cortices between the OH-PD and NOH-PD groups. ReHo was significantly decreased in OH-PD patients in parts of the traditional olfactory regions (e.g. the amygdala, olfactory gyrus, orbital frontal cortex, parahippocampal gyrus and insula) and some non-traditional olfactory centers (e.g. the rectal gyrus and superior temporal pole), while increased in the left anterior/posterior cingulate cortex. FC analysis revealed decreased functional connectivity within the limbic/paralimbic cortices, especially in regions with reduced ReHo in the OH-PD group. PD with hyposmia is related to altered functional activity not only in the traditional olfactory center, but also in some non-traditional olfactory regions of the limbic/paralimbic cortices.


Phycicoccus ochangensis sp. nov., isolated from soil of a potato cultivation field.
Two novel, Gram-positive, motile, coccal bacteria, strains L1b-b9(T) and B5a-b5, were isolated from a potato cultivation field in Ochang, Korea. These isolates grew at 10-45°C, pH 5.0-10.0, and in the presence of 8% (w/v) NaCl. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The major menaquinone was MK-8(H(4)) and the main cellular fatty acids were iso-C(14:0), iso-C(15:0), and anteiso-C(15:0). Polar lipids in strain L1b-b9(T) consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, and an unknown glyco-amino lipid. The G+C content of genomic DNA was 73.6 mol%. A phylogenetic analysis based on 16S rRNA gene sequences showed that strains L1b-b9(T) and B5a-b5 shared 99.36% similarity and formed a robust clade with the type species of the genus Phycicoccus. Strain L1b-b9(T) is related most closely to Phycicoccus cremeus V2M29(T) (97.52% 16S rRNA gene sequence similarity). On the basis of phylogenetic characteristics, the name Phycicoccus ochangensis sp. nov. is proposed for strain LIb-b9(T) (=KCTC 19695(T) [corrected] =JCM 17595(T)).


Diastereoselective palladium-catalyzed alpha-arylation of 4-substituted cyclohexyl esters.
A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.


Covalent immobilization of metal-organic frameworks onto the surface of nylon--a new approach to the functionalization and coloration of textiles.
The prevention of refractory organic pollution caused by conventional dyeing and the development of new fabrics with various functions are two issues to be solved urgently in the field of textile fabrication. Here, we report a new environmentally friendly route for the simultaneous coloration and functionalization of textiles by the covalent immobilization of a metal-organic framework, Cr-based MIL-101(Cr), onto the surfaces of nylon fabrics by co-graft polymerization with 2-hydroxyethyl acrylate initiated by γ-ray irradiation. The Cr(III) clusters color the nylon fabric, and the color intensity varies with the MIL-101 content, providing a "green" textile coloration method that is different from conventional dyeing processes. An X-ray diffraction (XRD) analysis shows that the nanoporous structure of the original MIL-101 particles is retained during radiation-induced graft polymerization. Numerous nanopores are introduced onto the surface of the nylon fabric, which demonstrated better sustained-release-of-aroma performance versus pristine nylon fabric in tests. The modified fabrics exhibit laundering durability, with MIL-101 nanoparticles intact on the nylon surface after 30 h of dry cleaning.


Enzymatic glycosylation of bioactive acceptors catalyzed by an immobilized fungal β-xylosidase and its multi-glycoligase variant.
A recombinant β-xylosidase (rBxTW1) from the ascomycete Talaromyces amestolkiae and a mutant derived from it, with mostly synthetic activity, have been immobilized as magnetic cross-linked enzyme aggregates (mCLEAs). The mCLEAs of rBxTW1 kept the excellent hydrolytic and O-transxylosylating activities of the free enzyme and had improved thermal and pH stability. The mCLEAs of the mutant also maintained or improved the catalytic properties of the soluble enzyme, synthetizing the O-xylosides of vanillin and (-)-epigallocatechin gallate, and the N- and S-xyloside of 3,5-dibromo-1,2,4-triazole and thiophenol, respectively. The mCLEAs were recyclable across 4 cycles of synthesis of the O-xylosides through a green and highly selective process. The magnetic properties of the scaffold used for immobilization may allow the easy recovery and reuse of the biocatalyst even from reactions containing insoluble lignocellulosic biomass.


[Role of parenteral feeding in an operative protocol of total artificial nutrition].
Two cases of enterocutaneous fistula treated with mixed artificial diet (NP + NE) where enteral nutrition played the principal role in weaning from i.v. nutrition have been examined. Gradual transit was possible to normal diet, demonstrating ease of use and effectiveness of the nutritional contribution.


Abbeymycin, a new anthramycin-type antibiotic produced by a streptomycete.
A new antibiotic, abbeymycin, has been isolated from Streptomyces sp. AB-999F-52. The structure of abbeymycin was assigned on the basis of NMR, mass spectrometric and UV spectral data. Abbeymycin has weak activity against a limited number of anaerobic bacteria.


Physical Activity Modulates the Overexpression of the Inflammatory miR-146a-5p in Obese Patients.
Specific microRNAs (miRs), including the "angio-miR-126" and the "inflamma-miR-146a-5p," have been proposed as biomarkers and even therapeutic targets of obesity-associated metabolic diseases. Physical activity, a key measure of prevention for obesity and its complications, is reported to influence the expression of these miRs. In this study, we investigate whether a physical activity program proven to improve metabolic parameters in obese patients can correct the circulating levels of these miRs. Plasma miR-126 and miR-146a-5p were measured in a cohort of obese patients (n = 31, 16F + 15M) before and after the 3-month physical activity program of the CURIAMO trial (registration number for clinical trials: ACTRN12611000255987) and in 37 lean controls (24F + 13M). miR-146a-5p, but not miR-126, was significantly increased in obese patients as compared with lean controls and decreased in approximately two-thirds of the participants post-intervention with a response that positively correlated with pre-intervention levels of this miR. Waist circumference, the inflammatory cytokine IL-8 and lipid parameters, principally total cholesterol, showed the strongest correlation with both the baseline levels and post-intervention correction of miR-146a-5p. Post-hoc analysis of experimental data supports the use of miR-146a-5p as a biomarker and predictor of the clinical response to physical activity in obese patients. Furthermore, miR-146a-5p expression was confirmed to increase together with that of the inflammatory genes TLR4, NF-κB, IL-6, and TNF-α in LPS-stimulated human mononuclear leukocytes. In conclusion, the inflamma-miR-146a-5p can serve as a personalized predictor of clinical outcome in obese patients entering physical activity weight-reduction programs. © 2018 IUBMB Life, 70(10):1012-1022, 2018.


A faith-based prescription for the Surgeon General: challenges and recommendations.
This article summarizes how the Office of the Surgeon General can leverage faith-based resources to fulfill its mission and that of the Surgeon General of the United States. Such resources, personal and institutional, have been utilized historically in health promotion and disease prevention efforts and are a valuable ally for public health, an alliance that continues under the Obama Administration. This paper outlines the history and mission of the Office; details the recent history of federal faith-based initiatives; and advocates an expanded alliance between the faith-based and public health sectors sensitive to legal and professional boundaries.


Sensitive electrochemical detection of aflatoxin B1 using DNA tetrahedron-nanostructure as substrate of antibody ordered assembly and template of aniline polymerization.
A novel strategy for AFB1 detection in grains was proposed based on DNA tetrahedron-structured probe (DTP) and horseradish peroxidase (HRP) triggered polyaniline (PANI) deposition. Briefly, the DNA tetrahedron nanostructures were assembled on the gold electrode, with carboxylic group designed on top vertex of them. The carboxylic group was conjugated with the AFB1 monoclonal antibody (mAb) to form DTP. The test sample and a known fixed concentration of HRP-labeled AFB1 were mixed and they compete for binding to DTP. The HRP assembled on the gold electrode catalyzed the polymerization of aniline on DTP. AFB1 in grains could be determined by using PANI as electrochemical signal molecules. Interestingly, DNA tetrahedron-structure, which has mechanical rigidity and structural stability, can improve antigen-antibody specific recognition and binding efficiency through the use of mAb ordered assembly. Meanwhile, nucleic acid backbone with a large amount of negative charge is good template for aniline polymerization under mild conditions.


A portable steady-state porometer for measuring the carbon dioxide and water vapour exchanges of leaves under natural conditions.
A portable porometer is described for measuring the steady-state CO2 and H2O exchange rates of leaves under natural conditions. The porometer has an open gas exchange system which monitors the differences in concentrations of CO2 and H2O entering and leaving a cuvette which is clamped on or around leaves. The cuvette is designed to maintain ambient air temperature and humidity around the leaf. This instrument may also be used to determine CO2 response curves in the field. Examples of diurnal courses are presented for attached leaves of different species having high and low rates of CO2 exchange.


[Mortality of a group of psychiatric patients under ambulatory care in Geneva].
It is known from former studies that psychiatric patients have a mortality rate higher than that of the general population. This cannot be explained by causes of death that may be specific of psychiatric illness (as suicide for example). The objective of our project is to find if there is such an over mortality in our population, to evaluate to what factors it is related and specially what are the causes of death.


Operating out of hours in acute orthopaedics: variations amongst surgeons and regions in the United Kingdom.
It is recommended that out of hours, surgery should be confined to emergency cases. What constitutes an emergency in orthopaedic surgery is not well defined. This study presents the results of a postal survey sent to orthopaedic surgeons practicing in the United Kingdom, asking them what is the time frame they would recommend operating upon, and whether they would operate out of hours for common acute orthopaedic presentations. Our results demonstrate variability both amongst individual surgeons as well as amongst different regions in the United Kingdom.


Penumbra in Acute Ischemic Stroke.
Acute ischemic stroke is one of the leading causes of disability and death worldwide. The brain tissue adjacent to the central necrotic core was first defined as ischemic penumbra characterized by reduced cerebral blood flow (CBF) with electrical failure but maintained ionic homeostasis and transmembrane electrical potential. Since then, the evolving concepts of the ischemic penumbra have been proposed based on energy metabolism, CBF thresholds, and protein synthesis, providing insight for the diagnosis and treatment of acute ischemic stroke. This paper summarizes the recent advances in the understanding of ischemic penumbra, from its discovery to the diagnosis methods based on imaging techniques and biomarkers, finally some of the treatments developed. In addition, we discussed future perspectives on therapeutic targets beyond the ischemic penumbra to develop a treatment for acute ischemic stroke.


"In sickness and in health": the peculiar occurrence of polymyalgia rheumatica in married cohabiting couples--a case series and review of the literature.
Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder in elderly people. It is frequently associated with giant-cell arteritis (GCA), although it is still debated if they are the same disease or two distinct pathologies. The etiology of PMR remains challenging, although current knowledge supports the role of both genetic and environmental factors. Among these, there is evidence that infectious agents could trigger the disease's onset in some cases. We describe the peculiar case where PMR occurred in two Italian married and cohabiting couples and provide a review of the literature for similar cases. This is the first reported occurrence of PMR in two conjugal pairs in Italy. Moreover, in the second case, the wife presented PMR associated with GCA. To date, seven cases of PMR and two of GCA in married couples are described in the literature. The occurrence of PMR in both a husband and a wife supports the pathogenetic role of an environmental factor.


Modeling the impact of early therapy for latent tuberculosis patients and its optimal control analysis.
Effective tuberculosis (TB) control depends on case findings to discover infectious cases, investigation of contacts of those with TB, as well as appropriate treatment. Adherence and successful completion of the treatment are equally important. Unfortunately, due to a number of personal, psychosocial, economic, medical, and health service factors, a significant number of TB patients become irregular and default from treatment. In this paper, a mathematical model is developed to assess the impact of early therapy for latent TB and non-adherence on controlling TB transmission dynamics. Equilibrium states of the model are determined and their local stability is examined. With the aid of the center manifold theory, it is established that the model undergoes a backward bifurcation. Qualitative mathematical analysis of the model suggests that a high level of latent tuberculosis case findings, coupled with a decrease of defaulting rate, may be effective in controlling TB transmission dynamics in the community. Population-level effects of organized campaigns to improve early therapy and to guarantee successful completion of each treatment are evaluated through numerical simulations and presented in support of the analytical results.


NAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate.
The solute carrier 34 (SLC34) family of membrane transporters is a major contributor to Pi homeostasis. Many factors are involved in regulating the SLC34 family. The roles of the bone mineral metabolism factors parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) in Pi homeostasis are well studied. Intracellular Pi is thought to be involved in energy metabolism, such as ATP production. Under certain conditions of altered energy metabolism, plasma Pi concentrations are affected by the regulation of a Pi shift into cells or release from the tissues. We recently investigated the mechanism of hepatectomy-related hypophosphatemia, which is thought to involve an unknown phosphaturic factor. Hepatectomy-related hypophosphatemia is due to impaired nicotinamide adenine dinucleotide (NAD) metabolism through its effects on the SLC34 family in the liver-kidney axis. The oxidized form of NAD, NAD+, is an essential cofactor in various cellular biochemical reactions. Levels of NAD+ and its reduced form NADH vary with the availability of dietary energy and nutrients. Nicotinamide phosphoribosyltransferase (Nampt) generates a key NAD+ intermediate, nicotinamide mononucleotide, from nicotinamide and 5-phosphoribosyl 1-pyrophosphate. The liver, an important organ of NAD metabolism, is thought to release metabolic products such as nicotinamide and may control NAD metabolism in other organs. Moreover, NAD is an important regulator of the circadian rhythm. Liver-specific Nampt-deficient mice and heterozygous Nampt mice have abnormal daily plasma Pi concentration oscillations. These data indicate that NAD metabolism in the intestine, liver, and kidney is closely related to Pi metabolism through the SLC34 family. Here, we review the relationship between the SLC34 family and NAD metabolism based on our recent studies.


Selective modulation of nucleotide levels in rat liver and hepatomas by high-orotate or arginine-deficient diets and by carbamoylating agents.
Transplanted Morris hepatomas in Buffalo-strain rats were found to be resistant to the changes in ribonucleotide levels in rat liver caused by a high-orotate diet or an arginine-deficient diet. The increase in UTP levels and decrease in ATP levels seen in the livers of rats on a 1%-orotate diet were less marked in the livers of BUB- and DBA-strain mice on this diet. Although the changes were less than in rat liver, there was a 2-3-fold increase in UTP concentration in the livers of mice on the high-orotate diet. However, there was a similar response in nucleotide levels in the two species when the animals were maintained on an arginine-deficient diet, and there was a greater than 10-fold increase in the UTP level in the livers of both rats and mice. These diets had much less effect on the levels of deoxyribonucleotides than of ribonucleotides. In contrast to the insensitivity of hepatomas to dietary modulation of nucleotide levels, treatment of hepatoma-bearing rats with carbamoylating agents (sodium cyanate and 2-chloroethyl isocyanate) caused decreases in the levels of nucleotides in the tumors which were generally greater than in host livers. For example, 2-chloroethyl isocyanate depressed ATP levels in the Morris hepatomas 5123C and 20 under conditions in which there was no significant effect on host liver ATP. The data revealed selective modulation of nucleotide levels in normal and neoplastic liver which may be achieved by either dietary modification or drug treatment.


Diagnostic value of chest radiography in the early management of severely injured patients with mediastinal vascular injury.
Time is of the essence in the management of severely injured patients. This is especially true in patients with mediastinal vascular injury (MVI). This rare, yet life threatening injury needs early detection and immediate decision making. According to the ATLS guidelines [American College of Surgeon Committee on Trauma in Advanced Trauma Life Support (ATLS®), 10th edn, 2018], chest radiography (CXR) is one of the first-line imaging examinations in the Trauma Resuscitation Unit (TRU), especially in patients with MVI. Yet thorough interpretation and the competence of identifying pathological findings are essential for accurate diagnosis and drawing appropriate conclusion for further management. The present study evaluates the role of CXR in detecting MVI in the early management of severely injured patients. We addressed the question in two ways. (1) We performed a retrospective, observational, single-center study and included all primary blunt trauma patients over a period of 2 years that had been admitted to the TRU of a Level-I Trauma Center. Mediastinal/chest (M/C) ratio measurements were calculated from CXRs at three different levels of the mediastinum to identify MVI. Two groups were built: with MVI (VThx) and without MVI (control). The accuracy of the CXR findings were compared with the results of whole-body computed tomography scans (WBCT). (2) We performed another retrospective study and evaluated the usage of sonography, CXR and WBCT over 15 years (2005-2019) in level-I-III Trauma Centers in Germany as documented in the TraumaRegister DGU® (TR-DGU). Study I showed that in 2 years 267 patients suffered from a significant blunt thoracic trauma (AIS ≥ 3) and met the inclusion criteria. 27 (10%) of them suffered MVI (VThx). Through the initial CXR in a supine position, MVI was detected in 56-92.6% at aortic arch level and in 44.4-100% at valve level, depending on different M/C-ratios (2.0-3.0). The specificity at different thresholds of M/C ratio was 63.3-2.9% at aortic arch level and 52.9-0.4% at valve level. The ROC curve showed a statistically random process. No significant differences of the cardiac silhouette were observed between VThx and Control (mean cardiac width was 136.5 mm, p = 0.44). Study II included 251,095 patients from the TR-DGU. A continuous reduction of the usage of CXR in the TRU could be observed from 75% in 2005 to 25% in 2019. WBCT usage increased from 35% in 2005 to 80% in 2019. This development was observed in all trauma centers independently from their designated level of care. According to the TRU management guidelines (American College of Surgeon Committee on Trauma in Advanced Trauma Life Support (ATLS®), 10th edn, 2018; Reissig and Kroegel in Eur J Radiol 53:463-470, 2005) CXR in supine position is performed to detect pneumothorax, hemothorax and MVI. Our study showed that sensitivity and specificity of CXR in detecting MVI was statistically and clinically not reliable. Previous studies have already shown that CXR is inferior to sonography in detecting pneumothorax and hemothorax. Therefore, we challenge the guidelines and suggest that the use of CXR in the early management of severely injured patients should be individualized. If sonography and WBCT are available and reasonable, CXR is unnecessary and time consuming. The clinical reality reflected in the usage of CXR and WBCT over time, as documented in the TR-DGU, seems to support our statement.


Sexual Violence, Mental Health, and Prescription Opioid Use and Misuse.
Previous research indicates that sexual violence is associated with prescription opioid use and misuse. However, this literature is limited by a lack of sex-specific analyses, an inability to establish temporality between experiences of sexual violence and prescription opioid outcomes, and little understanding of mechanisms underlying these associations. Data from Waves IV (2008) and V (2016-2018) of the National Longitudinal Study of Adolescent to Adult Health (N=10,685) were analyzed in March 2020. The association of sexual violence with past 30-day prescription opioid use and misuse among women and men and mediation by depression and anxiety diagnoses were examined using generalized structural equation modeling. Temporality was established using self-reported age at the first experience of sexual violence and age at first depression and anxiety diagnoses. Sexual violence was associated with an increased likelihood of prescription opioid use and misuse among women (OR=1.68, 95% CI=1.19, 2.39 for use; OR=1.18, 95% CI=0.95, 1.55 for misuse) and men (OR=2.37, 95% CI=1.37, 4.12 for use; OR=1.71, 95% CI=1.06, 2.75 for misuse). Among women, depression (p=0.0420) and anxiety (p=0.0450) diagnoses mediated the association with prescription opioid use, and anxiety diagnosis (p=0.0210) mediated the association with prescription opioid misuse. Among men, anxiety diagnosis (p=0.038) mediated the association with prescription opioid use, and depression diagnosis (p=0.0390) mediated the association with prescription opioid misuse. Secondary prevention efforts focused on evidence-based, trauma-informed behavioral health treatment among survivors of sexual violence may prevent prescription opioid use and misuse as strategies for coping with the psychological impact of these traumatic experiences.


Palladium(0)-catalyzed intramolecular dearomative arylation of pyrroles.
The palladium(0)-catalyzed dearomative arylation of pyrroles has been accomplished to afford the spironaphthalenepyrrole derivatives in good to excellent yields.


In situ quantitative and visual investigation of the retention of polycyclic aromatic hydrocarbons on the root surface of Kandelia obovata using a microscopic fluorescence spectral analysis method.
A novel approach for in situ determination of individual benzo[a]pyrene (B[a]P), pyrene (Pyr) and anthracene (Ant) on the root surface micro-zone (0.960mm2) of Kandelia obovata (K. obovata) was established using a microscopic fluorescence spectral analysis (MFSA) system. The detection limits for the three polycyclic aromatic hydrocarbons (PAHs) were 44.2, 59.7 and 36.3ngg-1 on lateral roots and were 42.8, 62.4 and 39.1ngg-1 on taproots of the K. obovata root micro-zone. Using the established MFSA method, retention of the PAHs on the K. obovata lateral root and taproot surface micro-zone were investigated in situ. The retention of PAHs on the lateral root and taproot surface of K. obovata showed uneven distribution, and both of the retained quantities showed significant differences, which was related to both passive uptake patterns or active uptake patterns of the PAH and the polarity index ((O+N)/C) of the root surface. In addition, increased quantities of retention of the PAHs on both lateral root and taproot surfaces of K. obovata were observed in the order of Ant<Pyr<B[a]P in the presence of graphene oxide (10mgL-1) for 7 days. The results of this work provided an in situ method for the investigation on the retention of PAHs on plant lateral root and taproot surfaces at the microscopic scale, contributing to the understanding of the mechanisms of plant root uptake of PAHs.


Plants cultivated for ecosystem restoration can evolve toward a domestication syndrome.
The UN Decade on Ecosystem Restoration calls for upscaling restoration efforts, but many terrestrial restoration projects are constrained by seed availability. To overcome these constraints, wild plants are increasingly propagated on farms to produce seeds for restoration projects. During on-farm propagation, the plants face non-natural conditions with different selection pressures, and they might evolve adaptations to cultivation that parallel those of agricultural crops, which could be detrimental to restoration success. To test this, we compared traits of 19 species grown from wild-collected seeds to those from their farm-propagated offspring of up to four cultivation generations, produced by two European seed growers, in a common garden experiment. We found that some plants rapidly evolved across cultivated generations towards increased size and reproduction, lower within-species variability, and more synchronized flowering. In one species, we found evolution towards less seed shattering. These trait changes are typical signs of the crop domestication syndrome, and our study demonstrates that it can also occur during cultivation of wild plants, within only few cultivated generations. However, there was large variability between cultivation lineages, and the observed effect sizes were generally rather moderate, which suggests that the detected evolutionary changes are unlikely to compromise farm-propagated seeds for ecosystem restoration. To mitigate the potential negative effects of unintended selection, we recommend to limit the maximum number of generations the plants can be cultivated without replenishing the seed stock from new wild collections.


Practical occupational medicine: astronaut selection; a diver's perspective from 300 m below sea level to 300 km above.
In 1989, public selection of a team of four astronauts for the Anglo-Soviet Juno space mission took place. In this article, the author, a Navy Medical Officer, relates his experiences of taking part and discusses the rationale behind the exhaustive protocol of medical investigations involved.


Indicators of selenium status in Australian infants.
To provide the first Australian data for the commonly used indicators of selenium (Se) status including plasma and erythrocyte Se and erythrocyte glutathione peroxidase (GSHPx) activity in newborn term and preterm infants from Adelaide, South Australia. Plasma Se levels from adults from Adelaide and Tasmania are also reported. Descriptive, cross-sectional study of the indicators of Se status of newborn Australian preterm and term infants. Mean (+/- SD) plasma Se concentrations in the first 5 days of life for term (n = 48) and preterm (n = 90) infants were similar at 33 +/- 11 and 29 +/- 14 microg/L, respectively. Glutathione peroxidase activity was lower in preterm than term infants (P < 0.001). Erythrocyte Se was lower in male (n = 74) compared with female (n = 57) infants (491 +/- 98 vs 561 +/- 134 ng/g Hb; P < 0.001). Adelaide adult plasma Se levels were 88 +/- 20 microg/L and higher than those of adult Tasmanian blood donors (77 +/- 13 microg/l, P < 0.05). These data indicate that values for indicators of Se status of Australian infants and adults are at the lower end of the international range. This article highlights the paucity of Australian data on the Se content in the food supply and the Se status of the Australian population. Given the increasing range and complexity of the biological roles of Se and the emerging evidence that Se may have important roles in prevention of cancer and other disorders, further data are required to clarify the Se status of Australians.


A Caenorhabditis elegans genetic-interaction map wiggles into view.
Systematic mapping of genetic-interaction networks will provide an essential foundation for understanding complex genetic disorders, mechanisms of genetic buffering and principles of robustness and evolvability. A recent study of signaling pathways in Caenorhabditis elegans lays the next row of bricks in this foundation.


HIV testing strategies employed in health care settings in the European Union/European Economic Area (EU/EEA): evidence from a systematic review.
Despite the availability of HIV testing guidelines to facilitate prompt diagnosis, late HIV diagnosis remains high across Europe. The study synthesizes recent evidence on HIV testing strategies adopted in health care settings in the European Union/European Economic Area (EU/EEA). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and systematic searches were run in five databases (2010-2017) to identify studies describing HIV testing interventions in health care settings in the EU/EEA. The grey literature was searched for unpublished studies (2014-2017). Two reviewers independently performed study selection, data extraction and critical appraisal. One hundred and thirty intervention and/or feasibility studies on HIV testing in health care settings were identified. Interventions included testing provision (n = 94), campaigns (n = 14) and education and training for staff and patients (n = 20). HIV test coverage achieved through testing provision varied: 2.9-94% in primary care compared to 3.9-66% in emergency departments. HIV test positivity was lower in emergency departments (0-1.3%) and antenatal services (0-0.05%) than in other hospital departments (e.g. inpatients: 0-5.3%). Indicator condition testing programmes increased HIV test coverage from 3.9-72% before to 12-85% after their implementation, with most studies reporting a 10-20% increase. There were 51 feasibility and/or acceptability studies that demonstrated that HIV testing interventions were generally acceptable to patients and providers in health care settings (e.g. general practitioner testing acceptable: 77-93%). This review has identified several strategies that could be adopted to achieve high HIV testing coverage across a variety of health care settings and populations in the EU/EEA. Very few studies compared the intervention under investigation to a baseline, but, where this was assessed, data suggested increases in testing.


The plasma potassium concentration in metabolic acidosis: a re-evaluation.
The purpose of these investigations was to describe the mechanisms responsible for the change in the plasma [K] during the development and maintenance of hyperchloremic metabolic acidosis. Acute metabolic acidosis produced by HCI infusion resulted in a prompt rise in the plasma [K], whereas no change was observed during acute respiratory acidosis in the dog. After 3 to 5 days of acidosis due to NH4Cl feeding, dogs became hypokalemic; this fall in the plasma [K] was due largely to increased urine K excretion. Despite hypokalemia, aldosterone levels were not low, and the calculated transtubular [K] gradient was relatively high, suggesting renal aldosterone action. Thus, rather than anticipating hyperkalemia in patients with chronic metabolic acidosis due to a HCl load, the finding of hyperkalemia should suggest that the rate of urinary K excretion is lower than expected (ie, there are low aldosterone levels or failure of the kidney to respond to this hormone).


Deferoxamine attenuates iron-induced long-term neurotoxicity in rats with traumatic brain injury.
This study investigated whether deferoxamine (DFO), an iron chelator attenuates iron-induced toxicity in rats with traumatic brain injury. In this study, three groups of Sprague-Dawley rats (sham, injury and DFO groups) were examined. Rats were killed on day 28 after Morris water maze testing and brains perfused for either non-heme brain binding or hemosiderin staining. Western blotting was used to measure protein levels of ferritin, transferrin and transient receptor potential canonical channel 6 (TRPC6). In TBI rats, there was a significant increase in brain iron on day 28, ferritin L, ferritin H, transferrin and TRPC6 levels were all significantly elevated post-TB1. There were also deficits in spatial learning and memory; however, DFO administration attenuated these effects in TBI rats supporting the notion that DFO may reduce brain injury accentuated by iron overload.


Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids.
The addition of an inhaled long-acting beta2-agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients and two fixed combination inhalers (salmeterol/fluticasone and formoterol/budesonide) are increasingly used as a convenient controller in patients with persistent asthma. There is a strong scientific rationale for the combination of these two drug classes. ICS suppress the chronic inflammation of asthma and reduce airway hyperresponsiveness and this is achieved at low doses in most patients. LABA act on different aspects of the pathophysiology of asthma. In addition to their bronchodilator action, LABA also inhibit mast cell mediator release, plasma exudation and may reduce sensory nerve activation. Thus these two classes of drug address complementary aspects of the pathophysiology of asthma that neither drug class is able to achieve alone. There are several positive interactions between LABA and ICS. Corticosteroids increase the expression of beta2-receptors by increasing gene transcription. Experimentally this protects against the loss of beta2-receptors in response to long-term exposure to beta2-agonists. While this is unlikely to be important in bronchodilator responses to beta2-agonists, in view of the large beta-receptor reserve, it is probably important in preventing loss of beta-agonist effects on the nonbronchodilator actions of LABA discussed earlier. beta2-Agonists may potentiate the molecular mechanism of corticosteroid actions, with increased nuclear localization of glucocorticoid receptors and additive or sometimes synergistic suppression of inflammatory mediator release. Thus LABA and ICS may optimize each others beneficial actions in the airways, but the low systemic effects of these drugs do not result in any increase in adverse effects. Long-acting beta2-agonists corticosteroid inhaler therapy is therefore a logical advance and results in effective control of asthma in the majority of patients without significant adverse effects. This simplified approach to long-term asthma therapy has a strong scientific rationale.


Operative reports: form and function.
Little is known about how closely operative reports reflect what was actually performed during an operation, nor has the construction of operative reports been adequately studied with the aims of clarifying the objectives of those reports and improving their efficacy. We hypothesized that if more attention is paid to the objectives of operative reports, their content will more predictably contain the most relevant information, which might channel thinking in beneficial directions during performance of the operation. Multivariate analysis of 250 laparoscopic cholecystectomy operative reports (125 uncomplicated and 125 with bile duct injury). Academic research. University (105 cases) and community (145 cases) hospitals. Variations in content and design of operative reports. Cognitive task analysis of laparoscopic cholecystectomy was conducted, and a model operative report was generated and compared with the actual operative reports. Descriptions of key elements in adequate dissection of the Calot triangle were present in 24.8% and 0.0% of operative reports from uncomplicated and bile duct injury cases, respectively. Thorough dissection of the Calot triangle, identification of the cystic duct-infundibulum junction, and lateral retraction of the infundibulum correlated with uncomplicated cases, while irregular cues (eg, perceived anatomic or other deviations) correlated with bile duct injury cases. Current practice generates operative reports that vary widely in content and too often omit important elements. This research suggests that the construction of operative reports should be constrained such that the reports routinely include the fundamental goals of the operation and what was performed to meet them. Cognitive task analysis is based on the ways the mind controls the performance of tasks; it is an excellent method for determining the extra content needed in operative reports. The resulting designs should also serve as mental guidelines to facilitate learning and to enhance the safety of the operation.


LncRNA EIF3J-AS1 enhanced esophageal cancer invasion via regulating AKT1 expression through sponging miR-373-3p.
Esophageal cancer (ECa) remains a major cause of mortality across the globe. The expression of EIF3J-AS1 is altered in a plethora of tumors, but its role in ECa development and progression are undefined. Here, we show that EIF3J-AS1 is up-regulated in ECa and that its expression correlates with advanced TNM stage (P = 0.014), invasion depth (P = 0.001), positive lymph node metastasis (P < 0.001) and poor survival (OS: P = 0.0059; DFS: P = 0.0037) in ECa. Functional experiments showed that knockdown EIF3J-AS1 inhibited ECa growth and metastasis through in vitro and in vivo experiments. Regarding the mechanism, EIF3J-AS1/miR-373-3p/AKT1 established the ceRNA network involved in the modulation of cell progression of ECa cells. Overall, EIF3J-AS1 may exhibit an oncogenic function in ECa via acting as a sponge for miR-373-3p to up-regulate AKT1 mRNA level, and may serve as a potential therapeutic target and a prognostic biomarker for ECa patients.


Halogenated Ether, Alcohol, and Alkane Anesthetics Activate TASK-3 Tandem Pore Potassium Channels Likely through a Common Mechanism.
The TWIK-related acid-sensitive potassium channel 3 (TASK-3; KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic-binding cavity. To understand the pharmacologic requirements for TASK-3 activation, we studied the concentration-response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α-chloralose, 2,2,2-trichloroethanol [TCE], and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic-binding cavity as observed in a TASK-3 homology model. TASK-3 activation was quantified by Ussing chamber voltage clamp analysis. We mutagenized the residue Val-136, which lines the anesthetic-binding cavity, its flanking residues (132 to 140), and Leu-122, a pore-gating residue. The 2-halogenated ethanols activate wild-type TASK-3 with the following rank order efficacy (normalized current [95% confidence interval]): 2,2,2-tribromo-(267% [240-294]) > 2,2,2-trichloro-(215% [196-234]) > chloral hydrate (165% [161-176]) > 2,2-dichloro- > 2-chloro ≈ 2,2,2-trifluoroethanol > ethanol. Similarly, carbon tetrabromide (296% [245-346]), carbon tetrachloride (180% [163-196]), and 1,1,1,3,3,3-hexafluoropropanol (200% [194-206]) activate TASK-3, whereas the larger carbon tetraiodide and α-chloralose inhibit. Clinical agents activate TASK-3 with the following rank order efficacy: halothane (207% [202-212]) > isoflurane (169% [161-176]) > sevoflurane (164% [150-177]) > desflurane (119% [109-129]). Mutations at and near residue-136 modify TCE activation of TASK-3, and interestingly M159W, V136E, and L122D were resistant to both isoflurane and TCE activation. TASK-3 function is activated by a multiple agents and requires a halogenated substituent between ∼30 and 232 cm3/mol volume with potency increased by halogen polarizeability. Val-136 and adjacent residues may mediate anesthetic binding and stabilize an open state regulated by pore residue Leu-122. Isoflurane and TCE likely share commonalities in their mechanism of TASK-3 activation.


Purification, properties, and kinetics of D-ribulokinase from Aerobacter aerogenes.
The enzyme D-ribulokinase from Aerobacter aerogenes was purified to near homogeneity. The molecular weight, as determined by Sephacryl gel chromatography, is 116,000. The subunit molecular weight, determined by sodium dodecyl sulfate-gel electrophoresis, is 59,000, suggesting that D-ribulokinase is a dimer of identical subunits. Initial rate kinetic studies, involving substrate analogs and products, were carried out. These investigations support a kinetic mechanism of the Random Bi Bi type. Isotope partitioning, utilizing D-[3H]ribulose, indicates that the mechanism is steady state Random Bi Bi.


Prognostic value of anesthesia type for patients treated for cutaneous melanoma.
General anesthesia has been reported to compromise several cell-mediated immune functions. Hence it is plausible that anesthesia could affect the postoperative outcome of cancer patients. To study the influence of the type of anesthesia on survival of 459 patients with localized cutaneous melanoma observed between 1980 and 1991. Crude survival proportions were calculated by the methods of Kaplan and Meier. Cox proportional hazards regression analysis was used to estimate the effect on death rates of the type of anesthesia. The 5-year survival proportions were 81% for patients treated under local anesthesia, 71.9% for patients receiving halothane isoflurane or enflurane, and 88.4% for neuroleptanalgesia (P < .05). After multiple adjustment for other prognostic variables (tumor thickness, presence of ulceration, age, sex, cross-sectional profile), using patients treated under local anesthesia as a reference group, the relative risk for general anesthesia with volatile agents was 1.3 (95% CI, 0.84-2.10). The type of anesthesia does not seem to affect the survival of patients with cutaneous melanoma, when other prognostic factors are considered.


ZNF208 polymorphisms associated with ischemic stroke in a southern Chinese Han population.
Ischemic stroke is one of the most common diseases with a high burden of neurological deficits, disability and death. Zinc finger protein 208 (ZNF208) was found to be involved in coronary heart disease, although little information is available about its association with ischemic stroke. We performed the present case-control study to clarify the association between single-nucleotide polymorphisms (SNPs) within ZNF208 and the risk of ischemic stroke in a southern Chinese Han population. A total of 799 subjects (400 cases and 399 healthy controls) were enrolled in the present study. Five SNPs within ZNF208 gene were selected and genotyped using Sequenom MassARRY technology (Sequenom, Inc., San Diego, CA, USA). Data management and statistical analyses were conducted using Sequenom Typer, version 4.0, and a chi-squared test, as well as unconditional logistic regression. Statistical results showed that three variants were associated with the risk of ischemic stroke under allele models (rs2188971, rs2188972, rs8103163 and rs7248488). The variant rs2188972 was also associated with the risk of ischemic stroke in a recessive model after adjustment for age and sex. Haplotype analysis suggested that a significant difference existed between the Ars2188972 Trs2188971 Ars8103163 Ars7248488 haplotype and the risk of ischemic stroke, although this disappeared after adjustment for sex and age. The results obtained in the present study indicate a potential association between ZNF208 variants and the risk of ischemic risk in a southern Chinese Han population.


[TAFRO syndrome and cutaneous necrotizing vasculitis].
TAFRO syndrome is a systemic inflammatory syndrome in the spectrum of Castleman's disease, associating thrombocytopenia, anasarca, fever, renal failure and/or reticulin myelofibrosis and organomegaly. Its association with necrotizing cutaneous vasculitis has not yet been reported. A 69-year-old woman presented with weight loss, fever, anasarca, organomegaly, lymphadenopathy, anuria and extensive necrotic livedo occurring after acute diarrhea. Biology showed anemia, thrombocytopenia, renal failure, hypergammaglobulinemia, a circulating B-lymphocyte clone, hypoparathyroidism and autoimmune hypothyroidism. The skin biopsy showed small vessel vasculitis with fibrinoid necrosis. Methylprednisolone infusions associated with tocilizumab were ineffective and the patient became anuric. Rituximab and plasma exchanges associated to corticosteroids allowed remission for 2 months. Combination of rituximab, cyclophosphamide and dexamethasone resulted in a prolonged remission. We report here the first case of severe cutaneous necrotizing vasculitis in a patient suffering from TAFRO syndrome. The possible resistance to tocilizumab should be known.


Influence of thyroid hormone therapy on the fracture rate - A claims data cohort study.
It has been debated for years whether long-term thyroid hormone intake causes fractures. Not only have previous studies suffered from design limitations, they also reached contradictory conclusions. We investigated thyroid hormones (thyroxine) as a possible risk factor for fractures in a cohort of 6.7 million persons based on administrative data. The database consists of anonymized settlement data of approximately 70 German statutory health insurances covering a time period of six years. All subjects aged 60 and above were included in the study; subjects with repeated thyroxine prescriptions were assigned to the exposure group; members without thyroxine prescriptions to the control group. Outcome was any incident fracture during a declared time period. In order to calculate fracture risk, we performed multivariate cox regression analyses to adjust for confounders. Of 798 770 subjects fulfilling the inclusion criteria, 11.7% took thyroxine regularly and belong to the exposure group. The final cox regression showed that subjects taking thyroxine have a 6.3% higher risk (HR 1.063; CI 1.046-1.080, p=<.0001) than members of the control group. The study supports the assumption that long term thyroxine intake leads to an increase in fracture risk among patients older than 60years. The findings have implications for long term thyroxine treatment.


Crystal structure and conformational analysis of 2-hy-droxy-3-(2-methyl-prop-1-en-1-yl)naphthalene-1,4-dione.
In the structure of the title compound, C14H12O3, the substituent side chain, in which the H atoms of both methyl groups are disordered over six equivalent sites, lies outside of the plane of the naphthalene-dione ring. The ring-to-chain C-C-C-C torsion angles are 50.7 (3), -176.6 (2) and 4.9 (4)°. An intra-molecular meth-yl-hy-droxy C-H⋯O hydrogen bond is present. In the crystal, mol-ecules are primarily connected by inter-molecular O-H⋯O hydrogen bonds, forming a centrosymmetric cyclic dimer motif [graph set R 2 (2)(10)]. Also present is a weak inter-molecular C-H⋯O hydrogen bond linking the dimers and a weak π-π ring inter-action [ring centroid separation = 3.7862 (13) Å], giving layers parallel to (10-3).


"Ejaculatory disorders and alpha1-adrenoceptor antagonists therapy: clinical and experimental researches".
It is well known that the use of the alpha-adrenergic receptor antagonists in the BPH therapy may induce ejaculatory disorder. A review of clinical literature shows a greater incidence of ejaculatory disorder during the use of tamsulosin compared with alfuzosin. Anejaculation has been until now referred to retrograde ejaculation due to relaxation of prostatic and bladder neck smooth muscle tone. In a recent researches was evaluated the effect of tamsulosin and alfuzosin on rat vas deferent "in vitro", concluding that tamsulosin may "cause ejaculatory dysfunction by altering the progression and emission of sperm". An abnormal increase of contraction would be the cause of ejaculatory disorder. The aim of our paper is to compare human and rat vas deferens contractile activity and to evaluate with a clinical study if tamsulosin causes retrograde ejaculation disorder. We have revaluated the human and rat vas deferens contractile activity in vitro according to our experience and literature. We have also performed a clinical study on 10 patients (48-72 y) affected by anejaculation. Post-coital urine was examined to search spermatozoa. Human and rat vas deferens activity is not comparable. Contractile activity induced by norepinephrin after tamsulosin incubation in rat prostatic vas deferens strips is similar to the contractile activity evoked by norepinephrin in human strips. Spermatozoa were found in post coital urine of 6 patients. In our opinion the treatment with tamsulosin may induce retrograde ejaculation but not other ejaculatory disorder due to abnormal sperm progression.


Marital Status and Problem Gambling Among Australian Older Adults: The Mediating Role of Loneliness.
Problem gambling rates in older adults have risen dramatically in recent years and require further investigation. Limited available research has suggested that social needs may motivate gambling and hence problem gambling in older adults. Un-partnered older adults may be at greater risk of problem gambling than those with a partner. The current study explored whether loneliness mediated the marital status-problem gambling relationship, and whether gender moderated the mediation model. It was hypothesised that the relationship between being un-partnered and higher levels of loneliness would be stronger for older men than older women. A community sample of Australian men (n = 92) and women (n = 91) gamblers aged from 60 to 90 years (M = 69.75, SD = 7.28) completed the UCLA Loneliness Scale and the Problem Gambling Severity Index. The results supported the moderated mediation model, with loneliness mediating the relationship between marital status and problem gambling for older men but not for older women. It appears that felt loneliness is an important predictor of problem gambling in older adults, and that meeting the social and emotional needs of un-partnered men is important.


Clinical characteristics and treatment outcomes of patients with relapsing polychondritis with airway involvement.
We investigated the clinical characteristics, management modalities, and outcomes in patients with relapsing polychondritis (RP) with airway involvement. The medical records of RP patients with airway involvement seen at Samsung Medical Center from August 2004 to December 2011 were collected. The clinical manifestations were investigated retrospectively, including rheumatologic record, diagnostic tests, treatment modalities, and clinical outcomes. Twelve patients (five females, seven males) with a median age of 48(interquartile range (IQR) 44-60) years were included. All patients had airway involvement, including the trachea (100 %), main bronchi (83 %), and larynx (25 %). Rheumatological manifestations were frequent, including inflammatory arthritis (50 %), auricular chondritis (42 %), keratoconjunctivitis (42 %), nasal chondritis (42 %), saddle nose (25 %), and sensorineural hearing loss (17 %). All patients who had acute exacerbations were treated with high-dose corticosteroids (1,000 mg per day) and were maintained on oral prednisolone (5-40 mg per day), with weekly methotrexate (2.5-15 mg per week) during follow up. One out of 12 patients required mechanical ventilation. Nine patients have survived without ventilator support and eight patients without a tracheostomy. Two patients underwent a tracheostomy with endobronchial stenting. During follow-up (median 24[IQR 7-50] months), the clinical outcome was favorable in nine patients, while three patients died of pneumonia and respiratory failure. High-doses of corticosteroids during an acute exacerbation followed by maintenance prednisolone with methotrexate could be recommended as a therapeutic option in RP patients with airway involvement. Airway intervention by an experienced clinician is sometimes required.


Quantification of intramyocardial blood volume using 99mTc-RBC SPECT/CT: a pilot human study.
Quantification of intramyocardial blood volume (IMBV), the fraction of myocardium that is occupied by blood, is a promising Index to measure microcirculatory functions. In previous large animal SPECT/CT studies injected with 99mTc-labeled Red Blood Cell (RBC) and validated by ex vivo microCT, we have demonstrated that accurate IMBV can be measured. In this study, we report the data processing methods and results of the first-in-human pilot study. Data from three subjects have been included to date. Each subject underwent rest and adenosine-induced stress 99mTc-RBC SPECT/CT on a dedicated cardiac system with both non-contrast and contrast-enhanced CT acquired. Corrections of attenuation (AC) and scatter (SC), respiratory and cardiac gating, and partial volume correction (PVC) were applied. We also performed automatic segmentation and registration approach based on the blood pool topology in both SPECT and CT images. The quantified IMBV across all subjects under resting conditions were 35.0% ± 3.3% for the end-diastolic phase and 24.1% ± 2.7% for the end-systolic phase. The cycle-dependent change in IMBV (ΔIMBV) between diastolic and systolic phases was 31.5% ± 3.0%. Under stress, IMBV were 40.6% ± 4.2% for the end-diastolic phase and 26.5% ± 2.8% for the end-systolic phase, and ΔIMBV was 34.7% ± 7.4%. It is feasible to quantify IMBV in resting and stress conditions in human studies using SPECT/CT with 99mTc-RBC.