A Multilaboratory, Multicountry Study To Determine MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing of Selected First-Line Antituberculosis Drugs, Second-Line Injectables, Fluoroquinolones, Clofazimine, and Linezolid.
Our objective was to establish reference MIC quality control (QC) ranges for drug susceptibility testing of antimycobacterials, including first-line agents, second-line injectables, fluoroquinolones, and World Health Organization category 5 drugs for multidrug-resistant tuberculosis using a 7H9 broth microdilution MIC method. A tier-2 reproducibility study was conducted in eight participating laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Three lots of custom-made frozen 96-well polystyrene microtiter plates were used and prepared with 2× prediluted drugs in 7H9 broth-oleic acid albumin dextrose catalase. The QC reference strain was Mycobacterium tuberculosis H37Rv. MIC frequency, mode, and geometric mean were calculated for each drug. QC ranges were derived based on predefined, strict CLSI criteria. Any data lying outside CLSI criteria resulted in exclusion of the entire laboratory data set. Data from one laboratory were excluded due to higher MIC values than other laboratories. QC ranges were established for 11 drugs: isoniazid (0.03 to 0.12 μg/ml), rifampin (0.03 to 0.25 μg/ml), ethambutol (0.25 to 2 μg/ml), levofloxacin (0.12 to 1 μg/ml), moxifloxacin (0.06 to 0.5 μg/ml), ofloxacin (0.25 to 2 μg/ml), amikacin (0.25 to 2 μg/ml), kanamycin (0.25 to 2 μg/ml), capreomycin (0.5 to 4 μg/ml), linezolid (0.25 to 2 μg/ml), and clofazimine (0.03 to 0.25 μg/ml). QC ranges could not be established for nicotinamide (pyrazinamide surrogate), prothionamide, or ethionamide, which were assay nonperformers. Using strict CLSI criteria, QC ranges against the M. tuberculosis H37Rv reference strain were established for the majority of commonly used antituberculosis drugs, with a convenient 7H9 broth microdilution MIC method suitable for use in resource-limited settings.


Acute copper toxicity in the euryhaline copepod Acartia tonsa: implications for the development of an estuarine and marine biotic ligand model.
Copepods (Acartia tonsa) were exposed (48 h) to waterborne, diet-borne (non-Cu-equilibrated and Cu-equilibrated food), and waterborne plus diet-borne Cu in either the absence or the presence of food (diatom Thalassiosira weissflogii). Toxicity tests were run in different salinities (5, 15, and 30 ppt) together with measurements of physicochemical parameters and total and dissolved Cu concentrations in the experimental media. Results show that most of the toxic Cu fraction was in the dissolved phase. In general, Cu toxicity was higher in low (5 ppt) than in high salinity (30 ppt), regardless of the pathway of Cu exposure tested. In the absence of food, data clearly indicate that differences in waterborne Cu toxicity can be explained by changes in water chemistry. However, addition of food (either non-Cu-equilibrated or Cu-equilibrated) to the experimental media protected against acute Cu toxicity in salinities 5 and 15 ppt, suggesting that A. tonsa requires extra energy to cope with the stressful condition imposed by Cu exposure associated with the ionoregulatory requirements in low salinities. For diet-borne exposure, a very high Cu concentration was necessary to precontaminate the diatoms to a level resulting in copepod mortality. Therefore, availability of food exerted a more important positive impact in protecting against acute Cu toxicity than its potential negative impact via contamination resulting in toxicity. Findings indicate the need for incorporation of both salinity and food in a future biotic ligand model (BLM) version for Cu in estuarine and marine waters. In this context, the euryhaline copepod A. tonsa would be a suitable model species with which to perform experiments to validate and calibrate any future saltwater BLM.


Reaction time and brain oscillations in Go/No-go tasks with different meanings of stimulus color.
Color has meaning in particular contexts, and the meaning of color can impact behavioral performance. For example, the meaning of color about traffic rules (blue/green and red mean "go" and "stop" respectively) influences reaction times (RTs) to signals. Specifically, in a Go/No-go task, RTs have been reported to be longer when responding to a red signal and withholding the response to a blue signal (Red Go/Blue No-go task) than when responding to a blue signal and withholding the response to a red signal (Blue Go/Red No-go task). However, the neurophysiological background of this phenomenon has not been fully understood. The purpose of this study was to investigate the brain oscillatory activity associated with the effect of meaning of color on RTs in the Go/No-go task. Twenty participants performed a Blue simple reaction task, a Red simple reaction task, a Blue Go/Red No-go task, and a Red Go/Blue No-go task. We recorded responses to signals and electroencephalogram (EEG) during the tasks and evaluated RTs and changes in spectral power over time, referred to as event-related synchronization (ERS) and event-related desynchronization (ERD). The behavioral results were similar to previous studies. The EEG results showed that frontal beta ERD and theta ERS were greater when signals were presented in blue than red color in both simple reaction and Go/No-go tasks. In addition, the onset of theta ERS was delayed in the Red Go than Blue Go trial in the Go/No-go task. The enhanced beta ERD may indicate that blue signals facilitate motor response, and the delayed onset of theta ERS may indicate the delayed onset of cognitive process when responding to red signals as compared to blue signals in the Go/No-go task. Thus, this delay in cognitive process can be involved in the slow response in the Red Go/Blue No-go task.


Palliative care in Italy: problem areas emerging from the literature.
The aim of this study was to review the Italian literature regarding attitudes toward palliative care in cancer patients, as well as cultural, educational and organizational problems in Italy with respect to palliative care services. The Italian literature published in the last ten years on PUBMED was reviewed. Clinical trials were excluded from this analysis, as their focus was beyond the scope of this study. Non-cancer studies were also excluded. Thirty-nine papers were retrieved. Several weaknesses were recognized in the studies, including a lack of knowledge and negative attitudes regarding cancer pain management and the use of alternative treatments. Communication with patients and family was also inadequate. In general, poor organization of palliative care services was also shown. An appropriate place to die was often not guaranteed and was dependent on the availability of local resources. However, the most striking finding was that there were geographical differences in the distribution of palliative care resources. The development of a range of palliative care programs integrating primary territorial care and specialized palliative services may constitute the ideal synthesis to respond to patients' needs.


Thiol Specific and Tracelessly Removable Bioconjugation via Michael Addition to 5-Methylene Pyrrolones.
5-Methylene pyrrolones (5MPs) are highly thiol-specific and tracelessly removable bioconjugation tools. 5MPs are readily prepared from primary amines in one step. 5MPs exhibit significantly improved stability under physiologically relevant conditions and cysteine specificity compared to commonly used analogues, maleimides. Michael addition of thiol to 5MPs occurs rapidly, cleanly, and does not generate a stereocenter. The conjugates efficiently release thiols via retro-Michael reaction in alkaline buffer (pH 9.5) or via thiol exchange at pH 7.5. This unique property makes 5MPs valuable for the controlled release of conjugated cargo and temporary thiol protection. The utilization of 5MPs for protein immobilization and pull-down of active complexes is illustrated using E. coli. acetohydroxyacid synthase isozyme I.


Optimum position of transthoracic intracardiac line following cardiac surgery.
The transthoracic intracardiac line placed in the right atrium provides a convenient access to the central venous system following cardiac surgery. However, it is associated with risks such as migration and bleeding. We conducted a retrospective study to determine whether position of transthoracic line with respect to site of exit from the chest makes a difference in the rate of complications. All infants receiving a transthoracic intracardiac line in the right atrium following cardiac surgery between June 2012 and December 2015 were part of the study. A 3.5-Fr double-lumen umbilical venous catheter was placed directly into the right atrium. The lines exited the thorax either above in the suprasternal notch (upper transthoracic line) or below the diaphragm across the abdominal wall (lower transthoracic line). Patients were analysed for complications such as catheter migration, bleeding upon removal, atrial thrombus, line occlusion, premature removal and failed removal. A total of 131 patients received a transthoracic intracardiac line during the study period. Of the total patients, 88 patients received the upper transthoracic line and 43 patients received the lower transthoracic line. The upper transthoracic line was associated with significantly lower incidence of catheter migration (1% vs 14%) and this held by multivariable logistic regression, adjusting for age and duration of the line (P = 0.003). There was no difference in the rate of other complications including bleeding. The upper transthoracic line is associated with significantly lower incidence of catheter migration and offers a more optimum position for central access following cardiac surgery.


Green Synthesis of Zn(OH)2/ZnO-Based Bionanocomposite using Pomegranate Peels and Its Application in the Degradation of Bacterial Biofilm.
The ability and potency of bacterial species to form biofilms, which show antibiotic resistance thereby avoiding antibiotic surfaces, is a major cause of prolonged infections. Various advanced approaches have been employed to prevent or damage bacterial biofilms, formed by a variety of bacterial strains, to help prevent the associated infectious disease. In this context, zinc-based nanostructures have been recognized as a potential antibiotic agent against a broad spectrum of bacterial communities. As a result, a sustainable and green synthesis method was adapted in the present study to synthesize a Zn(OH)2/ZnO-based bionanocomposite, in which aqueous extracts of waste pomegranate peels (Punica granatum) were employed as a natural bioreducing agent to prepare the bionanocomposite at room temperature. Furthermore, FT-IR, XRD, DLS, UV-Visible, PL spectroscopy, FE-SEM, and TEM were used to characterize the green route synthesized a Zn(OH)2/ZnO bionanocomposite. The average crystallite size was determined using the Scherrer relation to be 38 nm, and the DLS results indicated that the Zn(OH)2/ZnO bionanocomposite had a hydrodynamic size of 170 nm. On the other hand, optical properties investigated through UV-Vis and PL spectroscopy explored the energy bandgap between 2.80 and 4.46 eV, corresponding to the three absorption edges, and it covered the blue spectrum when the sample was excited at 370 nm. Furthermore, the impact of this green route synthesized a Zn(OH)2/ZnO bionanocomposite on the biofilm degradation efficiency of the pathogenic bacterial strain Bacillus subtilis PF_1 using the Congored method was investigated. The Congored assay clearly explored the biofilm degradation efficiency in the presence of a 50 mg/mL and 75 mg/mL concentration of the Zn(OH)2/ZnO bionanocomposite against the bacterial strain Bacillus subtilis PF_1 grown for 24 h. This study can be further applied to the preparation of bionanocomposites following a low-cost green synthesis approach, and thus prepared nanostructures can be exploited as advanced antimicrobial agents, which could be of great interest to prevent various infectious diseases.


Prognosis of ARF in hospitalized elderly patients.
Differentiation between hospital-acquired acute renal failure (ARF) and community-acquired ARF may have epidemiological implications that lead to different prognoses in hospitalized patients. Such a comparison has not yet been made among elderly individuals. We performed a 3-year prospective study in a tertiary referral hospital of 325 patients aged 60 years or older who presented with ARF. Patients were divided into 2 groups; those with hospital-acquired ARF (n = 154) and community-acquired ARF (n = 171), and were followed up in relation to mortality. Multiple logistic regression was used in the analysis. The overall mortality rate in this elderly population was 54%; 59% for the group with hospital-acquired ARF and 41% for the group with community-acquired ARF (P < 0.001). Groups differed (P < 0.01) in relation to cause of ARF, preexisting diseases, organ failure, sepsis, and performance of dialysis, among other factors. The adjusted mortality risk for the group with hospital-acquired ARF was 2.23 times greater than for the group with community-acquired ARF (95% confidence interval [CI], 1.21 to 4.08). In the group with hospital-acquired ARF, factors associated with mortality were neurological failure (odds ratio [OR], 2.97; 95% CI, 1.17 to 7.60), hematologic failure (OR, 4.30; 95% CI, 1.63 to 11.34), and oliguria (OR, 12.14; 95% CI, 4.62 to 31.87). In the group with community-acquired ARF, significant factors were neoplasia, cardiac disease, hepatic disease, cardiovascular failure, oliguria, and sepsis. Differentiation between hospital-acquired ARF and community-acquired ARF is important in determining the prognosis of ARF in the elderly. Mortality risk factors are different in these 2 groups, and knowledge of their characteristics may allow better management of such patients.


Age estimation by ossification of thyroid cartilage of Japanese males using Bayesian analysis of postmortem CT images.
Many studies have reported that the degree of thyroid cartilage ossification correlates with age. However, its use in forensics has been limited by individual variation, tissue fragility, and observer subjectivity. We examined a new method for age estimation from the degree of ossification of thyroid cartilage using postmortem computed tomography (CT) and Bayesian analysis. The scoring of CT density values, ossification rate, and morphological changes was performed in 131 Japanese males (20-80years old), and an age estimation table was created and verified in 39 other Japanese males. We tried two types of prior probability; one was males undergoing postmortem CT imaging at our institute, and the other was the age composition of the male population in Japan. The differences in percentage in each age group were observed, especially in the ninth decade, but they were not large enough to change the result. Two decedents in their 30s and 80s could not be assigned an age group. Likelihood might have had more significant influence than prior probability. Bayesian approach and new scoring system of thyroid cartilage ossification might be useful as an age estimation method. Although the low posterior probability in decedents the age ≧70 remains a problem, the advantage of Bayesian estimation that it can sequentially update the age estimation table by factoring in exceptional data can solve this problem. In this study, accuracy of age estimation did not dramatically increase, however, Bayesian statistics might become a useful technique for examining any tissue samples subject to age-related calcification.


A prospective, longitudinal study to assess use of continuous and reactive low-pressure mattresses to reduce pressure ulcer incidence in a pediatric intensive care unit.
Pressure between bony prominences and sleep surfaces, as well as pressure from the use of medical devices, put children admitted to pediatric intensive care units (PICUs) at risk of developing pressure ulcers (PUs). To assess the effect of two pediatric-specific, continuous and reactive low-pressure mattresses on the incidence of PUs, an observational, descriptive, prospective, longitudinal (2009-2011) study was conducted among PICU patients. The two pediatric mattresses - one for children weighing between 500 g and 6 Kg and another for children weighing more than 6 Kg - were provided to patients at risk for PUs (Braden-Q ≤16, Neonatal Skin Risk Assessment Scale [NSRAS] ≤13, or per nurse assessment of clinical need). Between 2009 and 2011, 30 children (13 [43.3%] girls and 17 [56.7%] boys), ages 0 to 10 years, at risk of developing PUs (NSRAS risk: n = 14 [13.2 ± 3.03] and Braden-Q risk: n = 10 [10.4 ± 2.4]) were placed on the study mattresses for a median of 4 (range 1 to 25) days. Primary reasons for PICU admission included disorders of the respiratory system (40%), infectious and parasitic diseases (23.3%), and illnesses of the musculoskeletal system and connective tissue (10%). All other PU prevention strategies (eg, repositioning, specialty devices) used as part of standard care protocols also were implemented. Of the 30 participants, only one (3.3%) (confidence interval [CI] 95% = 0.08 -17.2%) developed a nondevice-related PU. No adverse events occurred. A 2008 incidence study in the same PICU, before use of these special surfaces, found a cumulative incidence of 20% nondevice-related PUs. The observed incidence rate of nonmedical device-related PUs in this high-risk population placed on these mattresses is encouraging and warrants future research.


Severe acute urticaria is associated with elevated plasma levels of D-dimer.
Evaluation of the disease severity of acute urticaria (AU) is essential for adequate treatment of patients. However, there are no reliable biomarkers for such an evaluation. In our department, we observed patients with severe AU having elevated plasma D-dimer levels. Thus, the objective of this study was to investigate the elevated D-dimer levels in patients with severe AU in more detail. One hundred and thirty-nine hospital patients diagnosed with severe AU were enrolled. Clinical laboratory data were collected from electronic medical records. One hundred and seventeen of the patients presented with elevated plasma D-dimer levels. Compared to the normal group, the elevated group had a significantly higher proportion of patients who were female, younger, febrile, and had a shorter prehospital time (P < 0.05). Univariate regression analysis showed that neutrophil percentage, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels increased as D-dimer levels increased, while prehospital time showed the opposite trend. Multiple regression analysis was used to estimate the simultaneous effects of CRP and LDH on D-dimer levels. Patients who responded to additional antibiotic treatment had higher levels of D-dimer. The group with highly elevated D-dimer levels required a higher maximum dose of daily glucocorticoids (GCs) to control the symptoms of AU. In conclusion, patients with severe AU might have elevated plasma D-dimer levels, which are positively correlated with CRP and LDH levels. Patients with severe AU with dramatically elevated D-dimer levels might need a higher dose of daily GCs and antibiotics to relieve symptoms. D-dimer may be a reasonable marker to evaluate the severity of AU and guide treatment.


A randomized controlled trial on the effect of blue-blocking glasses compared to partial blue-blockers on melatonin profile among nulliparous women in third trimester of the pregnancy.
In pregnancy melatonin regulates circadian rhythms, induce sleep, and has a neuroprotective positive effect on fetal development. Artificial blue light in the evening delays and suppresses melatonin production. Thus, we investigated the effect of blocking blue light on the melatonin profile. A randomized controlled trial (n=30 blue-blocking glasses vs. n=30 control glasses with partial blue-blocking effect) including healthy nulliparous pregnant women in the beginning of the third trimester. Salivary melatonin and subjective sleep were measured before and after two weeks of intervention/control condition. Saliva was sampled at 30-min intervals from 3 h before normal bedtime. Melatonin onset was set at 4.0 pg/ml. Due to missing data melatonin onset was estimated for 47 participants. At posttreatment, melatonin onset advanced by 28 min in the blue-blocking group compared with the control condition (p=.019). Melatonin levels were significantly higher, favoring the blue-blocking glass condition, at clock time 20:00, 21:00 and 22:00 h, and for sample number 3 and 4. The phase angle (time interval) between melatonin onset and sleep bedtime and sleep onset time increased within the blue blocking group (+45 min and +41 min, respectively), but did not reach statistical significance compared to control condition (+13 min and +26 min, respectively). Blocking blue light in the evening had a positive effect on the circadian system with an earlier onset and rise of melatonin levels in healthy nulliparous pregnant women. This demonstrated the effectiveness and feasibility of a simple non-pharmacological chronobiological intervention during pregnancy.


Structural basis of beta-adrenergic receptor subtype specificity studied with chimeric beta 1/beta 2-adrenergic receptors.
The beta 1- and beta 2-adrenergic receptors are two structurally related, but pharmacologically distinguishable, receptor subtypes, both of which activate adenylyl cyclase in a catecholamine-dependent manner through the guanine nucleotide-binding regulatory protein Gs. The receptors are approximately 50% identical in amino acid sequence and each is characterized by the presence of seven putative transmembrane domains. To elucidate the structural basis for the pharmacological distinctions between these two receptor subtypes, we constructed a series of chimeric beta 1/beta 2-adrenergic receptor genes and expressed them by injection of RNA into Xenopus laevis oocytes. The pharmacological properties of the expressed chimeric receptor proteins were assessed by radioligand binding and adenylyl cyclase assays utilizing subtype-selective agonists and antagonists. Our data indicate that transmembrane region IV is largely responsible for determining beta 1 vs. beta 2 properties with respect to agonist binding (relative affinities for epinephrine and norepinephrine). Transmembrane regions VI and VII play an important role in determining binding of beta 1 vs. beta 2 selective antagonists. However, a number of the other transmembrane regions also contribute, to a lesser extent, to the determination of beta-adrenergic receptor subtype specificity for agonists and antagonists. Thus, several of the membrane-spanning regions appear to be involved in the determination of receptor subtype specificity, presumably by formation of a ligand-binding pocket, with determinants for agonist and antagonist binding being distinguishable.


Synthesis of amorphous-MnO2/Clinoptilolite and its utilization for NH4+-N oxidation in an anoxic environment.
Mediating the anoxic ammonia oxidation with manganese oxide (MnOx) can reduce the requirements of dissolved oxygen (DO) concentrations in constructed wetlands (CWs) and improve the removal of ammonium nitrogen (NH4+-N). Recent studies that employed natural manganese ore and/or mine waste as substrates in CWs may develop potentially negative environmental effects due to leachates. However, removing NH4+-N by anoxic ammonia oxidation is influenced by the crystal form of MnOx. In this study, a novel clinoptilolite-based amorphous-MnO2 (amorphous-MnO2/clinoptilolite) was synthesized by the sol-gel method as an alternative substrate to improve the efficiency of anoxic ammonia oxidation and reduce the impact of Mn ion leaching. According to the anoxic ammonia oxidation experiment of clinoptilolite, amorphous-MnO2/clinoptilolite, and manganese ore on NH4+-N, the amounts of NH4+-N removed were 24.55 mg/L/d, 44.55 mg/L/d, and 11.04 mg/L/d, respectively, and the initial NH4+-N concentration was 49.53 mg/L. These results indicated that the amorphous-MnO2/clinoptilolite had both the adsorption and the anoxic ammonia oxidation performance. The recycling experiment demonstrated that the effect of anoxic ammonia oxygen mediated by amorphous-MnO2 would not diminish with the gradual saturation of clinoptilolite for NH4+-N. Furthermore, the anoxic ammonia oxidation consumed NH4+-N in the clinoptilolite, which restored the adsorption capacity of the clinoptilolite and simultaneously decreased the leakage of manganese ions in the process, making it environmentally friendly. Therefore, the amorphous-MnO2/clinoptilolite provided an excellent substrate material for the constructed wetland under an anoxic environment, which greatly improved the nitrogen removal capacity compared to existing substrate materials.


Microbial diversity of ticks and a novel typhus group Rickettsia species (Rickettsiales bacterium Ac37b) in Inner Mongolia, China.
Ticks can carry multiple pathogens, and Inner Mongolia's animal husbandry provides excellent environmental conditions for ticks. This study characterized the microbiome of ticks from different geographical locations in Inner Mongolia; 905 Dermacentor nuttalli and 36 Ixodes persulcatus were collected from sheep in three main pasture areas and from bushes within the forested area. Mixed DNA samples were prepared from three specimens from each region and tick species. Microbial diversity was analyzed by 16S rRNA sequencing, and α and β diversity were determined. The predominant bacterial genera were Rickettsia (54.60%), including Rickettsiales bacterium Ac37b (19.33%) and other Rickettsia (35.27%), Arsenophonus (11.21%), Candidatus Lariskella (10.84%), and Acinetobacter (7.17%). Rickettsia bellii was identified in I. persulcatus, while Rickettsiales bacterium Ac37b was found in D. nuttalli from Ordos and Chifeng. Potential Rickettsia and Anaplasma coinfections were observed in the Ordos region. Tick microbial diversity analysis in Inner Mongolia suggests that sheep at the sampling sites were exposed to multiple pathogens.


Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection.
SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.


Single-Port Robotic Radical Prostatectomy Using Transvesical and Transperineal Access in Patients with a Hostile Abdomen.
Introduction Prostate cancer diagnosis and treatment is challenging in surgically complex patients. Radical prostatectomy can be performed without peritoneal entry using novel single port (SP) transperineal (TP) and transvesical (TV) approaches. We sought to examine the outcomes of radical prostatectomy using novel TP and TV approaches in patients with extensive prior abdominal surgeries. Materials and Methods From 2019 to 2023, 51 patients with extensive prior abdominal surgeries were identified who underwent TP (18) and SP TV (33) robotic radical prostatectomy. Indications included history of various surgeries with open laparotomy including J-pouch reconstruction (22, 43%), active stoma (14, 27%), and open bowel resection (9, 18%). In all patients, 12/51 (24%) had a history of incisional hernia repair with mesh. A retrospective analysis was performed. Results All cases were completed without open conversion, bowel injuries, or blood transfusions. Length of stay was 5.6 hours for TV and 22 hours for TP. No opioids were prescribed in 91% of TV versus 56% of TP. One intraoperative complication (ureteral injury) occurred in a patient undergoing the TP approach. Postoperative complications were noted in 14/51 (27%), including 10/18 (56%) TP versus 4/33 (12%) TV. High grade complications (Clavien 3) occurred in 3 patients (6%, all TP). Pathologic staging showed pT3 in 26/51 (17 TV vs 9 TP), while the remainder were pT2. Biochemical recurrences were noted in 4 patients (8%, 3 TV and 1 TP). Immediate continence was noted in 30% of TV patients. Long-term continence after 12 months was 92% in TV and 67% in TP. Conclusions In patients with extensive prior abdominal surgeries, radical prostatectomy is feasible using a TP or TV approach. No bowel injuries or open conversion were observed. The SP TV approach offers advantages of shorter hospital stay, shorter catheter duration, less opioid use, fewer complications, and improved continence recovery.


Neuroprotective and anti-inflammatory activity of DAT inhibitor R-phenylpiracetam in experimental models of inflammation in male mice.
R-phenylpiracetam (R-PhP, (4R)-2-(4-phenyl-2-oxopyrrolidin-1-yl)acetamide) is an optical isomer of phenotropil, a clinically-used nootropic drug that improves physical condition and cognition. Recently, R-PhP was shown to bind to the dopamine transporter (DAT). Since growing evidence suggests that dysfunction of the dopaminergic system is associated with persistent neuroinflammation, the aim of this study was to determine whether R-PhP, an inhibitor of DAT, has neuroprotective and anti-inflammatory effects in male mice. The pharmacokinetic profiles of R-PhP in mouse plasma and its bioavailability in brain tissue were assessed. To study possible molecular mechanisms involved in the anti-inflammatory activity of R-PhP, target profiling was performed using radioligand binding and enzymatic activity assays. To clarify the neuroprotective and anti-inflammatory effects of R-PhP, we used a lipopolysaccharide (LPS)-induced endotoxaemia model characterized by reduced body temperature and overexpression of inflammatory genes in the brain. In addition, the antinociceptive and anti-inflammatory effects of R-PhP were tested using carrageenan-induced paw oedema and formalin-induced paw-licking tests. R-PhP (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (ip) and peroral (po) injections. The maximal concentration of R-PhP in the brain tissues was 28 µg/g and 18 µg/g tissue after ip and po administration, respectively. In radioligand binding assays, DAT was the only significant molecular target found for R-PhP. A single ip injection of R-PhP significantly attenuated the LPS-induced body temperature reduction and the overexpression of inflammatory genes, such as tumour necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β) and inducible nitric oxide synthase (iNOS). Seven-day po pretreatment with R-PhP dose-dependently reduced paw oedema and the antinociceptive response, as shown by the carrageenan-induced paw oedema test. In addition, R-PhP decreased the nociceptive response during the inflammatory phase in the formalin-induced paw-licking test. Our study showed that R-PhP possesses neuroprotective and anti-inflammatory effects, demonstrating the potential of DAT inhibitors as effective therapeutics.


Surgical management and outcome of dogs with primary spontaneous pneumothorax: 110 cases (2009-2019).
To describe surgical management and associated outcomes for dogs with primary spontaneous pneumothorax. 110 client-owned dogs with primary spontaneous pneumothorax that underwent surgical management. Medical records at 7 veterinary teaching hospitals were reviewed. Data collected included signalment, history, clinical signs, radiographic and CT findings, surgical methods, intraoperative and postoperative complications, outcomes, and histopathologic findings. Follow-up information was obtained by contacting the referring veterinarian or owner. 110 dogs were included, with a median follow-up time of 508 days (range, 3 to 2,377 days). Ninety-nine (90%) dogs underwent median sternotomy, 9 (8%) underwent intercostal thoracotomy, and 2 (2%) underwent thoracoscopy as the sole intervention. Bullous lesions were most commonly found in the left cranial lung lobe (51/156 [33%] lesions) and right cranial lung lobe (37/156 [24%] lesions). Of the 100 dogs followed up for > 30 days, 13 (13%) had a recurrence of pneumothorax, with median time between surgery and recurrence of 9 days. Recurrence was significantly more likely to occur ≤ 30 days after surgery, compared with > 30 days after surgery. Recurrence > 30 days after surgery was rare (3 [3%]). No risk factors for recurrence were identified. Lung lobectomy via median sternotomy resulted in resolution of pneumothorax in most dogs with primary spontaneous pneumothorax. Recurrence of pneumothorax was most common in the immediate postoperative period, which may have reflected failure to identify lesions during the initial thoracic exploration, rather than development of additional bullae.


Neurotensin releases norepinephrine differentially from perfused hypothalamus of sated and fasted rat.
The central injection of neurotensin (NT) has been reported to attenuate the intake of food in the fasted animal. To determine whether endogenous norepinephrine (NE) is involved in the satiating effect of NT, the in vivo activity of NE in circumscribed sites in the hypothalamus of the unanesthetized rat was examined. Bilateral guide tubes for push-pull perfusion were implanted stereotaxically to rest permanently above one of several intended sites of perfusion, which included the paraventricular nucleus (PVN), ventromedial nucleus (VMN), and the lateral hypothalamic (LH) area. After endogenous stores of NE at a specific hypothalamic locus were radiolabeled by microinjection of 0.02-0.5 mu Ci of [3H]NE, an artificial cerebrospinal fluid was perfused at the site at a rate of 20 microliter/min over successive intervals of 5.0 min. When 0.05 or 0.1 micrograms/microliter NT (0.03-0.6 mM) was added to the perfusate, the peptide served either to enhance or reduce the local release of NE at 50% of the sites of perfusion. In these experiments, the circumscribed effect of NT on the characteristics of catecholamine efflux depended entirely on the state of hunger or satiety of the rat. That is, when NT was perfused in the fully satiated rat, NE release was augmented within the PVN or VMN; conversely, NE release was inhibited in the LH. In the animal fasted for 18-22 h, NT exerted an opposite effect on the activity of NE within the same anatomical loci in that the efflux of NE was enhanced in the LH but attenuated or unaffected in the PVN or VMN.(ABSTRACT TRUNCATED AT 250 WORDS)


A circadian clock entrained by melatonin is ticking in the rat fetal adrenal.
The adrenal gland in the adult is a peripheral circadian clock involved in the coordination of energy intake and expenditure, required for adaptation to the external environment. During fetal life, a peripheral circadian clock is present in the nonhuman primate adrenal gland. Whether this extends to the fetal adrenal gland like the rat is unknown. Here we explored in vivo and in vitro whether the rat fetal adrenal is a peripheral circadian clock entrained by melatonin. We measured the 24-h changes in adrenal content of corticosterone and in the expression of clock genes Per-2 and Bmal-1 and of steroidogenic acute regulatory protein (StAR), Mt1 melatonin receptor, and early growth response protein 1 (Egr-1) expression. In culture, we explored whether oscillatory expression of these genes persisted during 48 h and the effect of a 4-h melatonin pulse on their expression. In vivo, the rat fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 in antiphase (acrophases at 2200 and 1300 h, respectively) as well as of Mt1 and Egr-1. This was accompanied by circadian rhythms of corticosterone content and of StAR expression both peaking at 0600 h. The 24-h oscillatory expression of Bmal-1, Per-2, StAR, Mt1, and Egr-1 persisted during 48 h in culture; however, the antiphase between Per-2 and Bmal-1 was lost. The pulse of melatonin shifted the acrophases of all the genes studied and restored the antiphase between Per-2 and Bmal-1. Thus, in the rat, the fetal adrenal is a strong peripheral clock potentially amenable to regulation by maternal melatonin.


Anti-HBs antibody status and some of its associated factors in dental health care workers in Tehran University of Medical Sciences: Anti-HBs Ab and associated factors in dental society.
Dental health care providers are at risk of infection with hepatitis B virus (HBV). Dentists can occupationally become infected with HBV through needle sticks or exposure to blood and other body fluids. To evaluate anti-HBs antibody titer in students, professors, clinical assistants and non-clinical staff of Faculty of Dentistry, Tehran University of Medical Sciences (TUMS), and to investigate the probable correlation between the level of immunity and a number of associated factors. 230 participants who had a history of previous HBV vaccination (receiving at least two doses of HBV vaccine) and a negative history of being infected with HBV were studied. Participants' data were recorded using a checklist, and the level of antibody was measured by enzyme-linked immunosorbent assay (ELISA). While there existed statistically significant correlations between age, occupation, smoking, complete and scheduled vaccination and time of the last vaccination with the level of anti-HBs antibody, the correlation between gender and level of the antibody was not significant. Multiple regression analysis revealed significant association between immune response and age and time of the last vaccination. Due to the significant correlation between younger age and anti-HBs antibody titer in our study, it makes sense to establish a mandatory complete and scheduled vaccination program for all members of dental society younger than 40 years.


[The value of indirect microlaryngo-stroboscopy in the follow-up care of patients with vocal cord carcinoma treated with primary irradiation].
On the value of indirect Microlaryngo-stroboscopy in the follow-up of patients with vocal cord tumors having had primary radiotherapy: The technique of stroboscopy is explained, its weight in the evaluation of vocal cords vibration is discussed. Arrest of vibration may be a hint for a malignoma, particularly if this state develops again after radiotherapy.


Impact of gene patents and licensing practices on access to genetic testing for Alzheimer disease.
Genetic testing for Alzheimer disease includes genotyping for apolipoprotein E, for late-onset Alzheimer disease, and three rare autosomal dominant, early-onset forms of Alzheimer disease associated with different genes (APP, PSEN1, and PSEN2). According to researchers, patents have not impeded research in the field, nor were patents an important consideration in the quest for the genetic risk factors. Athena Diagnostics holds exclusive licenses from Duke University for three "method" patents covering apolipoprotein E genetic testing. Athena offers tests for apolipoprotein E and genes associated with early-onset, autosomal-dominant Alzheimer disease. One of those presenilin genes is patented and exclusively licensed to Athena; the other presenilin gene was patented but the patent was allowed to lapse; and one (amyloid precursor protein) is patented as a research tool. Direct-to-consumer testing is available for some Alzheimer disease-related genes, apparently without a license. Athena Diagnostics consolidated its position in the market for Alzheimer disease genetic testing by collecting exclusive rights to patents arising from university research. Duke University also used its licenses to Athena to enforce adherence to clinical guidelines, including elimination of the service from Smart Genetics, which was offering direct-to-consumer risk assessment based on apolipoprotein E genotyping.


Analysis of context-dependent errors for illumina sequencing.
The new generation of short-read sequencing technologies requires reliable measures of data quality. Such measures are especially important for variant calling. However, in the particular case of SNP calling, a great number of false-positive SNPs may be obtained. One needs to distinguish putative SNPs from sequencing or other errors. We found that not only the probability of sequencing errors (i.e. the quality value) is important to distinguish an FP-SNP but also the conditional probability of "correcting" this error (the "second best call" probability, conditional on that of the first call). Surprisingly, around 80% of mismatches can be "corrected" with this second call. Another way to reduce the rate of FP-SNPs is to retrieve DNA motifs that seem to be prone to sequencing errors, and to attach a corresponding conditional quality value to these motifs. We have developed several measures to distinguish between sequence errors and candidate SNPs, based on a base call's nucleotide context and its mismatch type. In addition, we suggested a simple method to correct the majority of mismatches, based on conditional probability of their "second" best intensity call. We attach a corresponding second call confidence (quality value) of being corrected to each mismatch.


Influence of different methods of collection from the canine epididymides on post-thaw caudal epididymal sperm quality.
Canine epididymal sperm was collected from the cauda epididymis using 2 different methods (flushing and mincing) to compare the qualities (the percentage of progressively motile, viable, morphologically abnormal, immature and intact acrosomes) before and after freezing and thawing. No significant difference was noted in the quality of the cauda epididymal sperm immediately after collection and after freezing-thawing between the collection methods, although the mean levels of sperm quality with the flushing method were slightly better than that of the mincing method. The flushing method is simple and free of blood contamination, although the vas deferens was too small to be perfused in only 1 dog, and our results suggest that the flushing method is preferable to the mincing method for collecting sperm from the canine cauda epididymis.


Assessment of Oral Albendazole and Fumagillin in the Treatment of Pseudoloma neurophilia in Adult Zebrafish.
Pseudoloma neurophilia ( Pn ), the causative agent of the most commonly reported disease of zebrafish, is a microsporidian parasite that confounds research by inducing behavioral and physiologic changes in zebrafish. Although a treatment for P. neurophilia has not been documented in zebrafish, albendazole (ALB) and fumagillin (FUM) have been used to treat microsporidian infections of other fish species. To investigate the efficacy of oral ALB and FUM in the treatment of Pn, we performed a pilot study that demonstrated the safety and palatability of novel gel-based diets containing FUM or ALB in adult AB zebrafish. In a subsequent study, approximately 250 adult AB zebrafish (previously infected with Pn ) were treated with these medicated diets for 4 wk. At 4 different time points (weeks 0, 5, 10, and 16 of the study), fish were euthanized and whole-body qPCR was performed to assess Pn prevalence across treatment and control groups. There was no statistically significant association between treatment group and Pn prevalence at any time point, although potential biologically relevant reductions in Pn prevalence occurred in the combination therapy group at weeks 5 and 16 and in the ALB group at week 5. Based on high-performance liquid chromatography analyses, the medicated diets contained less ALB and more FUM than expected, highlighting the importance of validating medicated feed concentrations to ensure safety, efficacy, and consistency. While Pn remains challenging to eradicate and control, results of this study warrant further investigation into the utility of ALB and FUM as potential treatments for this pathogen.


Graded alpha1-adrenoceptor activation of arteries involves recruitment of smooth muscle cells to produce 'all or none' Ca(2+) signals.
Confocal laser scanning microscopy and Fluo-4 were used to visualize Ca(2+) transients within individual smooth muscle cells (SMC) of rat resistance arteries during alpha(1)-adrenoceptor activation. The typical spatio-temporal pattern of [Ca(2+)] in an artery after exposure to a maximally effective concentration of phenylephrine (PE, 10.0 microM) was a large, brief, relatively homogeneous Ca(2+) transient, followed by Ca(2+) waves, which then declined in frequency over the course of 5 min and which were asynchronous in different SMC. Concentration-Effect (CE) curves relating the concentration of PE (range: 0.1 microM to 10.0 microM) to the effects (fraction of cells producing at least one Ca(2+) wave, and number of Ca(2+) waves during 5 min) had EC(50) values of approximately 0.5 microM and approximately 1.0 microM respectively. The initial Ca(2+) transient and the subsequent Ca(2+) waves were abolished in the presence of caffeine (10.0 mM). A repeated exposure to PE, 1.5 min after the first had ended, elicited fewer Ca(2+) waves in fewer cells than did the initial exposure. Caffeine-sensitive Ca(2+) stores were not depleted at this time, however, as caffeine alone was capable of inducing a large release of Ca(2+)1.5 min after PE. In summary, the mechanism of a graded response to graded alpha(1)-adrenoceptor activation is the progressive 'recruitment' of individual SMC, which then respond in 'all or none' fashion (viz. asynchronous Ca(2+) waves). Ca(2+) signaling continues in the arterial wall throughout the time-course (at least 5 min) of activation of alpha(1)-adrenoceptors. The fact that the Ca(2+) waves are asynchronous accounts for the previously reported fall in 'arterial wall [Ca(2+)]' (i.e. spatial average [Ca(2+)] over all cells).


Spontaneous Object Exploration in a Recessive Gene Knockout Model of Parkinson's Disease: Development and Progression of Object Recognition Memory Deficits in Male Pink1-/- Rats.
Cognitive impairments appear at or before motor signs in about one third of patients with Parkinson's disease (PD) and have a cumulative prevalence of roughly 80% overall. These deficits exact an unrelenting toll on patients' quality and activities of daily life due in part to a lack of available treatments to ameliorate them. This study used three well-validated novel object recognition-based paradigms to explore the suitability of rats with knockout of the PTEN-induced putative kinase1 gene (Pink1) for investigating factors that induce cognitive decline in PD and for testing new ways to mitigate them. Longitudinal testing of rats from 3-9 months of age revealed significant impairments in male Pink1-/- rats compared to wild type controls in Novel Object Recognition, Novel Object Location and Object-in-Place tasks. Task-specific differences in the progression of object discrimination/memory deficits across age were also seen. Finally, testing using an elevated plus maze, a tapered balance beam and a grip strength gauge showed that in all cases recognition memory deficits preceded potentially confounding impacts of gene knockout on affect or motor function. Taken together, these findings suggest that knockout of the Pink1 gene negatively impacts the brain circuits and/or neurochemical systems that support performance in object recognition tasks. Further investigations using Pink1-/- rats and object recognition memory tasks should provide new insights into the neural underpinnings of the visual recognition memory and visuospatial information processing deficits that are often seen in PD patients and accelerate the pace of discovery of better ways to treat them.


Contrasting genomic patterns and infection strategies of two co-existing Bacteroidetes podovirus genera.
Bacterial viruses (phages) are abundant, ecologically important biological entities. However, our understanding of their impact is limited by model systems that are primarily not well represented in nature, e.g. Enterophages and their hosts. Here, we investigate genomic characteristics and infection strategies among six aquatic Bacteroidetes phages that represent two genera of exceptionally large (∼70-75 kb genome) podoviruses, which were isolated from the same seawater sample using Cellulophaga baltica as host. Quantitative host range studies reveal that these genera have contrasting narrow (specialist) and broad (generalist) host ranges, with one-step growth curves revealing reduced burst sizes for the generalist phages. Genomic comparisons suggest candidate genes in each genus that might explain this host range variation, as well as provide hypotheses about receptors in the hosts. One generalist phage, φ38:1, was more deeply characterized, as its infection strategy switched from lytic on its original host to either inefficient lytic or lysogenic on an alternative host. If lysogenic, this phage was maintained extrachromosomally in the alternative host and could not be induced by mitomycin C. This work provides fundamental knowledge regarding phage-host ranges and their genomic drivers while also exploring the 'host environment' as a driver for switching phage replication mode.


Preliminary Clinical, Radiographic, and Patient-Reported Outcomes of the Medial Femoral Trochlea Osteochondral Free Flap for Lunate Reconstruction in Advanced Kienböck Disease.
We aimed to describe the radiographic, functional, and patient-reported outcomes (PROs) of medial femoral trochlea osteochondral free flap reconstruction of the proximal lunate in stage IIIA and IIIB Kienböck disease. Eighteen adult patients underwent medial femoral trochlea reconstruction of the proximal lunate for advanced Kienböck disease by a single surgeon. Eight of these patients returned for clinical examination, radiographs, and completion of PRO questionnaires. An additional 4 patients completed PRO questionnaires remotely. The mean patient age was 28.4 years. The mean radiographic and physical examination follow-up was 1.4 and 2.2 years, respectively. The mean PRO follow-up was 2.1 years. Radiographic measurements (carpal height ratio, radioscaphoid angle) demonstrated that carpal collapse was halted, and carpal alignment was maintained, after surgery. Wrist flexion (38.3°) and extension (37.3°) were unchanged by this operation, and postoperative pinch and grip strength were 90% and 68% of the uninjured side, respectively. The mean postoperative Disabilities of the Arm, Shoulder, and Hand score was 10.8, and the Patient-Rated Wrist Evaluation score was 18.1. Knee Injury and Osteoarthritis Outcomes Score subscales, International Knee Documentation Committee, and Kujala lower extremity PRO scores ranged from 83.1 to 96.8. The Patient-Reported Outcomes Measurement Information System Global Health, Physical Function, Pain Intensity, Pain Interference, and Pain Behavior scores reflected good postoperative patient health and function and low pain levels. Following medial femoral trochlea reconstruction of the proximal lunate for advanced Kienböck disease, we observed a cessation of radiocarpal collapse. After surgery, patients demonstrated acceptable levels of function, pain, and wrist range of motion. Therapeutic V.


Effect of proparacaine on tropicamide-induced mydriasis.
The use of a topical anesthetic before the instillation of a mydriatic is recommended in order to enhance both the rate and magnitude of pupillary dilation. However, there is a paucity of data supporting the prior use of topical anesthetics with tropicamide, the most commonly used mydriatic agent in optometric practice. Therefore, we conducted a study to determine the clinical effect of proparacaine on tropicamide-induced pupillary dilation. We investigated the effects of prior instillation of 0.5% proparacaine (Ophthetic) on pupillary dilation with 0.5% tropicamide (Mydriacyl) using a double-blind, placebo-controlled protocol on two groups of young adult subjects. Thirty subjects, aged between 18 and 30 years, were divided into 2 groups of 15, based on whether they had light- or dark-colored irides. The pupils of both eyes of each subject were dilated with tropicamide, but only one eye, chosen at random, received proparacaine (experimental condition), whereas the other was administered a saline placebo (control condition). Pupil diameter was measured using a ruler and magnifying loupe. Subjects with light-colored irides had a greater average pupil dilation than subjects with dark-colored irides. There was a small, statistically significant difference in pupil diameter between the control and experimental conditions, but only for subjects with light-colored irides. The rate of pupillary dilation to peak pupil diameter and the rate of decrease in pupil diameter after peak pupil diameter was reached did not differ between experimental conditions or subject groups. Although prior instillation of topical proparacaine produced a statistically significant difference in pupil diameter for subjects with light-colored irides, the result was not clinically significant. Therefore, we do not recommend the use of a topical anesthetic before tropicamide-induced mydriasis for young adult patients.


Protective effect of tretinoin derivative and TXNRD1 protein on streptozotocin induced gestational diabetes via an age-rage signaling-pathway.
In the present study effect of tretinoin derivative was investigated on the pathogenesis of gestational diabetes mellitus (GDM) in mice model in vivo. Diabetes was induced in mice by injecting Streptozotocin (STZ) for 5consecutive days at a dose of 65 mg/kg body weight through the intraperitoneal route. Tretinoin derivative was given to the mice at 0.12 and 0.25 mg/kg doses through gavage in normal saline alternately for one week after STZ injection. The results demonstrated that tretinoin derivative administration to the diabetic mice significantly (P<0.05) alleviated the blood FBG and FINS levels. Administration of tretinoin derivative to the diabetic mice significantly (P<0.05) promoted the blood HDL level and alleviated TC and TG levels. The administration of tretinoin derivative to the diabetic mice significantly (P<0.05) alleviated the CRP, IL-6and TNF-α production in pancreatic tissues. Tretinoin derivative administration to the diabetic mice significantly (P<0.05) elevated the SOD activity, and CAT level and lowered the MDA level in pancreatic tissues. The TXNRD1 expression in diabetic mice was comparable to that in the normal group after administration of tretinoin derivativeat the dose of 0.25 mg/kg dose. In silico data demonstrated that tretinoin derivativeinteracts with TXNRD1 protein with the binding affinity ranging from -10 to 9.4 kcal/ mol. In conclusion, tretinoin derivative administration effectively regulated streptozotocin-induced changes in fasting blood glucose, insulin level, high-density lipid level and triglyceride level in diabetic mice in vivo. The streptozotocin-induced excessive production of C-reactive protein and inflammatory cytokines was also down-regulated in diabetic mice on administration of tretinoin derivative. Therefore, tretinoin derivative can be investigated further as a therapeutic agent for the treatment of gestational diabetes mellitus.


Are Farmers Willing to Substitute Tobacco Cultivation? Evidence From Lichuan City, China.
Tobacco crop substitution is a critical element in implementing comprehensive tobacco control policies. Understanding tobacco farmers' willingness or preferences is imperative to implement policies on tobacco crop substitution. This article assesses tobacco farmers' individual willingness to substitute tobacco cultivation and investigates the factors that influence their willingness in Lichuan City, China. We conducted a face-to-face survey with 280 tobacco farmers in Lichuan City of China to assess their willingness to substitute tobacco cultivation. The binary probit model was used to examine the factors influencing farmers' willingness to substitute tobacco growing. The results show that fewer than one in five tobacco farmers are willing to substitute tobacco growing with other crops. The main reason for their unwillingness is that they thought the comparative income of growing tobacco was higher and more stable. The regression results show that tobacco farmers with higher education levels and more knowledge of tobacco crop substitution are more willing to take up tobacco crop substitution. Tobacco farmers' household income decreased the likelihood of their willingness to replace tobacco cultivation. Farmers who perceived the economic benefits and health benefits of tobacco crop substitution are more likely to substitute tobacco cultivation with other crops. Farmers' willingness to substitute tobacco cultivation is low. Policy interventions are needed to increase farmers' willingness to stop growing tobacco and to replace it with other alternative crops. Few studies have investigated local farmers' willingness to substitute tobacco cultivation in China. We found most tobacco farmers in the Lichuan City of China are unwilling to substitute tobacco growing with other crops. Farmers' low support of tobacco crop substitution is associated with economic factors. Better education and more knowledge of tobacco crop substitution can increase farmers' willingness to substitute tobacco cultivation.


Racial disparities in outcomes of adult heart transplantation.
This study evaluated whether minority orthotopic heart transplant (OHT) recipients tend to be transplanted at worse performing centers. OHT recipients between 2000 and 2010 were identified in the United Network for Organ Sharing database and stratified by race. Center performance was evaluated using observed-to-expected mortality ratios that were calculated using validated indexes for recipient and donor risk in OHT. The primary outcome was 1-year post-OHT mortality. A total of 102 centers performed OHT in 18 085 patients. Blacks had higher unadjusted 1-year mortality, which was confirmed after risk adjustment. Blacks had increased risk-adjusted mortality at poor performing centers (observed-to-expected mortality ratio, >1.2; odds ratio, 1.37 [95% confidence interval, 1.12-1.69]; P=0.002) and a strong trend toward increased mortality at excellent performing centers (observed-to-expected mortality ratio, <0.8; odds ratio, 1.42 [95% confidence interval, 0.99-2.02]; P=0.06). A higher proportion of blacks were treated at centers with higher-than-expected mortality (56.4% versus 47.1% whites versus 48.1% Hispanics; P<0.001), a finding that persisted after adjusting for insurance type and highest education level. In addition, there was a positive correlation between the percentage of blacks and observed-to-expected mortality ratios at the center level (r=0.32; P=0.001). In multivariable analysis incorporating immunologic and socioeconomic variables, there was no clear dominant source for the disparities in outcomes of OHT between races. Blacks have a propensity to be transplanted at worse performing centers; however, center effect alone does not explain the mortality difference between ethnicities. Although referral of minorities to better performing centers would improve absolute survival, it would not likely eliminate the racial disparities that exist in OHT outcomes.


What frail, older patients talk about when they talk about self-care-a qualitative study in heart failure care.
Self-care plays a crucial role in the management of heart failure (HF) and is especially important for older patients who are frail. However, there is limited knowledge about how frail, older patients with HF perceive and experience self-care. Therefore, the aim of this study was to describe the experiences of self-care among frail, older patients with HF. A qualitative descriptive design with semi-structured interviews with frail, older patients diagnosed with HF (n = 19; median age 82 years). Thematic analysis, guided by Braun and Clarke, was used to analyse the data. Two main themes emerged from the analysis: 1) "To maintain my health," encompassing various aspects such as hygiene practices, engaging in physical activity, medication adherence, following a healthy diet, and ensuring adequate rest; and 2) "To maintain my well-being and happiness," highlighting the importance of hobbies, maintaining independence, participating in social activities, and creating a supportive environment. This study provides valuable insights into the perspectives of frail, older patients with HF regarding self-care. It was observed that older patients often associate self-care with general well-being, hygiene, and happiness. Clear communication between healthcare providers and patients is essential to align different perspectives on self-care and ensure that self-care plans are tailored to individual needs. Moreover, addressing the emotional well-being and happiness of patients should be prioritized, as these factors play a significant role in promoting self-care adherence.


Cardiac rehabilitation following myocardial infarction.
This article provides an overview of current recommendations regarding cardiac rehabilitation (CR) after myocardial infarction and its clinical application. Evidence shows that exercise- based CR after cardiac events positively affects the extent of disability and level of quality of life, and has also important beneficial role in modifying morbidity and mortality. Cardiac rehabilitation is an integral component of the care for patients who have undergone acute myocardial infarction, after invasive coronary procedures and those with chronic stable angina. Although in the last four decades physical training has assumed a major role in health care of coronary artery disease patients, cardiac rehabilitation does not consist exclusively of regular exercising. Comprehensive cardiac rehabilitation should include the following components: clinical evaluation, optimization of pharmacotherapy, physical training, psychological rehabilitation, evaluation and reduction of coronary disease risk factors, life style modification, and patient education. Comprehensive cardiac rehabilitation should be addressed by the designated team (physician, physiotherapist, nurse, psychologist, dietician, social worker) immediately after acute phase of myocardial infarction and should contain individualized programs designed to optimize physical, psychological, social and emotional status. Modern model of comprehensive cardiac rehabilitation should be initiated as early as possible, continued for required time, properly staged, and individualized depending on clinical status of the patients.


Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells.
Expression of molecules involved in lipid homeostasis such as the low density lipoprotein receptor (LDLr) on antigen presenting cells (APCs) has been shown to enhance invariant natural killer T (iNKT) cell function. However, the contribution to iNKT cell activation by other lipoprotein receptors with shared structural and ligand binding properties to the LDLr has not been described. In this study, we investigated whether a structurally related receptor to the LDLr, known as LDL receptor-related protein (LRP), plays a role in iNKT cell activation. We found that, unlike the LDLr which is highly expressed on all immune cells, the LRP was preferentially expressed at high levels on F4/80+ macrophages (MΦ). We also show that CD169+ MΦs, known to present antigen to iNKT cells, exhibited increased expression of LRP compared to CD169- MΦs. To test the contribution of MΦ LRP to iNKT cell activation we used a mouse model of MΦ LRP conditional knockout (LRP-cKO). LRP-cKO MΦs pulsed with glycolipid alpha-galactosylceramide (αGC) elicited normal IL-2 secretion by iNKT hybridoma and in vivo challenge of LRP-cKO mice led to normal IFN-γ, but blunted IL-4 response in both serum and intracellular expression by iNKT cells. Flow cytometric analyses show similar levels of MHC class-I like molecule CD1d on LRP-cKO MΦs and normal glycolipid uptake. Survey of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages and no homeostatic disruption as evidenced by the absence of programmed death-1 and Ly-49 surface receptors. Mixed bone marrow chimeras showed that the inability iNKT cells to make IL-4 is cell extrinsic and can be rescued in the presence of wild type APCs. Collectively, these data demonstrate that, although MΦ LRP may not be necessary for IFN-γ responses, it can contribute to iNKT cell activation by enhancing early IL-4 secretion.


Item-specific processing reduces false memories.
We examined the effect of item-specific and relational encoding instructions on false recognition in two experiments in which the DRM paradigm was used (Deese, 1959; Roediger & McDermott, 1995). Type of encoding (item-specific or relational) was manipulated between subjects in Experiment 1 and within subjects in Experiment 2. Decision-based explanations (e.g., the distinctiveness heuristic) predict reductions in false recognition in between-subjects designs, but not in within-subjects designs, because they are conceptualized as global shifts in decision criteria. Memory-based explanations predict reductions in false recognition in both designs, resulting from enhanced recollection of item-specific details. False recognition was reduced following item-specific encoding instructions in both experiments, favoring a memory-based explanation. These results suggest that providing unique cues for the retrieval of individual studied items results in enhanced discrimination between those studied items and critical lures. Conversely, enhancing the similarity of studied items results in poor discrimination among items within a particular list theme. These results are discussed in terms of the item-specific/ relational framework (Hunt & McDaniel, 1993).


Density functional theory study of the structure and vibrational modes of acrylonitrile adsorbed on Cu(100).
We present a theoretical study of the structure and vibrations of acrylonitrile adsorbed on a Cu(100) metal surface. Simulations have been carried out by means of the density functional theory adopting periodic boundary conditions and including van der Waals dispersion forces. The two most stable structures (which are almost degenerate in energy) correspond to the molecule adsorbed parallel to the metal surface. In both geometries, the vinyl (C=C) and the cyano (C≡N) groups are the anchorage sites to the surface atoms. Low energy transition barriers allow fast isomerization between both structures. Molecular adsorption shifts some of their vibrational frequencies with respect to the gas phase, mainly the C=C and the C≡N stretching modes, in agreement with recent experimental measurements [Tornero et al., Phys. Chem. Chem. Phys., 2011, 13, 8475].


Internal mammary perforators: a cadaver study.
Microsurgeons currently employ the internal mammary artery and vein as recipient vessels for microvascular reconstruction of the breast with increasing frequency. Recent reports have demonstrated that the perforating branches of the internal mammary artery and vein can also be used as recipient vessels. The purpose of the following cadaver study was to determine the location and diameter of these internal mammary perforators and whether they are suitable as recipient vessels. Ten fresh cadavers were obtained for this project. Using a micrometer under loupe magnification, bilateral measurements were taken of the perforators from the first five interspaces. The largest arterial perforator averaged 1.74 mm in diameter and the largest venous perforator averaged 1.78 mm in diameter. The largest perforators were most commonly found in the second interspace. Based on the results of this study, the internal mammary perforators appear to have suitable diameter for microvascular anastomosis and should be considered.


FETR-ALS Study Protocol: A Randomized Clinical Trial of Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis.
Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.


Evolutionary consequences of genomic deletions and insertions in the woolly mammoth genome.
Woolly mammoths had a set of adaptations that enabled them to thrive in the Arctic environment. Many mammoth-specific single nucleotide polymorphisms (SNPs) responsible for unique mammoth traits have been previously identified from ancient genomes. However, a multitude of other genetic variants likely contributed to woolly mammoth evolution. In this study, we sequenced two woolly mammoth genomes and combined these with previously sequenced mammoth and elephant genomes to conduct a survey of mammoth-specific deletions and indels. We find that deletions are highly enriched in non-coding regions, suggesting selection against structural variants that affect protein sequences. Nonetheless, at least 87 woolly mammoth genes contain deletions or indels that modify the coding sequence, including genes involved in skeletal morphology and hair growth. These results suggest that deletions and indels contributed to the unique phenotypic adaptations of the woolly mammoth, and were potentially critical to surviving in its natural environment.


The relationship between a chief complaint of "altered mental status" and delirium in older emergency department patients.
Altered mental status is a common chief complaint among older emergency department (ED) patients. Patients with this chief complaint are likely delirious, but to the authors' knowledge, this relationship has not been well characterized. Additionally, health care providers frequently ascribe "altered mental status" to other causes, such as dementia, psychosis, or depression. The objective was to determine the relationship between altered mental status as a chief complaint and delirium. This was a secondary analysis of a cross-sectional study designed to validate three brief delirium assessments, conducted from July 2009 to March 2012. English-speaking patients who were 65 years or older and in the ED for <12 hours were included. Patients who were comatose or nonverbal or unable to follow simple commands prior to the acute illness were excluded. Chief complaints were obtained from the ED nurse triage assessment. The reference standard for delirium was a comprehensive psychiatrist assessment using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Sensitivity, specificity, positive likelihood ratio (LR), and negative LR with their 95% confidence intervals (CIs) were calculated using the psychiatrist's assessment as the reference standard. A total of 406 patients were enrolled. The median age was 73.5 years old (interquartile range [IQR] = 69 to 80 years), 202 (49.8%) were female, 57 (14.0%) were nonwhite race, and 50 (12.3%) had delirium. Twenty-three (5.7%) of the cohort had chief complaints of altered mental status. The presence of this chief complaint was 38.0% sensitive (95% CI = 25.9% to 51.9%) and 98.9% specific (95% CI = 97.2% to 99.6%). The negative LR was 0.63 (95% CI = 0.50 to 0.78), and the positive LR was 33.82 (95% CI = 11.99 to 95.38). The absence of a chief complaint of altered mental status should not reassure the clinician that delirium is absent. This syndrome will be missed unless it is actively looked for using a validated delirium assessment. However, patients with this chief complaint are highly likely to be delirious, and no additional delirium assessment is necessary.


Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.
In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.


Under the Hood: Skeletal Muscle Determinants of Endurance Performance.
In the past decades, researchers have extensively studied (elite) athletes' physiological responses to understand how to maximize their endurance performance. In endurance sports, whole-body measurements such as the maximal oxygen consumption, lactate threshold, and efficiency/economy play a key role in performance. Although these determinants are known to interact, it has also been demonstrated that athletes rarely excel in all three. The leading question is how athletes reach exceptional values in one or all of these determinants to optimize their endurance performance, and how such performance can be explained by (combinations of) underlying physiological determinants. In this review, we advance on Joyner and Coyle's conceptual framework of endurance performance, by integrating a meta-analysis of the interrelationships, and corresponding effect sizes between endurance performance and its key physiological determinants at the macroscopic (whole-body) and the microscopic level (muscle tissue, i.e., muscle fiber oxidative capacity, oxygen supply, muscle fiber size, and fiber type). Moreover, we discuss how these physiological determinants can be improved by training and what potential physiological challenges endurance athletes may face when trying to maximize their performance. This review highlights that integrative assessment of skeletal muscle determinants points toward efficient type-I fibers with a high mitochondrial oxidative capacity and strongly encourages well-adjusted capillarization and myoglobin concentrations to accommodate the required oxygen flux during endurance performance, especially in large muscle fibers. Optimisation of endurance performance requires careful design of training interventions that fine tune modulation of exercise intensity, frequency and duration, and particularly periodisation with respect to the skeletal muscle determinants.


Functional and analytical recapitulation of osteoclast biology on demineralized bone paper.
Osteoclasts are the primary target for osteoporosis drug development. Recent animal studies revealed the crucial roles of osteoblasts in regulating osteoclastogenesis and the longer lifespans of osteoclasts than previously thought with fission and recycling. However, existing culture platforms are limited to replicating these newly identified cellular processes. We report a demineralized bone paper (DBP)-based osteoblast culture and osteoclast assay platform that replicates osteoclast fusion, fission, resorption, and apoptosis with high fidelity and analytical power. An osteoid-inspired DBP supports rapid and structural mineral deposition by osteoblasts. Coculture osteoblasts and bone marrow monocytes under biochemical stimulation recapitulate osteoclast differentiation and function. The DBP-based bone model allows longitudinal quantitative fluorescent monitoring of osteoclast responses to bisphosphonate drug, substantiating significantly reducing their number and lifespan. Finally, we demonstrate the feasibility of humanizing the bone model. The DBP-based osteo assay platforms are expected to advance bone remodeling-targeting drug development with improved prediction of clinical outcomes.


A spontaneous deletion of α-synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: effects on alcohol consumption.
α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6(Snca-/-) ) and their respective controls (C57BL/6(Snca) (+/) (+) ). These animals were monitored for spontaneous alcohol consumption (3-10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg(-1) ) was also assessed. Compared with the C57BL/6(Snca+/+) mice, we found that the C57BL/6(Snca-/-) mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6(Snca-/-) mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions.


Prediabetes and Associated Risk of Cardiovascular Events and Chronic Kidney Disease Among Adult Survivors of Childhood Cancer in the St Jude Lifetime Cohort.
Little is known about the prevalence of prediabetes and associated risk of cardiovascular events and chronic kidney disease (CKD) with this reversable condition in survivors. Prevalence of prediabetes (fasting plasma glucose 100-125 mg/dL or hemoglobin A1c 5.7%-6.4%) and diabetes was clinically assessed in 3,529 adults ≥5 years from childhood cancer diagnosis and 448 controls stratified by age. Cox proportional hazards regression estimated progression from prediabetes to diabetes, and risk of future cardiac events, stroke, CKD, and death. Among survivors, median age 30 years (IQR, 18-65), and the prevalence of prediabetes was 29.2% (95% CI, 27.7 to 30.7) versus 18.1% (14.5 to 21.6) in controls and of diabetes was 6.5% (5.7 to 7.3) versus 4.7% (2.7 to 6.6). By age 40-49 years, more than half of the survivors had prediabetes (45.5%) or diabetes (14.0%). Among 695 survivors with prediabetes and longitudinal follow-up, 68 (10%; median follow-up, 5.1 years) progressed to diabetes. After adjustment for demographic factors and body composition, risk of progression was associated with radiation exposure to the pancreatic tail ≥10 Gy (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.8]) and total-body irradiation (4.4 [1.5 to 13.1]). Compared with survivors with normal glucose control, adjusting for relevant treatment exposures, those with prediabetes were at increased risk of future myocardial infarction (HR, 2.4 [95% CI, 1.2 to 4.8]) and CKD (2.9 [1.04 to 8.15]), while those with diabetes were also at increased risk of future cardiomyopathy (3.8 [1.4 to 10.5]) or stroke (3.4 [1.3 to 8.9]). Prediabetes is highly prevalent in adult survivors of childhood cancer and independently associated with an increased risk of future cardiovascular and kidney complications. Prediabetes, a modifiable risk factor among childhood cancer survivors, represents a new target for intervention that may prevent subsequent morbidity and mortality.


Re-thinking the Etiological Framework of Neurodegeneration.
Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients; a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.


Concomitant cardiac and pulmonary operations.
From 1965 through 1983, 43 patients underwent concomitant cardiac and pulmonary procedures at our institution. Most patients presented with cardiac symptoms and were incidentally found to have a roentgenographically indeterminate lung nodule. The pulmonary diagnosis of 38 patients was unknown preoperatively, and nine of these had a malignant lesion. All 43 cardiac procedures necessitated extracorporeal circulation. Thirty-one patients had benign pulmonary disease, 10 had bronchogenic carcinoma, and two had metastatic carcinoma. Concomitant pulmonary procedures were performed via median sternotomy and included single wedge resections in 32 patients, lobectomy in seven, multiple wedge resections in three, and pneumonectomy in one. Most resections were performed either before or after institution of bypass, without systemic anticoagulation. Of the two operative deaths (4.6%), one was related to intraparenchymal pulmonary hemorrhage after multiple wedge resections during anticoagulation. Thus, pulmonary resections performed during anticoagulation may be associated with increased risk and probably should be avoided. The second death was cardiac in origin and not related to pulmonary resection. The remaining patients recovered uneventfully. Definitive correction of both cardiac and pulmonary disease can be performed at one operation via a single incision with safety and benefit to the carefully selected patient.


[Headache of unknown origin: brain tumor? Indications for computer tomography].
Headache is the most frequent initial as well as the principle symptom of brain tumours. In 25 patients with brain tumours, in whom the initial symptom was headache, a further symptom of cerebral origin did not appear until after an interval of 40 months on average (median 11.5 months, 95% confidence limits of the median 4 and 60 months). Whereas tumours associated with short case-histories of headache are mostly glioblastomas, previously unrecognised tumours associated with long-standing headache are predominantly slow-growing, in the main easily operable, brain tumours. Pure headache-tumours occur predominantly in "silent" regions: in the subdominant (right) hemisphere and also in the frontal lobes as well as mid-basal in the sella area. In comparison with electroencephalography, X-ray of the skull, scintigraphy and sonography, computerised tomography is the superior non-invasive diagnostic procedure. A tumour-excluding headache does not exist. A typical migraine attack, when appearing for the first time in middle-age, can be the first indication of a brain tumour. Any reservations on the use of computerised tomography in regard to headache, when this has not been present since childhood as intermittent migraine, are, even from the point of view of cost, no longer tenable.


Prenatal exposure to DDE and PCB 153 and respiratory health in early childhood: a meta-analysis.
Persistent organic pollutants may affect the immune and respiratory systems, but available evidence is based on small study populations. We studied the association between prenatal exposure to dichlorodiphenyldichloroethylene (DDE) and polychlorinated biphenyl 153 (PCB 153) and children's respiratory health in European birth cohorts. We included 4608 mothers and children enrolled in 10 birth cohort studies from 7 European countries. Outcomes were parent-reported bronchitis and wheeze in the first 4 years of life. For each cohort, we performed Poisson regression analyses, modeling occurrences of the outcomes on the estimates of cord-serum concentrations of PCB 153 and DDE as continuous variables (per doubling exposure) and as cohort-specific tertiles. Summary estimates were obtained through random-effects meta-analyses. The risk of bronchitis or wheeze (combined variable) assessed before 18 months of age increased with increasing DDE exposure (relative risk [RR] per doubling exposure = 1.03 [95% confidence interval = 1.00-1.07]). When these outcomes were analyzed separately, associations appeared stronger for bronchitis. We also found an association between increasing PCB 153 exposure and bronchitis in this period (RR per doubling exposure = 1.06 [1.01-1.12]) but not between PCB 153 and wheeze. No associations were found between either DDE or PCB 153 and ever-wheeze assessed after 18 months. Inclusion of both compounds in the models attenuated risk estimates for PCB 153 tertiles of exposure, whereas DDE associations were more robust. This large meta-analysis suggests that prenatal DDE exposure may be associated with respiratory health symptoms in young children (below 18 months), whereas prenatal PCB 153 levels were not associated with such symptoms.


Microbiome profile of the amniotic fluid as a predictive biomarker of perinatal outcome.
Chorioamnionitis (CAM), an inflammation of the foetal membranes due to infection, is associated with preterm birth and poor perinatal prognosis. The present study aimed to determine whether CAM can be diagnosed prior to delivery based on the bacterial composition of the amniotic fluid (AF). AF samples from 79 patients were classified according to placental inflammation: Stage III (n = 32), CAM; Stage II (n = 27), chorionitis; Stage 0-I (n = 20), sub-chorionitis or no neutrophil infiltration; and normal AF in early pregnancy (n = 18). Absolute quantification and sequencing of 16S rDNA showed that in Stage III, the 16S rDNA copy number was significantly higher and the α-diversity index lower than those in the other groups. In principal coordinate analysis, Stage III formed a separate cluster from Stage 0-I, normal AF, and blank. Forty samples were classified as positive for microbiomic CAM (miCAM) defined by the presence of 11 bacterial species that were found to be significantly associated with CAM and some parameters of perinatal prognosis. The diagnostic accuracy for CAM according to miCAM was: sensitivity, approximately 94%, and specificity, 79-87%. Our findings indicate the possibility of predicting CAM prior to delivery based on the AF microbiome profile.


Smart role of plant 14-3-3 proteins in response to phosphate deficiency.
Higher plants adapt to phosphorus deficiency through a complex of biological processes. Among of them, two adaptive processes are very important for the response of higher plants to phosphorus deficiency. One is the enhancement of root growth by regulating carbohydrate metabolism and allocation, and the other is rhizosphere acidification to acquire phosphorus efficiently from soil. TFT6 and TFT7, two different members of tomato 14-3-3 gene family, play the distinct roles in the adaption of plants to phosphorus deficiency by taking part in the two processes respectively. TFT6 which acts mainly in leaves is involved in the systemic response to phosphorus deficiency by regulating leaf carbon allocation and increasing phloem sucrose transport to promote root growth, while TFT7 directly functions in root by activating root plasma membrane H (+) -ATPase to release more protons under phosphorus deficiency. Based on these results, we propose that 14-3-3 proteins play the smart role in response to phosphorus deficiency in higher plants.


[Ultrasound controlled percutaneous transhepatic cholangiography].
A method of performing transcutaneous cholangiography under sonographic control is presented. This method makes it possible to enter the distended intrahepatic bile ducts accurately. The sonographic control enables the needle to be inserted into the superficial bile ducts. The method reduces liver traumatisation. Under the control of sonography the procedure is safer, and there are fewer complications.


Prehospital Lactate Measurement by Emergency Medical Services in Patients Meeting Sepsis Criteria.
We aimed to pilot test the delivery of sepsis education to emergency medical services (EMS) providers and the feasibility of equipping them with temporal artery thermometers (TATs) and handheld lactate meters to aid in the prehospital recognition of sepsis. This study used a convenience sample of prehospital patients meeting established criteria for sepsis. Paramedics received education on systemic inflammatory response syndrome (SIRS) criteria, were trained in the use of TATs and hand-held lactate meters, and enrolled patients who had a recent history of infection, met ≥ 2 SIRS criteria, and were being transported to a participating hospital. Blood lactate was measured by paramedics in the prehospital setting and again in the emergency department (ED) via usual care. Paramedics entered data using an online database accessible at the point of care. Prehospital lactate values obtained by paramedics ranged from 0.8 to 9.8 mmol/L, and an elevated lactate (i.e. ≥ 4.0) was documented in 13 of 112 enrolled patients (12%). The unadjusted correlation of prehospital and ED lactate values was 0.57 (p< 0.001). The median interval between paramedic assessment of blood lactate and the electronic posting of the ED-measured lactate value in the hospital record was 111 minutes. Overall, 91 patients (81%) were hospitalized after ED evaluation, 27 (24%) were ultimately diagnosed with sepsis, and 3 (3%) died during hospitalization. Subjects with elevated prehospital lactate were somewhat more likely to have been admitted to the intensive care unit (23% vs 15%) and to have been diagnosed with sepsis (38% vs 22%) than those with normal lactate levels, but these differences were not statistically significant. In this pilot, EMS use of a combination of objective SIRS criteria, subjective assessment of infection, and blood lactate measurements did not achieve a level of diagnostic accuracy for sepsis that would warrant hospital prenotification and committed resources at a receiving hospital based on EMS assessment alone. Nevertheless, this work provides an early model for increasing EMS awareness and the implementation of novel devices that may enhance the prehospital assessment for sepsis. Additional translational research studies with larger numbers of patients and more robust methods are needed.


Structural insight into the evolution of a new chemokine family from zebrafish.
The mammalian chemokine family is segregated into four families - CC, CXC, CX3C, and XC-based on the arrangement of cysteines and the corresponding disulfides. Sequencing of the Danio rerio (zebrafish) genome has identified more than double the amount of human chemokines with the absence of the CX3C family and the presence of a new family, CX. The only other family with a single cysteine in the N-terminal region is the XC family. Human lymphotactin (XCL1) has two interconverting structures due to dynamic changes that occur in the protein. Similar to an experiment with XCL1 that identified the two structural forms, we probed for multiple forms of zCXL1 using heparin affinity. The results suggest only a single form of CXL1 is present. We used sulfur-SAD phasing to determine the three-dimensional structure CXL1. Zebrafish CXL1 (zCXL1) has three disulfides that appear to be important for a stable structure. One disulfide is common to all chemokines except those that belong to the XC family, another is similar to a subset of CC chemokines containing three disulfides, but the third disulfide is unique to the CX family. We analyzed the electrostatic potential of the zCXL1 structure and identified the likely heparin-binding site for glycosaminoglycans (GAGs). zCXL1 has a similar sequence identity with human CCL5 and CXCL12, but the structure is more related to CCL5. Our structural analysis supports the phylogenetic and genomic studies on the evolution of the CXL family.