A simple way to look at DNA.
A method is presented for embedding nucleotide sequence data in a simple metric space. Computer graphical examination of spatially-represented sequences permits rapid searches for canonical patterns or interesting structures. Sequence comparisons are facilitated by plots of distance measures for homologous sequences, and the large-scale structure of the genetic code can be studied by measures such as fractal dimensionality.


Epileptic seizures induced by cycloplegic eye drops.
To assess the incidence of seizures induced by cycloplegic ophthalmic drops. A survey among members of the American Association for Pediatric Ophthalmology and Strabismus yielded five patients who received cycloplegic eye drops between 1998 and 2010 and who consequently developed a seizure. The median age of the patients was 5 years (range 3 months to 12 years). Cyclopentolate hydrochloride 1% was the only causative agent. The seizure happened on average 12 min after the instillation of dilating eye drops. Three were generalized convulsions, and two patients had a focal seizure. Past medical history was unremarkable in four cases. In total, 16 previous cases of seizures induced by cycloplegic drugs were identified in reports published between 1890 and 2004, implicating atropine in nine reports, tropicamide and phenylephrine eye drops in one and cyclopentolate in six. A small amount of cyclopentolate drops could induce convulsions in young children after only minutes to less than an hour, while a larger dosage of atropine over the span of several hours could cause this rare and unpredictable complication. Predisposing factors were rare and those developing the seizures were healthy subjects. Generalized seizures were much more frequent than focal convulsions. Seizures after instillation of cycloplegic drops are extremely rare.


Direct Analysis of Glyphosate, Glufosinate, and Their Metabolites in Palm Oil Using Liquid Chromatography with Tandem Mass Spectrometry.
Glyphosate and glufosinate are broad-spectrum herbicides which are frequently used in palm oil plantations for weed control. Metabolites of these herbicides are known to have environmental and food safety implications. As there is no validated method for multiresidue testing of these herbicides and their metabolites in palm oil products, a new method was needed for the purpose of regulatory analysis. In this study, we endeavored to develop a rapid method for multiresidue analysis of glyphosate (+aminomethylphosphonic acid) and glufosinate (+3-methylphosphinicopropionic acid and N-acetyl-glufosinate) in refined and crude palm oil matrices using liquid chromatography (LC) tandem mass spectrometry (MS/MS). The optimized sample preparation workflow included extraction of refined or crude palm oil (10 g) with acidified water (0.1 M HCl), cleanup by phase separation with dichloromethane, and analysis by LC-MS/MS with multiple reaction monitoring. The use of a Torus-DEA LC column ensured simultaneous analysis of these compounds within a runtime of 10 min. The LOQ of these analytes was 0.01 mg/kg, except that of aminomethylphosphonic acid which was 0.02 mg/kg. The method sensitivity complied with the national maximum residue limits of Malaysia and the European Union. Also, the method selectivity, sensitivity, accuracy, and precision were aligned with the SANTE/12682/2019 guidelines of analytical quality control. The potentiality of the optimized method lies in a high throughput direct analysis of glyphosate and glufosinate with their metabolites in a single chromatographic run. The method is fit for purpose for regulatory testing of these residues in a broad range of palm oil matrices. The study reports for the first time a validated method for simultaneous analysis of glyphosate, glufosinate, and their metabolites in a range of palm oil products. The method did not require a derivatization step and provided a high throughput analysis of these compounds with satisfactory selectivity, sensitivity, accuracy, and precision.


Carotenoids of Gemmatimonas aurantiaca (Gemmatimonadetes): identification of a novel carotenoid, deoxyoscillol 2-rhamnoside, and proposed biosynthetic pathway of oscillol 2,2'-dirhamnoside.
Gemmatimonas aurantiaca strain T-27(T) is an orange-coloured, Gram-negative, facultatively aerobic, polyphosphate-accumulating bacterium belonging to a recently proposed phylum, Gemmatimonadetes. We purified its pigments and identified them as carotenoids and their glycoside derivatives using spectral data. The major carotenoid was (2S,2' S)-oscillol 2,2'-di-(alpha-l-rhamnoside), and the minor carotenoids were (2S)-deoxyoscillol 2-( alpha-l-rhamnoside) and didemethylspirilloxanthin. Deoxyoscillol 2-rhamnoside is a novel carotenoid. Oscillol 2,2'-diglycosides have hitherto only been reported in a limited number of cyanobacteria, and this is believed to be the first finding of such carotenoids in another bacterial phylum. Based on the identification of the carotenoids and the completion of the entire nucleotide sequence, we propose a biosynthetic pathway for the carotenoids and the corresponding genes and enzymes. We propose the involvement of geranylgeranyl pyrophosphate synthase (CrtE), phytoene synthase (CrtB) and phytoene desaturase (CrtI) for lycopene synthesis; and of carotenoid 1,2-hydratase (CruF) and carotenoid 2-O-rhamnosyltransferase (CruG) for oscillol 2,2'-dirhamnoside synthesis. Further, isopentenyl pyrophosphate could be synthesized by a non-mevalonate pathway (DXP pathway).


[Usefulness of determining urinary trypsinogen-2 in diagnosis and prognosis of patients with acute pancreatitis].
To study the role of urinary trypsinogen-2 in diagnosing and early prognosis of patients with acute pancreatitis (AP) and the relationship to length of hospital stay and mortality. Forty-two patients were included in the study. In all cases, blood cell count, serum chemistry, urine amylase and urine trypsinogen-2 were measured. A cut-off of 50 microg/L was established and, when positive, a second dilution was made (2000 microg/L). Other variables included were etiology, mean length of hospital stay, transfer to an ICU and death. Out of the 42 patients, 29 (69%) were men and 13 (31%) women. Average age was 61 years. The most frequent cause was biliary, followed by alcohol. Mean hospital stay was 8.38 days. Transferred to an ICU: 4 (9.5%) patients. Two of them and a third, who had not been transferred, died (7.14%). High serum amylase was found in 33 (78.57%) patients and high lipase in 36 (85.71%). Urinary trypsinogen-2 was positive in 34 patients (80.95%). Statistical association between urinary trypsinogen-2 and age (p=0.016; r=0.893), glucose (p=0.005; r=0.901), serum amylase (p=0.029; r=0.852), lipase (p=0.022; r=0.809) and hypoxemia (p=0.001; r=0.962) was found. Regarding hospital stay, there was statistical association with age (p=0.046; r=0.784) and metabolic acidosis (p=0.016; r=0.839). With respect to mortality there was statistical association with hypocalcemia (p=0.008; r=0.899) and metabolic acidosis (p=0.032; r=0.814). Testing urinary trypsinogen-2 in patients with AP is rapid and useful. Patients over the age of 65 with hypoxia, metabolic acidosis and hypocalcemia tend to present a prolonged average hospital stay and higher mortality.


The retrospectroscope-the invention of the rechargeable cardiac pacemaker: vignette #9.
The idea for a rechargeable cardiac pacemaker came to the author in the late 1960s after reading an advertisement stating that a company's batteries were so good they would last two years in a heart pacemaker. This meant that pacemaker patients would have to undergo surgery for their replacement frequently. Having worked on the development of hermetically sealed, nickel-cadmium batteries that could function for a decade or longer in an orbiting spacecraft, the author constructed the first prototype of a rechargeable cardiac pacemaker around 1968 to show cardiologists at Johns Hopkins Hospital that a pacemaker of indefinitely long life and much smaller size and weight could be built readily. The subsequent development and marketing of the device, which came on the market in 1973, is recounted.


Electrostatic Limit of Detection of Nanowire-Based Sensors.
Scanning gate microscopy is used to determine the electrostatic limit of detection (LOD) of a nanowire (NW) based chemical sensor with a precision of sub-elementary charge. The presented method is validated with an electrostatically formed NW whose active area and shape are tunable by biasing a multiple gate field-effect transistor (FET). By using the tip of an atomic force microscope (AFM) as a local top gate, the field effect of adsorbed molecules is emulated. The tip induced charge is quantified with an analytical electrostatic model and it is shown that the NW sensor is sensitive to about an elementary charge and that the measurements with the AFM tip are in agreement with sensing of ethanol vapor. This method is applicable to any FET-based chemical and biological sensor, provides a means to predict the absolute sensor performance limit, and suggests a standardized way to compare LODs and sensitivities of various sensors.


An Inverted-Sandwich Diuranium μ-η(5):η(5)-Cyclo-P5 Complex Supported by U-P5 δ-Bonding.
Reaction of [U(Tren(TIPS))] [1, Tren(TIPS)=N(CH2CH2NSiiPr3)3] with 0.25 equivalents of P4 reproducibly affords the unprecedented actinide inverted sandwich cyclo-P5 complex [{U(Tren(TIPS))}2(μ-η(5):η(5)-cyclo-P5)] (2). All prior examples of cyclo-P5 are stabilized by d-block metals, so 2 shows that cyclo-P5 does not require d-block ions to be prepared. Although cyclo-P5 is isolobal to cyclopentadienyl, which usually bonds to metals via σ- and π-interactions with minimal δ-bonding, theoretical calculations suggest the principal bonding in the U(P5)U unit is polarized δ-bonding. Surprisingly, the characterization data are overall consistent with charge transfer from uranium to the cyclo-P5 unit to give a cyclo-P5 charge state that approximates to a dianionic formulation. This is ascribed to the larger size and superior acceptor character of cyclo-P5 compared to cyclopentadienyl, the strongly reducing nature of uranium(III), and the availability of uranium δ-symmetry 5f orbitals.


[On the use of eponyms in medicine].
A distinctive feature of medical language is the use of eponyms or denominations constructed using the names of real or imaginary persons. Some consider this practice as inappropriate, because eponyms are sometimes more a reflection of influence and power rather than the real authorship of discoveries. On the other hand, others consider valid the use of eponyms since they are a part of a scientific domain used to name objects and diseases. The fact is that tradition and use have finally imposed eponyms in medical language and demonstrated its usefulness. They facilitate the communication between peers and are also a tribute to the clinical sagacity and observational skills of their discoverers. A reasonable practice is to favor the use of those classical eponyms that have endured the pass of time due to their clinical importance, specificity diagnostic significance or historical relevance. Moreover, the knowledge of the biography or historical environment of discoverers of signs, syndromes or diseases gives us a historical perspective of medicine and sheds light on the past, evolution and present knowledge and practice of medicine.


Recognition of two classes of oligoproline sequences in profilin-mediated acceleration of actin-based Shigella motility.
The gram negative rod Shigella flexneri uses it surface protein IcsA to induce host cell actin assembly and to achieve intracellular motility. Yet, the IcsA protein lacks the oligoproline sequences found in ActA, the surface protein required for locomotion of the gram positive rod Listeria monocytogenes. Microinjection of a peptide matching the second ActA oligoproline repeat (FEFPPPPTDE) stops Listeria locomotion (Southwick, F.S., and D.L. Purich. 1994a. Proc. Natl. Acad. Sci. USA. 91:5168-5172), and submicromolar concentrations (intracellular concentration 80-800 nM) similarly arrest Shigella rocket-tail assembly and intracellular motility. Coinjection of a binary solution containing profilin and the ActA analogue increased the observed rates of intracellular motility by a factor of three (mean velocity 0.90 +/- 0.07 mu m/s, SD n=16 before injection vs 0.3 +/- 0.1 mu m/s, n=33 postinjection, intracellular concentration = 80 nM profilin plus 80 nM ActA analogue). Recent evidence suggests the ActA analogue may act by displacing the profilin-binding protein VASP (Pistor, S.C., T. Chakaborty, V. Walter, and J. Wehland. 1995. Curr. Biol. 5:517-525). At considerably higher intracellular concentrations (10 muM), the VASP oligoproline sequence (GPPPPP)3 thought to represent the profilin-binding site (Reinhard, M., K. Giehl, K. Abel, C. Haffner, T. Jarchau, V. Hoppe, B.M. Jockusch, and U. Walter. 1995. EMBO (Eur. Mol. Biol. Organ.) J. 14:1583-1589) also inhibited Shigella movement. A binary mixture of the VASP analogue and profilin (each 10 muM intracellular concentration) led to a doubling of Shigella intracellular migration velocity (0.09 +/- 0.06 mu m/s, n = 25 preinjection vs 0.18 +/- 0.10 mu m/s, n = 61 postinjection). Thus, the two structurally divergent bacteria, Listeria and Shigella, have adopted convergent mechanisms involving profilin recognition of VASP oligoproline sequences and VASP recognition of oligoproline sequences in ActA or an ActA-like host protein to induce host cell actin assembly and to provide the force for intracellular locomotion and cell-cell spread.


Promoter and histone methylation and p16(INK4A) gene expression in colon cancer.
The inactivation of the cyclin-dependent kinase inhibitor p16(INK4A) gene by hypermethylation is observed in numerous types of cancer. New findings indicate that DNA and histone methylation act in concert in gene silencing. In this study, we investigated the methylation status of the p16(INK4A) gene promoter and the histone 3 lysine 9 residue in the tumors and matched normal tissue samples from patients with colorectal cancer and analyzed their association with gene expression. The methylation and expression of the p16(INK4A) gene were analyzed by real-time PCR, and histone methylation was analyzed by chromatin immunoprecipitation followed by real-time PCR. p16(INK4A) expression was significantly higher in the tumors compared to normal tissue. Mono-, di- and trimethylation levels of the H3K9 residue were similar in the tumor and normal tissue samples. We did not observe any significant correlation between p16(INK4A) methylation or expression and clinical parameters. Our results suggest that epigenetic modifications of the p16(INK4A) gene and histone lysine methylation do not play a major role in colon carcinogenesis.


Beneficial Effects of Amnion-Chorion Stem Cell Grafting in the Long Term Management of Nonuremic Calciphylaxis Wounds.
Calciphylaxis is a poorly understood disease with high morbidity and mortality. The current primary literature on treatment is lacking; however, disease management often involves a multifaceted approach with a primary focus on consistent wound care. This report describes a case outlining the long-term management of nonuremic calciphylaxis wounds in a patient with severe malnutrition with the use of human amniotic membrane grafts, aggressive surgical debridement, nutritional therapy, and advanced wound healing techniques. A 38-year-old African American female with a history of non-uremic calciphylaxis presented from a transitional facility with numerous non-healing wounds in the setting of severe malnutrition secondary to bariatric surgery. Biweekly wound debridement was initiated utilizing an amniotic stem cell skin graft, dry applicable absorbent dressing, high-frequency ultrasonic ablation, and wound vacuum-assisted closure (VAC) over the course of approximately nine months. Nutritional supplementation was given in the form of jejunostomy tube feed due to a gastric bypass and a perforated viscus. At the current date, the patient demonstrates significant improvement in pain and wound healing. The patient is also able to ambulate with care and has begun steps towards independent management of wounds. Future goals of care include independent bedside wound management, placement of allograft, and discharge to a long-term care facility. Most patients with refractory pain, widespread necrotic wounds, and dangerous comorbidities will inevitably be referred to palliative care. This case creates a framework for the long term management of medically complex patients with nonuremic calciphylaxis using human amniotic membrane stem cell grafts and appropriate advanced wound care techniques.


Obstructive Sleep Apnea and Posttraumatic Stress Disorder among OEF/OIF/OND Veterans.
This study examined: (a) the relationship between self-reported posttraumatic stress disorder (PTSD) symptoms and risk of obstructive sleep apnea (OSA) in a younger, Iraq and Afghanistan (OEF/OIF/OND) veteran sample seeking treatment for PTSD; and (b) the relationships between PTSD symptom scores and each risk factor of OSA (snoring, fatigue, high blood pressure/BMI). Participants were 195 Iraq and Afghanistan veterans presenting to a VA outpatient PTSD clinic for evaluation. Veterans were 21 to 59 years old (mean 33.40, SD 8.35) and 93.3% male (n = 182). Logistic regressions were run to examine whether veterans with greater PTSD symptom severity had an increased probability of screening as high risk for OSA, even after controlling for known risk factors (older age, positive smoking status, and use of CNS depressants). Of 159 veterans screened, 69.2% were assessed as being at high risk for OSA. PTSD symptom severity increased the risk of screening positive for OSA. PTSD symptom severity increased risk of screening positive for snoring and fatigue, but not high blood pressure/BMI. OEF/OIF/OND veterans with PTSD screen as high risk for OSA at much higher rates than those seen in community studies and may not show all classic predictors of OSA (i.e., older and higher BMI). This study is the first to suggest that the Berlin may be a useful screener for OSA in a younger OEF/OIF/OND veteran population with PTSD. Screening of younger veterans with PTSD for OSA should be standard care, and polysomnography and OSA interventions should be readily available to younger veterans.


Shaking up the Salpetriere: Jean-Martin Charcot and mercury-induced tremor.
To analyze Jean-Martin Charcot's studies of mercury-induced tremor. This study examines Charcot's original notes on mercury intoxication from the Bibliothèque Charcot, Paris, and his show-and-tell patient presentations that were hand-transcribed by his students and later published. Using his standard method of presenting multiple patients with a similar disorder side by side, Charcot assembled a series of patients with mercurial intoxication from the clinics of Paris. He emphasized the rest and action components of mercury-induced tremor and stressed the value of using graphical tremor recordings rather than relying only on visual observation. He drew attention to the importance of air ventilation to avoid intoxication and of removal from intoxicating environments. He distinguished the characteristics of mercury-induced tremor from tremor associated with Parkinson disease, multiple sclerosis, and general paresis. Based on the similar intention tremor in multiple sclerosis and mercury intoxication, human pathology studies in multiple sclerosis, and animal experiments with mercury, he suggested that axonal demyelination underlay this form of tremor in both conditions, the former restricted to the CNS and the second to peripheral nerves. These cases illuminate Charcot's diagnostic strategy and his reliance on the clinico-anatomic method to correlate pathology with clinical signs. Whereas much of Charcot's work emphasized hereditary etiologies of neurologic disease, these examples allow an understanding of his views on environmental factors in neurologic disorders as well as treatment strategies.


Virological course of herpes zoster in otherwise normal hosts.
The virological course of herpes zoster infection in 42 otherwise normal hosts was studied by virus isolation and antibody titration. Varicella-zoster virus (VZV) was isolated from vesicle fluid from all three patients examined on the first day of the vesicular eruption and from five out of six examined on the second day. The isolation rate fell to one out of six patients on the seventh day of illness and VZV was not isolated from patients at a later stage of the illness. IgG antibodies were detected by IFAMA and ELISA, in sera from all the patients by the end of the first week of illness; IgG antibody titres were highest during the second and the third weeks. IgM antibodies to VZV were detected in sera from six of the 42 patients with herpes zoster after fractionation by ion-exchange chromatography.


Analysis of dose distribution reproducibility based on a fluence map of in vivo transit dose using an electronic portal imaging device.
Morphological changes can affect distribution of dose in patients. Determination of the dose distribution changes for each fraction radiotherapy can be done by relativein vivodosimetry (IVD). This study analysed the distribution of doses per fraction based on the fluence map recorded by the electronic portal imaging device (EPID) of the patient's transit dose. This research examined cases involving the cervix, breast, and nasopharynx. Transit dose analysis was performed by calculating the gamma index (GI) with composite and field-by-field methods. The gamma passing rate (GPR) value was assessed for its correlation with the subject's body weight. In the case of the nasopharynx, breast, and cervix, the GPR value decreased as the fraction increased. In the case of the nasopharynx, the correlation between the GPR and fraction radiotherapy showed no difference when using either composite or field-by-field methods. However, in cases involving the cervix and breast, there was a difference in the correlation values between the composite and field-by-field methods, where the subject had a significant correlation (p< 0.05) when it was done using a field-by-field method. In addition, the nasopharynx had the highest number of subjects with significant correlation (p< 0.05) between GPR and body weight, followed by the cervix and breast. In the nasopharynx, breast, and cervix, the reproducibility of the dose distribution decreased. This decreased reproducibility was associated with changes in body weight.


Effect of leaf temperature on the estimation of photosynthetic and other traits of wheat leaves from hyperspectral reflectance.
A growing number of leaf traits can be estimated from hyperspectral reflectance data. These include structural and compositional traits, such as leaf mass per area (LMA) and nitrogen and chlorophyll content, but also physiological traits such a Rubisco carboxylation activity, electron transport rate, and respiration rate. Since physiological traits vary with leaf temperature, how does this impact on predictions made from reflectance measurements? We investigated this with two wheat varieties, by repeatedly measuring each leaf through a sequence of temperatures imposed by varying the air temperature in a growth room. Leaf temperatures ranging from 20 °C to 35 °C did not alter the estimated Rubisco capacity normalized to 25 °C (Vcmax25), or chlorophyll or nitrogen contents per unit leaf area. Models estimating LMA and Vcmax25/N were both slightly influenced by leaf temperature: estimated LMA increased by 0.27% °C-1 and Vcmax25/N increased by 0.46% °C-1. A model estimating Rubisco activity closely followed variation associated with leaf temperature. Reflectance spectra change with leaf temperature and therefore contain a temperature signal.


Airway smooth muscle in health and disease; methods of measurement and relation to function.
Smooth muscle is present and probably functional in the airways in utero and increases in absolute area during growth with little further change during adulthood. It encircles the entire airway below the level of the main bronchus, in a roughly circular orientation, except at high lung volumes. It occupies relatively more of the airway wall in the peripheral airways, reaching a maximum in the membranous bronchioles. Measurement of smooth muscle area in the airway wall is confounded by clinical classification of cases, methods of tissue retrieval and preparation, staining and orientation of sections, magnification, image analysis and statistical methods of comparison between groups. Airway smooth muscle area is pathologically increased in inflammatory conditions of the airways such as chronic obstructive pulmonary disease, in relation to airways obstruction, and asthma, in relation to severity and airway size (between 25 and 250% compared with control cases). It is increased in sudden infant death syndrome, but there are few studies in other conditions such as bronchiectasis. In asthma, smooth muscle must shorten (not necessarily to an abnormal degree) for the structural abnormalities of the airway to manifest as excessive airway narrowing. Not surprisingly there is renewed interest in the relationships between the mechanical and contractile properties of smooth muscle, parenchymal properties and lung volume and how these interact to determine smooth muscle length. The relative importance of smooth muscle area and mechanical properties, altered airway structure and airway inflammation in disease are yet to be determined.


Results of immediate breast reconstruction after skin-sparing mastectomy.
Skin sparing mastectomy (SSM) removes the breast, nipple-areolar complex, previous biopsy incisions, and skin overlying superficial tumors. Preservation of the native skin envelope facilitates immediate breast reconstruction. The procedure has been adopted for the treatment of breast cancer. All cases of SSM and immediate breast reconstruction performed by the senior author (G.W.C.) from January 1, 1993, through December 12, 1997, were reviewed. Patient demographics, cancer staging, treatment, types of surgery performed, and postoperative outcomes were examined. Aesthetic outcomes were measured using four 3-point subscales. A total of 100 patients underwent 118 SSMs during the study period. The American Joint Committee on Cancer staging was as follows: stage 0, 27 patients; stage I, 25 patients; stage II, 39 patients; stage III, 7 patients; stage IV, 3 patients; recurrent, 2 patients; and cystosarcoma phylloides, 1 patient. The mean follow-up was 42.7 months. Local recurrence occurred in 2 patients (2.7%). Reconstructive methods included the transverse rectus abdominis musculocutaneous flap (N = 82; pedicled, 73; free, 9), the latissimus flap (N = 18), and tissue expansion (N = 20). Two patients underwent contralateral delayed reconstruction. The aesthetic results achievable with the three methods were similar. The failure rate was higher for expander reconstruction (10%) than those observed for transverse rectus abdominis musculocutaneous (4.9%) and latissimus (5.6%) flaps. SSM can be used in the treatment of invasive breast cancer without compromising local control. The aesthetic results of the three methods were similar, but tissue expander reconstruction had a higher failure rate.


The clue of a possible etiology about spontaneous regression of hepatocellular carcinoma: a perspective on pathology.
Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event. However, only a few of the causes of cases of HCC spontaneous regression are clear. More cases are ambiguous. We report on a patient who had a spontaneous regression of HCC as detected by histological and immunohistochemical exam, and compared this case to 20 cases of non-specific HCC. In our case, we found that the odd phenomenon is that CD163(+) macrophages are overactivated in surviving HCC, which is spontaneously regressing. Concomitantly, we cannot find a similar phenomenon in peritumoral liver tissue or non-specific HCC. According to our microscopical morphology and immunohistochemical study, we considered that a clue of a possible etiology about HCC spontaneous regression is that CD163(+) macrophages are overactivated.


Preresidency Publication Number Does Not Predict Academic Career Placement in Neurosurgery.
It is unclear if preresidency and/or residency research work impacts academic neurosurgery placement post residency. The goal of this study is to evaluate the impact that preresidency and residency research publication has on attaining academic faculty positions. Alumni information was collected from 65 of the 108 (60%) neurosurgery residency websites. Graduates from these programs between 2005 and 2015 (n = 949) were analyzed to determine factors associated with an academic career. Information on publications, citations, and H-index were obtained from Web of Science. Current position was designated as academic if the physician had a teaching position at a university hospital and private if the physician was not affiliated with a university hospital. Univariate and multivariate logistic regression models were used to identify factors associated with academic faculty positions post residency. Of the 949 physicians included in the analysis, 339 (36%) were in academic positions, 518 (55%) in private practice, and 92 (10%) were still in training. More than a fifth (212, or 22%) of physicians performed a research fellowship (8.2%) or attained a Ph.D. (14.1%) during medical school. Among those who had completed training, an academic career was associated with having 2 or more publications during residency (odds ratio [OR] [95% confidence interval, CI]: 3.87 [1.59-9.45]; P < 0.003), H-index ≥ 2 during residency (OR [95% CI]: 2.32 [1.40-1.69]; P < 0.0001) and having devoted research time before residency (OR [95% CI]: 1.56 [1.10-2.22]; P < 0.012). Notably, publications before residency were not an independent indicator of academic placement. These findings may help guide residency programs to identify and/or cultivate neurosurgeons to become academic neurosurgeons.


Effect of Anacetrapib on Cholesterol Efflux Capacity: A Substudy of the DEFINE Trial.
Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard β, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men (P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard β, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes (P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.


Micro/nanostructured surfaces for self-powered and multifunctional electronic skins.
Flexible electronic devices are regarded as one of the key technologies in wearable healthcare systems, wireless communications and smart personal electronics. For the realization of these applications, wearable energy and sensor devices are the two main technologies that need to be developed into lightweight, miniaturized, and flexible forms. In this review, we introduce recent advances in the controlled design of device structures into bioinspired micro/nanostructures and 2D/3D structures for the enhancement of energy harvesting and multifunctional sensing properties of flexible electronic skins. In addition, we highlight their potential applications in flexible/wearable electronics, sensors, robotics and prosthetics, and biomedical devices.


Multi-element fingerprinting as a tool in origin authentication of four east China marine species.
The contents of 25 elements in 4 types of commercial marine species from the East China Sea were determined by inductively coupled plasma mass spectrometry and atomic absorption spectrometry. The elemental composition was used to differentiate marine species according to geographical origin by multivariate statistical analysis. The results showed that principal component analysis could distinguish samples from different areas and reveal the elements which played the most important role in origin diversity. The established models by partial least squares discriminant analysis (PLS-DA) and by probabilistic neural network (PNN) can both precisely predict the origin of the marine species. Further study indicated that PLS-DA and PNN were efficacious in regional discrimination. The models from these 2 statistical methods, with an accuracy of 97.92% and 100%, respectively, could both distinguish samples from different areas without the need for species differentiation.


Frequency domain approach to the steady state and stability analysis of dual injection-locked optoelectronic oscillators.
A frequency domain algorithm is proposed for deriving all of the possible steady state modes of dual injection-locked optoelectronic oscillators (DIL-OEOs), corresponding to the detailed system parameters, such as the fiber lengths, small signal open loop gains, radio frequency filters' bandwidths, phase shifting values, and injection parameters. It is shown that some or all of the modes computed by the new approach may be unstable; these are just mathematical solutions of the steady state equations. Therefore, it is necessary to check the stability of these modes. A stability analysis approach is proposed, which is based on simulating the slowly varying time domain dynamic governing the perturbation variables. The steady state and stability analysis approaches enable one to predict the required injection parameters for having a reliable steady state injection-locked mode in the DIL-OEO system. The new method requires a much smaller runtime compared to the corresponding time domain methods. In addition, it avoids many simplifying assumptions of the corresponding frequency domain approaches presented in the literature. The validities of the steady state and stability analysis methods are verified by comparing their results with full time domain integrations and with other predictions regarding the required injection parameters for phase locking, as presented in the literature.


Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers.
Representing the fourth leading cause of cancer-related mortality worldwide, liver cancers constitute a major global health concern. Hepatocellular carcinoma (HCC), the most frequent type of liver cancer, is associated with dismal survival outcomes and has traditionally had few treatment options available. In fact, up until 2017, treatment options for advanced HCC were restricted to broad acting tyrosine kinase inhibitors, including Sorafenib, which has been the standard of care for over a decade. Since 2017, a multitude of mono- and combination immunotherapies that include pembrolizumab, nivolumab, ipilumumab, atezolizumab, and bevacizumab have been FDA-approved for the treatment of advanced HCC with unprecedented response rates ranging from 20 to 30% of patients. However, this also means that ~70% of patients do not respond to this treatment and currently very little is known regarding mechanisms of action of these immunotherapies as well as predictors of response to facilitate patient stratification. With the recent success of immunotherapies in HCC, there is a pressing need to understand mechanisms of tumor immune evasion and resistance to these immunotherapies in order to identify biomarkers of resistance or response. This will enable better patient stratification as well as the rational design of combination immunotherapies to restore sensitivity in resistant patients. The aim of this review is to summarize the current knowledge to date of tumor-intrinsic mechanisms of immune escape in liver cancer, specifically in the context of HCC.


Stereological analysis of bacterial load and lung lesions in nonhuman primates (rhesus macaques) experimentally infected with Mycobacterium tuberculosis.
Infection with Mycobacterium tuberculosis primarily produces a multifocal distribution of pulmonary granulomas in which the pathogen resides. Accordingly, quantitative assessment of the bacterial load and pathology is a substantial challenge in tuberculosis. Such assessments are critical for studies of the pathogenesis and for the development of vaccines and drugs in animal models of experimental M. tuberculosis infection. Stereology enables unbiased quantitation of three-dimensional objects from two-dimensional sections and thus is suited to quantify histological lesions. We have developed a protocol for stereological analysis of the lung in rhesus macaques inoculated with a pathogenic clinical strain of M. tuberculosis (Erdman strain). These animals exhibit a pattern of infection and tuberculosis similar to that of naturally infected humans. Conditions were optimized for collecting lung samples in a nonbiased, random manner. Bacterial load in these samples was assessed by a standard plating assay, and granulomas were graded and enumerated microscopically. Stereological analysis provided quantitative data that supported a significant correlation between bacterial load and lung granulomas. Thus this stereological approach enables a quantitative, statistically valid analysis of the impact of M. tuberculosis infection in the lung and will serve as an essential tool for objectively comparing the efficacy of drugs and vaccines.


Fc gamma RI and Fc gamma RII on monocytes and granulocytes are cytotoxic trigger molecules for tumor cells.
As part of an effort to define the cytotoxic trigger molecules on human myeloid cells, the ability of the different Fc receptors for IgG (Fc gamma R) to mediate killing of tumor cell lines by monocytes and granulocytes was examined. This was accomplished by studying cytolysis of hybridoma cell (HC) targets bearing surface antibody directed toward the different Fc gamma R. The HC line, HC IV.3A, which bears Ig directed to the low affinity Fc gamma R (Fc gamma RII) on monocytes and neutrophils was lysed by human monocytes. The extent of lysis of HC IV.3A was approximately equal to that of anti-Fc gamma RI (the high affinity Fc gamma R on human monocytes) bearing HC lines (HC 32.2A and HC 62A) and was not augmented by treatment of the monocytes with interferon-gamma (IFN-gamma). In contrast, neutrophils lysed HC IV.3A and HC 32.2A only after activation with IFN-gamma. Since Fc gamma RI is not detectable on untreated neutrophils and is induced by IFN-gamma on these cells, lysis of HC 32.2A by IFN-gamma-activated neutrophils correlated with receptor induction. On the other hand, Fc gamma RII was present at equal levels on untreated and IFN-gamma-treated neutrophils, but only IFN-gamma-treated neutrophils mediated cytotoxicity via Fc gamma RII. In this case, enhanced killing appeared to be due to events other than an increase in Fc gamma RII number. Neither untreated nor IFN-gamma-treated neutrophils mediated the lysis of the anti-Fc gamma RIII bearing HC 3G8A. Thus, binding to the tumor target via this Fc receptor does not lead to lysis and may initiate signals distinct from those triggered through Fc gamma RI or Fc gamma RII. Surprisingly, HC bearing high amounts of mouse IgG1 antibody of irrelevant specificity were also lysed by monocytes. This lysis was blocked by soluble IV.3 antibody and thus appeared to be due to binding of the Fc portion of the surface Ig to Fc gamma RII on monocytes. Furthermore, monocytes from donors with a form of Fc gamma RII incapable of binding aggregated mouse IgG1 did not lyse these HC, but displayed normal lysis of HC IV.3, demonstrating that this structurally different Fc gamma RII remained a functional trigger molecule. Overall, these studies have demonstrated the specificity of Fc receptors in triggering monocyte- and granulocyte-mediated antibody-dependent tumor cell killing and have begun to dissect functional similarities and differences among the three defined Fc gamma R on human myeloid cells.


[Genetic effects of the breakdown of tritium incorporated into Saccharomyces cerevisiae yeast cells. IV. The lethal and mutagenic effects and the nature of the mutations induced by tritium breakdown in the 5th position of cytosine].
We have studied in lethal and mutagenic effects and the nature of mutations induced by 3H decays in the 5-th position of cytosine (5-3H-C). The lethal efficiency was determined as alpha 1 = (10.3 +/- 6.7) x 10(-3) decay-1 or alpha 1 = (12.9 +/- 9.4) x 10(-5) rad-1 and the mutagen efficiency for ade1, ade2 genes -- as alpha m = (4.3 +/- 2.3) x 10(-7) decay-1 or alpha m = (5.4 +/- 2.9) x 10(-9) rad-1. For ade2 gene the spectrum of mutations induced by 5-3H-C was as follows: 1% of frameshifts and 99% of base pair substitutions -- 9% of transversions, 3% of AT leads to GC transitions and 87% of GC leads to AT transitions. Our results establish the 5-3H-C as one of the most effective and specific mutagens reported so far for yeast. According to the scheme of Krasin with coworkers, the final product of 3H decay in the 5-th position of cytosine is uracil. Our calculations show that more than 90% of uracil residues are removed from the yeast genome by cell repair systems.


High antisite defect concentrations in hard-sphere colloidal Laves phases.
Binary mixtures of hard spheres can spontaneously self-assemble into binary crystals. Computer simulations have been especially useful in mapping out the phase behaviour of these mixtures, under the assumption that the stoichiometry of the binary crystal is ideal. Here we show that for a size ratio of q = 0.82 this assumption is not valid near the coexistence region between the fluid and the stable binary crystal, the MgZn2 Laves phase. Instead we find a surprisingly high number of antisite defects: up to 2% of the large spheres are replaced by small spheres in equilibrium. We demonstrate that the defect concentration can be estimated using simple approximations, providing an easy way to identify systems where antisite defects play an important role. Our results shed new light on the self-assembly of colloidal Laves phases, and demonstrate the importance of antisite defects in binary crystals.


Novel treatment for massive lower extremity avulsion injuries in children: slow, but effective with good cosmesis.
Extended avulsion injuries are associated with significant loss of skin and subcutaneous fat, leaving the reconstructive surgeon with the challenge of substituting all tissues lost in the best possible way. We wanted to test whether the combined use of a Vacuum Assisted Closure system (VAC) and Integra Dermal Regeneration Template (IDRT) matched the required treatment profile encompassing initial control of infection, remodeling of body contours, and reconstruction of near normal skin. 4 children with massive lower extremity avulsion injuries were treated with early necrosectomy, VAC application for 3-5 weeks for wound cleansing and wound bed conditioning, subsequent implantation of IDRT, and finally autologous split thickness skin grafting (STSG) for definitive wound closure. Thereafter, a standard rehabilitation program was used. The key parameters of VAC and IDRT application, take rates of IDRT and STSG, complications, length of stay, and final outcome were recorded. In all patients, early removal of necrosis and infection control was successfully achieved. Continuous VAC application fostered the formation of a several millimeters thick new tissue layer partly compensating for the lost hypodermis. IDRT implantation and subsequent STSG yielded take rates of nearly 100% and both functionally and cosmetically excellent long-term results. There were no major complications. The combination of VAC and IDRT in children with massive leg avulsion injuries is feasible, safe, and delivers high-quality long-term outcomes that appear to justify the multiple operative procedures, the long hospitalization times, and the comparatively high costs entailed.


Laser-assisted delivery enhances topical uptake of the anticancer agent cisplatin.
Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration. We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin's pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 μm depth) and deep dermis (MAZ-DD; 912 μm depth) (λ = 10,600 nm, 196 MAZ/cm2). Assessed in an in vitro Franz cell model after 0.5-, 4-, 24 h topical exposure (n = 8), cisplatin delivery was greatly accelerated by AFL, shown by quantitative- and imaging-based inductively coupled plasma-mass spectrometry (ICP-MS). After 30 minutes, cisplatin concentrations were 91.5, 90.8 and 37.8 μg/cm3 in specific 100-, 500, and 1500 μm skin layers respectively, contrasting to 8.08, 3.12, 0.64 μg/cm3 in non-laser-exposed control skin (p < .001; control vs MAZ-MD). Supported by element bioimaging, the greatest relative increases occurred in the deep skin compartment and at later time points. After 24 h, cisplatin concentrations thus rose to 1829, 1732 and 773 μg/cm3, representing a 25-, 103- and 447-fold enhancement in the 100, 500, and 1500 μm deep skin layers versus corresponding controls (p < .001; MAZ-MD). A significant difference in cutaneous uptake using MAZ-MD and MAZ-DD was not shown at any time point, though deeper laser channels resulted in increased transdermal cisplatin permeation (p ≤ .015). In conclusion, AFL is a rapid, practical and existing skin treatment that may provide greatly enhanced uptake of topical cisplatin for treatment of superficial and deep skin cancer.


Epigenetic regulation of planarian stem cells by the SET1/MLL family of histone methyltransferases.
Chromatin regulation is a fundamental mechanism underlying stem cell pluripotency, differentiation, and the establishment of cell type-specific gene expression profiles. To examine the role of chromatin regulation in stem cells in vivo, we study regeneration in the freshwater planarian Schmidtea mediterranea. These animals possess a high concentration of pluripotent stem cells, which are capable of restoring any damaged or lost tissues after injury or amputation. Here, we identify the S. mediterranea homologs of the SET1/MLL family of histone methyltransferases and COMPASS and COMPASS-like complex proteins and investigate their role in stem cell function during regeneration. We identified six S. mediterranea homologs of the SET1/MLL family (set1, mll1/2, trr-1, trr-2, mll5-1 and mll5-2), characterized their patterns of expression in the animal, and examined their function by RNAi. All members of this family are expressed in the stem cell population and differentiated tissues. We show that set1, mll1/2, trr-1, and mll5-2 are required for regeneration and that set1, trr-1 and mll5-2 play roles in the regulation of mitosis. Most notably, knockdown of the planarian set1 homolog leads to stem cell depletion. A subset of planarian homologs of COMPASS and COMPASS-like complex proteins are also expressed in stem cells and implicated in regeneration, but the knockdown phenotypes suggest that some complex members also function in other aspects of planarian biology. This work characterizes the function of the SET1/MLL family in the context of planarian regeneration and provides insight into the role of these enzymes in adult stem cell regulation in vivo.


Medical radiation exposure and human carcinogenesis-genetic and epigenetic mechanisms.
Ionizing radiation (IR) is a potential carcinogen. Evidence for the carcinogenic effect of IR radiation has been shown after long-term animal investigations and observations on survivors of the atom bombs in Hiroshima and Nagasaki. However, IR has been widely used in a controlled manner in the medical imaging for diagnosis and monitoring of various diseases and also in cancer therapy. The collective radiation dose from medical imagings has increased six times in the last two decades, and grow continuously day to day. A large number of evidence has revealed the increased cancer risk in the people who had frequently exposed to x-rays, especially in childhood. It has also been shown that secondary malignancy may develop within the five years in cancer survivors who have received radiotherapy, because of IR-mediated damage to healthy cells. In this article, we review the current knowledge about the role of medical x-ray exposure in cancer development in humans, and recently recognized epigenetic mechanisms in IR-induced carcinogenesis.


Titanium-bone-anchored penile epithesis: preoperative planning and immediate postoperative results.
The principle of osseointegration is accepted and used in reconstructive surgery. This study presents the first series of five patients where titanium implants have been implanted into the pubic bones of female-to-male (FTM) transsexual patients, in order to attach a "bone-anchored" penile epithesis. Following patient selection based on patients' wishes, pubic bones of 10 FTM transsexuals were analysed by CT-scan and a virtual planning was made. A surgical plan was also developed. To date, five FTM transsexuals have undergone the two-stage surgery. During stage-1, two titanium implants ("fixtures") are implanted onto the pubic bone. Four weeks postop, a new CT scan is performed to analyze osseointegration and the final implant position. During stage-2, the soft tissue of the pubic area is reduced; abutments are inserted and passed through the skin. A few weeks after stage 2 surgery, a penile epithesis is connected to the skin-penetrating titanium implants. Two out of 10 patients who received preoperative CT scan presented with smaller pubic bones, not able to accommodate the fixtures as chosen originally. Preoperative virtual planning is crucial for the selection of the appropriate implants size. The stage-1 and stage-2 surgery occurred uneventfully in all five patients. One patient presented with a wound infection 1 week after stage-2 surgery. Postoperative CT scan demonstrates implant osseointegration in all cases. This experimental clinical study demonstrates that titanium osseointegration is feasible onto the pubic bone. This new approach for penile reconstruction constitutes another alternative for both transsexual patients and cases following genital development disorders, post-trauma and surgery.


Road ahead to respiratory health: experts chart future research directions.
Respiratory illnesses are a huge and rising burden to health-care systems and societies worldwide. Research is crucial to tackle the enormous problem of chest diseases. However the vast number of research questions and available research approaches often creates confusion and risks dilution of resources by spreading them too diffusely. Clear research directions will help to use research funds efficiently to provide treatment advances that benefit patient care. This paper presents the visions of leading experts on future research directions, focusing on what should rather than what is going to be done. These opinions provide a guide for new investigators and a platform for intellectual debates through which coordinated research efforts can help progress towards respiratory health.


Clinical assessment and grading of back pain in horses.
The clinical presentation of horses with back pain (BP) vary considerably with most horse's willingness to take part in athletic or riding purpose becoming impossible. However, there are some clinical features that are directly responsible for the loss or failure of performance. To investigate the clinical features of the thoracolumbar region associated with BP in horses and to use some of the clinical features to classify equine BP. Twenty-four horses comprised of 14 with BP and 10 apparently healthy horses were assessed for clinical abnormality that best differentiate BP from normal horses. The horses were then graded (0-5) using the degree of pain response, muscular hypertonicity, thoracolumbar joint stiffness and overall physical dysfunction of the horse. The common clinical features that significantly differentiate horses with BP from non-BP were longissimus dorsi spasm at palpation (78.6%), paravertebral muscle stiffness (64.3%), resist lateral bending (64.3%), and poor hindlimb impulsion (85.7%). There were significantly (p < 0.05) higher scores for pain response to palpation, muscular hypertonicity, thoracolumbar joint stiffness and physical dysfunction among horses with BP in relation to non-BP. A significant relationship exists between all the graded abnormalities. Based on the cumulative score, horses with BP were categorized into mild, mild-moderate, moderate and severe cases. BP in horse can be differentiated by severity of pain response to back palpation, back muscle hypertonicity, thoracolumbar joint stiffness, physical dysfunctions and their cumulative grading score is useful in the assessment and categorization of BP in horses.


Virus evolution in Wolbachia-infected Drosophila.
Wolbachia, a common vertically transmitted symbiont, can protect insects against viral infection and prevent mosquitoes from transmitting viral pathogens. For this reason, Wolbachia-infected mosquitoes are being released to prevent the transmission of dengue and other arboviruses. An important question for the long-term success of these programmes is whether viruses can evolve to escape the antiviral effects of Wolbachia. We have found that Wolbachia altered the outcome of competition between strains of the DCV virus in Drosophila. However, Wolbachia still effectively blocked the virus genotypes that were favoured in the presence of the symbiont. We conclude that Wolbachia did cause an evolutionary response in viruses, but this has little or no impact on the effectiveness of virus blocking.


Neuroinvasive disease due to West Nile virus: Clinical and imaging findings associated with a re-emerging pathogen.
The West Nile virus (WNV) is an arbovirus than can infect human beings and cause severe neuroinvasive disease. Taking the outbreak that occurred in Spain in 2020 as a reference, this article reviews the clinical and imaging findings for neuroinvasive disease due to WNV. We collected demographic, clinical, laboratory, and imaging (CT and MRI) variables for 30 patients with WNV infection diagnosed at our center. The main clinical findings were fever, headache, and altered levels of consciousness. Neuroimaging studies, especially MRI, are very useful in the diagnosis and follow-up of these patients. The most common imaging findings were foci of increased signal intensity in the thalamus and brainstem in T2-weighted sequences; we illustrate these findings in cases from our hospital.


Lateral Position versus Prone Position for Cervical Laminoplasty: A Retrospective Comparative Study.
To examine the safety of lateral decubitus positions for cervical laminoplasty. A retrospective comparative study was conducted on the safety between the lateral and prone positions in cervical laminoplasty. After screening, 466 patients who underwent cervical laminoplasty at a single medical center were enrolled and categorized into the lateral (n=229) and prone (n=237) groups. Data on positioning time, surgical time, blood loss, complication rates, and surgical outcomes were collected and compared between the two groups. The patients were further divided into underweight, normal weight, overweight, and obesity subgroups according to their body mass index, and the collected data were compared between the lateral and prone groups. The lateral group had a lower incidence of facial pressure ulcers (2.18%) than the prone group (11.39%). However, positioning time, surgical time, blood loss, and surgical outcomes were not significantly different between the two groups. In the subgroup analysis, no significant difference in positioning time, operative time, and blood loss was observed in the underweight, normal weight, and overweight patients between the two groups, but in the obesity subgroup, the lateral group had a significantly shorter positioning time (15.23±6.44 vs 21.63±9.43 min, P=0.045) and operative time (140.16±40.48 vs 178.62±51.82 min, P=0.037) and lesser blood loss (285.31±171.75 vs 430.46±189.84 mL, P=0.044) than the prone group. The lateral position is as safe as the prone position for cervical laminoplasty, but it has advantages over the prone position for patients with obesity.


Executive frontal functions.
This chapter presents a conceptual model of the representational and executive functions of the cortex of the frontal lobe derived from empirical evidence obtained principally in the monkey. According to this model, the neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of the temporal organization of behavior. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term memory or sensory working memory, and the other prospective, of attentive set (or motor working memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of working memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex secures the temporal closure at the top of the perception-action cycle.


Antidiabetic Drugs as Antihypertensives: New Data on the Horizon.
The prevalence of Type 2 Diabetes Mellitus (T2DM) is increasing worldwide; this is stimulating more research into the optimal management of this disease. Cardiovascular Disease (CVD) remains the commonest cause of death in individuals with T2DM. Besides hyperglycaemia, an explanation for the increased mortality in this population is the increased prevalence of comorbidities, such as hypertension and dyslipidaemia. Recent population-based studies described a prevalence of hypertension >80% in patients with T2DM. In the last decade new classes of antidiabetic medications have been developed that are effective not only for the management of hyperglycaemia and but also for tailoring treatment according to individual needs and characteristics. Regulatory authorities demand the new antidiabetic medications to be examined for Cardiovascular (CV) safety. Interestingly it has been shown, mainly through CV safety trials, that some new antidiabetic medications not only have glucose lowering effects, but also Blood Pressure (BP) lowering effects, contributing to CV risk reduction. This review considers the effect of older and newer antidiabetic medications on BP in patients with T2DM.


Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage.
Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.


First case of pachyonychia congenita in the Czech Republic.
Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by hypertrophic nail dystrophy, oral leukokeratosis, and painful palmoplantar keratoderma. It is associated with a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The International PC Research Registry (IPCRR) confirms that as of January 2014 there have been 547 cases of PC genetically confirmed. It is estimated that there are between 2000 and 10,000 cases of PC in the world. However, the exact prevalence of PC is not yet established. We report a case of PC-K6a, p.Arg164Pro, in a 40-year-old man. Initially he was diagnosed with onychomycosis and was treated with systemic antifungals. This is the first genetically confirmed case of PC in the Czech Republic.


Benefits of the nonfasting ketogenic diet compared with the initial fasting ketogenic diet.
The ketogenic diet (KD) is traditionally introduced with an initial period of fasting and fluid restriction that is difficult and sometimes complicated by moderate dehydration. This investigation compares the efficacy and tolerability of the nonfasting ketogenic diet (NFKD) and the conventional initial-fasting ketogenic diet (IFKD). Forty-one children with intractable epilepsy were treated with the NFKD, beginning with a gradual increase in calories with no initial fasting or fluid restriction. This NFKD population was compared retrospectively with 83 recent historical control subjects who were treated with the IFKD. Efficacy, tolerability, time until strong ketosis, and occurrence of complications were compared. Fourteen (34.1%) patients became seizure-free for at least 3 months after the NFKD, compared with 29 (34.9%) after the IFKD. There was no significant difference in days until strong urinary ketosis between the 2 groups. The incidence of hypoglycemia was also not significantly different between the groups as most other laboratory findings, although the blood urea nitrogen was elevated in 24.1% of the IFKD group and in only 12.2% of the NFKD patients without statistical significance. Conversely, moderate dehydration was significantly less frequent in the NFKD group (12.2%) than in the IFKD group (62.7%). Finally, these results were reflected to the shortening of the hospitalization period in the NFKD group. These observations suggest that initial fasting and fluid restriction are not essential for the KD and that the tolerability of this treatment may be improved. These data support our intention to conduct a formal, prospective, randomized trial comparing 2 forms of the KD.


Broadband infrared mirror using guided-mode resonance in a subwavelength germanium grating.
We demonstrate a broadband mirror for the IR wavelength region comprising a subwavelength grating made of germanium. We design and optimize the guided-mode resonances in the structure for TM-polarized incident light by rigorous electromagnetic simulations. The grating structure is realized by nanoimprint lithography and dry etching. The reflectivity of the mirror is over 95% for the wavelength range between 2245 and 3080nm.


The new dimension of silver.
Although significant progress in the fabrication and applications of graphene-like materials has been made, free-standing metal monolayers are extremely rare due to the challenges in fabrication. Furthermore, such structures are often unstable versus 3D close-packed forms. Silver is an important noble metal with many unique properties, and has a wide range of applications in daily life and industry. Here, we display a new dimension of silver, i.e., a 2D Ag monolayer, with reduced dimensionality and quantum confinement. We observe that the Ag monolayer is stable in ab initio molecular dynamics simulations up to 800 K for 10 ps. The bond strength per atom actually increases from 0.21 eV for the bulk with twelve bonds to 0.33 eV for the 2D layer with six bonds. This increase in bond strength contributes to the stability of the free-standing 2D layer. Detailed density functional theory calculations are used to predict the properties of this material. The 2D Ag monolayer is the global minimum structure. One electron is delocalized into the whole sheet and is donated to a nearly free 2D electron gas.


Association of neighbourhood migrant density and risk of non-affective psychosis: a national, longitudinal cohort study.
Elevated risk of psychotic disorders in migrant groups is a public mental health priority. We investigated whether living in areas of high own-region migrant density was associated with reduced risk of psychotic disorders among migrants and their children, and whether generation status, probable visible minority status, or region-of-origin affected this relationship. We used the Swedish registers to identify migrants and their children born between Jan 1, 1982, and Dec 31, 1996, and living in Sweden on or after their 15th birthday. We tracked all included participants from age 15 years or date of migration until emigration, death, or study end (Dec 31, 2016). The outcome was an ICD-10 diagnosis of non-affective psychosis (F20-29). We calculated own-region and generation-specific own-region density within the 9208 small areas for market statistics neighbourhoods in Sweden, and estimated the relationship between density and diagnosis of non-affective psychotic disorders using multilevel Cox proportional hazards models, adjusting for individual confounders (generation status, age, sex, calendar year, lone dwelling, and time since migration [migrants only]), family confounders (family income, family unemployment, and social welfare), and neighbourhood confounders (deprivation index, population density, and proportion of lone dwellings), and using the Akaike information criterion (AIC) to compare model fit. Of 468 223 individuals included in the final cohort, 4582 (1·0%) had non-affective psychotic disorder. Lower own-region migrant density was associated with increased risk of psychotic disorders among migrants (hazard ratio [HR] 1·05, 95% CI 1·02-1·07 per 5% decrease) and children of migrants (1·03, 1·01-1·06), after adjustment. These effects were stronger for probable visible minority migrants (1·07, 1·04-1·11), including migrants from Asia (1·42, 1·15-1·76) and sub-Saharan Africa (1·28, 1·15-1·44), but not migrants from probable non-visible minority backgrounds (0·99, 0·94-1·04). Among migrants, adding generation status to the measure of own-region density provided a better fit to the data than overall own-region migrant density (AIC 36 103 vs 36 106, respectively), with a 5% decrease in generation-specific migrant density corresponding to a HR of 1·07 (1·04-1·11). Migrant density was associated with non-affective psychosis risk in migrants and their children. Stronger protective effects of migrant density were found for probable visible minority migrants and migrants from Asia and sub-Saharan Africa. For migrants, this risk intersected with generation status. Together, these results suggest that this health inequality is socially constructed. Wellcome Trust, Royal Society, Mental Health Research UK, University College London, National Institute for Health Research, Swedish Research Council, and FORTE.


Effect of titanium dioxide crystalline structure on the photocatalytic production of hydrogen.
The effect of the crystalline phase of TiO(2) (anatase, rutile and brookite) on its photocatalytic activity in hydrogen production from methanol-water vapours has been investigated by testing a series of both home-made and commercial TiO(2) photocatalysts, either bare or surface-modified by deposition of a fixed amount, i.e. 1 wt%, of platinum as co-catalyst. For all of the TiO(2) samples the rate of hydrogen production increased by one order of magnitude upon Pt deposition, because of the ability of Pt to enhance the separation of photoproduced electron-hole pairs. Under irradiation in the 350-450 nm wavelength range, brookite and anatase showed similar photoactivities, both superior to that of rutile. By contrast, rutile, possessing a narrower band gap, was active also under visible light (λ > 400 nm), whereas no hydrogen evolution was observed with anatase and brookite under such conditions. Surface area proved to be a key parameter, strongly influencing photoactivity. However, as the particle size became ultra-small, the semiconductor absorption edge was blue-shifted because of size quantisation effects, with a consequent decrease in hydrogen production rate due to the smaller portion of incident photons absorbed by the photocatalyst.


The evolving role of plerixafor in hematopoietic progenitor cell mobilization.
The introduction of plerixafor as a peripheral blood stem cell mobilization agent has allowed more patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease to mobilize sufficient hematopoietic progenitor cells (HPCs) to proceed to autologous transplantation. Because of the high cost of plerixafor, it is not routinely used in all patients undergoing HPC mobilization. If cost were not an issue, an argument could be made that plerixafor could be added to every mobilization regimen, but cost is an issue so in an attempt to be more cost-effective, many centers have limited plerixafor use to patients who have failed or who are predicted to fail collection of adequate numbers of cells by other methods. Additionally, plerixafor is now under investigation both for HPC collection of healthy donors for allogeneic stem cell transplantation and as an adjunct therapy (i.e., chemosensitizing agent) for acute leukemias. This article briefly reviews the role of plerixafor in autologous and allogeneic transplantation as well as its emerging role in the treatment of acute leukemias. Emphasis is placed on the choice of appropriate patients for plerixafor use to assure an adequate stem cell yield while maximizing the cost effectiveness of using plerixafor. The role of prophylactic collections and future areas of research are also presented.


Lower vaccine uptake amongst older individuals living alone: A systematic review and meta-analysis of social determinants of vaccine uptake.
Vaccination is a key intervention to reduce infectious disease mortality and morbidity amongst older individuals. Identifying social factors for vaccine uptake enables targeted interventions to reduce health inequalities. To systematically appraise and quantify social factors associated with vaccine uptake amongst individuals aged ≥60years from Europe. We searched Medline and Embase from inception to 24/02/2016. The association of vaccine uptake was examined for social factors relevant at an individual level, to provide insight into individuals' environment and enable development of targeted interventions by healthcare providers to deliver equitable healthcare. Factors included: living alone, marital status, education, income, vaccination costs, area-level deprivation, social class, urban versus rural residence, immigration status and religion. Between-study heterogeneity for each factor was identified using I2-statistics and Q-statistics, and investigated by stratification and meta-regression analysis. Meta-analysis was conducted, when appropriate, using fixed- or random-effects models. From 11,754 titles, 35 eligible studies were identified (uptake of: seasonal influenza vaccine (SIV) only (n=27) or including pneumococcal vaccine (PV) (n=5); herpes zoster vaccine (n=1); pandemic influenza vaccine (n=1); PV only (n=1)). Higher SIV uptake was reported for individuals not living alone (summary odds ratios (OR)=1.39 (95% confidence interval (CI): 1.16-1.68). Lower SIV uptake was observed in immigrants and in more deprived areas: summary OR=0.57 (95%CI: 0.47-0.68) and risk ratio=0.93 (95%CI: 0.92-0.94) respectively. Higher SIV uptake was associated with higher income (OR=1.26 (95%CI: 1.08-1.47)) and higher education (OR=1.05 (95%CI: 1-1.11)) in adequately adjusted studies. Between-study heterogeneity did not appear to result from variation in categorisation of social factors, but for education was partly explained by varying vaccination costs (meta-regression analysis p=<0.0001); individuals with higher education had higher vaccine uptake in countries without free vaccination. Quantification of associations between social factors and lower vaccine uptake, and notably living alone (an overlooked factor in vaccination programmes), should enable health professionals target specific social groups to tackle vaccine-related inequalities.


A conceptual framework for patient-reported outcomes in non-muscle invasive bladder cancer.
Non-muscle invasive bladder cancer (NMIBC) is a chronic condition requiring repeated treatment and endoscopic examinations that can be life-long. In this context, health-related quality of life (HRQOL) is important to patients and managing clinicians, and integral to treatment recommendations for NMIBC. The aim of this study was to develop a conceptual framework of patient-reported NMIBC symptoms, treatment side effects, and HRQOL impacts from three sources: (1) literature, (2) patients and (3) treating clinicians. First, we undertook a scoping literature review for studies reporting patient-reported outcomes associated with NMIBC. Outcomes were extracted and grouped conceptually. Then, we conducted semi-structured interviews with patients with NMIBC and treating clinicians. Patients were asked about symptoms and HRQOL impacts experienced from their NMIBC and treatments. Clinicians were asked about commonly reported outcomes, and outcomes they felt were important to assess clinically. Interviews were audio recorded, transcribed and content analysed. A total of 125 symptom- and functioning-related expressions from 18 studies, 26 patients and 20 clinicians were coded into three themes and 18 sub-themes. Patients commonly reported blood in urine and frequent urination. Clinicians considered BCG sepsis and flu-like symptoms important outcomes to assess during treatment for NMIBC. Our empirically derived conceptual framework identifies patient-reported outcomes that are important to people with NMIBC, provides the basis for the development of a new NMIBC-specific symptom index, and guides the design of a comprehensive PRO assessment plan for clinical practice in NMIBC and future clinical trials of treatments for NMIBC.


Two-Dimensional Fe8N Nanosheets: Ferromagnets and Nitrogen Diffusion.
We perform a first-principles study and identify two intriguing ferromagnets, hollow-Fe8N (H-Fe8N) and bridge-Fe8N (B-Fe8N) monolayers, by extensive structural searches. Both H-Fe8N and B-Fe8N nanosheets are buckled triangular lattices with a similar motif, but they are distinguishable by the positions of N atoms. The magnetic and electronic properties show that H-Fe8N is a low-spin ferromagnet; in contrast, B-Fe8N is a high-spin ferromagnet, which originates from the 3d orbital splitting of the Fe atom due to the low/high symmetric crystal field. Surprisingly, two stable Fe8N monolayers can be transferred to each other by N atom diffusion from the bridge position to the hollow position with the migration energy barrier of 1.5 eV. The energy barrier is affected by introduced Fe defects and rare earth metal dopants. These findings introduce a new tactic to regulate the 2D Fe-nitride monolayers at the atomic scale.


Analysis of expression patterns of breast cancer-specific markers (mammaglobin and gross cystic disease fluid protein 15) in lung and pleural tumors.
The lung is the most common site of metastasis during the natural history of malignant tumors. Breast carcinoma has a propensity for distant metastasis, and the lung and pleura are among the most common metastatic sites. Although it is often difficult to make a clear-cut differential diagnosis between the two, distinguishing primary lung carcinoma from breast carcinoma metastatic to the lung is important because the treatment modalities are different. To elucidate the utility of mammaglobin and gross cystic disease fluid protein 15 (GCDFP-15), which are known to be breast-specific antigens, in distinguishing various primary lung and pleural tumors from breast carcinoma metastasizing to the lung. A total of 20 cases of breast carcinoma metastatic to the lung and 263 tumors of nonbreast origin located in the lung and pleura were analyzed. Of the 20 cases of breast carcinoma metastatic to the lung, 10 (50.0%) were immunoreactive for mammaglobin and 9 (45.0%) for GCDFP-15, the frequency of positivity being slightly higher for the former than for the latter. The area immunopositive for mammaglobin showed more diffuse staining than the area immunopositive for GCDFP-15. Furthermore, the specificity of mammaglobin for breast carcinoma metastatic to the lung was superior (98.9%) to that of GCDFP-15 (91.8%). The sensitivity of mammaglobin is equal or superior to that of GCDFP-15 for investigation of breast carcinoma. Immunopositivity for mammaglobin is more diffuse than that for GCDFP-15. In terms of practical diagnosis, mammaglobin immunohistochemistry can serve as a differential marker of breast carcinoma and should be added to the immunohistochemical panel.


[Practical Optimization and Application of Time-delay Exposure System for Mobile Digital Radiography Equipment].
This study introduced a time-delay exposure system independent of the mobile digital radiography equipment. The system consisted of lithium battery, delay control circuit, micro electric motor and related auxiliary facilities. When the starting time was reached through the delay circuit, the motor pushed out the rod to squeeze the exposure button and completed the exposure. The accessories used in this system were easy to purchase and cheap. At the same time, the technology was mature and had good compatibility. The exposure success rate was high and the exposure effect was satisfactory. This time-delay exposure system had good practicability and popularization value.


Exchange-Correlation Energy Densities and Response Potentials: Connection between Two Definitions and Analytical Model for the Strong-Coupling Limit of a Stretched Bond.
We analyze in depth two widely used definitions (from the theory of conditional probability amplitudes and from the adiabatic connection formalism) of the exchange-correlation energy density and of the response potential of Kohn-Sham density functional theory. We introduce a local form of the coupling-constant-dependent Hohenberg-Kohn functional, showing that the difference between the two definitions is due to a corresponding local first-order term in the coupling constant, which disappears globally (when integrated over all space), but not locally. We also design an analytic representation for the response potential in the strong-coupling limit of density functional theory for a model single stretched bond.


Intracranial calcification and tumoural calcinosis during vitamin D therapy.
Extraskeletal calcifications are frequently observed in patients with chronic renal failure. However, clinically, they usually remain silent. In this report, we describe two patients with massive extraskeletal calcifications that caused significant morbidity. The first patient had tumoural calcification located on the shoulder and the second patient had severe neurological symptoms caused by intracranial calcifications. High calcium phosphorus product and severe secondary hyperparathyroidism were present in both patients. Furthermore, they both received inappropriately high doses of active vitamin D, even though they failed to respond to this therapy. We suggest to monitor closely the calcium, phosphorus and parathyroid hormone levels during calcitriol therapy and to perform parathyroidectomy, without delay, in patients who were resistant to calcitriol.


Evaluation of clarity of presentation and applicability of monitoring instructions for patients using lithium in clinical practice guidelines for treatment of bipolar disorder.
Clinical practice guidelines (CPGs) for treatment of bipolar disorder (BD) aim to provide guidance to health care professionals on monitoring of patients using lithium. The aim was to assess the clarity of presentation and applicability of monitoring instructions for patients using lithium in CPGs for treatment of BD. CPGs for treatment of BD were selected from acknowledged professional organizations from multiple continents. CPGs were rated on the clarity of presentation and applicability of lithium monitoring instructions using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The applicability of monitoring instructions was assessed according to the Systematic Information for Monitoring (SIM) score. Monitoring instructions were considered applicable when a SIM score of ≥3 was found. The clarity of presentation for six out of the nine CPGs was good (>70%) using the AGREE II tool. Only one CPG scored >70% on applicability. Descriptions of the resource implications and facilitators of and barriers to monitoring were most often missing. All CPGs contained instructions for monitoring of lithium serum levels and renal and thyroid function. Information provided in monitoring instructions (n = 247) was in general applicable to clinical practice (77%) based on the SIM score. Overall, a median SIM score of 3 (interquartile range 3-4) was found. Improvement of the applicability of CPGs is recommended, and can be achieved by describing the resource implications and facilitators of and barriers to monitoring. In addition, information on critical values and instructions on how to respond to aberrant monitoring parameters are needed. With such improvements, CPGs may better aid health care professionals to monitor patients using lithium.


Quantification of insulin adherence in adults with insulin-treated type 2 diabetes: A systematic review.
This systematic review aims to identify current methods used for the assessment of insulin adherence in adults with insulin-treated type 2 diabetes. The primary goal is to offer recommendations for clinical practice to improve quantification of adherence. The review was conducted in accordance with PRISMA 2020 and registered at PROSPERO (CRD42022334134). PubMed, Embase, CINAHL, and PsycINFO were searched on 15 November 2022 and included three blocks: Type 2 diabetes, insulin, and adherence. We considered primary full-text studies describing an assessment method and a threshold for assessment of insulin adherence in adults with insulin-treated type 2 diabetes. A final sample of 50 studies were included. Identified methods fell into four categories: self-report, pharmacy claims, inulin count, and data from an insulin pen device. Commonly reported methods included: The Morisky Medication Adherence Scale, the (adjusted) Medication Possession Ratio, and the Proportions of Days Covered. A threshold of <80% was used to define non-adherence in nearly half of the studies. Yet, several thresholds were reported. Most available methods for assessing insulin adherence in adults with insulin-treated type 2 diabetes are severely limited in providing in-depth insights into timing, dosing size, injection patterns, and adherence behavior. However, recognizing diverse types of non-adherence is crucial, as they denote unique behavioral entities requiring targeted intervention. Employing insulin injection data (e.g., from a smart insulin pen cap) to underlie an assessment method is a potential new approach to objectively assess insulin timing and dosing adherence in adults with insulin-treated type 2 diabetes.


Mathematical analysis of mandibular morphogenesis by micro-CT-based mouse and alizarin red S-stained-based human studies during development.
Prenatal development of the mandible is an important factor in its postnatal function. To examine quantitatively normal and abnormal developmental changes of the mandible, we here evaluated morphological changes in mineralizing mandibles by thin-plate spline (TPS) including bending energy (BE) and Procrustes distance (PD), and by Procrustes analyses including warp analysis, regression analysis, and discriminant function analysis. BE and PD were calculated from lateral views of the mandibles of mice or of human fetuses using scanned micro-computed tomography (CT) images or alizarin red S-stained specimens, respectively. BE and PD were compared (1) between different developmental stages, and further, to detect abnormalities in the data sets and to evaluate the deviation from normal development in mouse fetuses, (2) at embryonic day (E) 18.5 between the normal and deformed mandibles, the latter being caused by suturing the jaw at E15.5, (3) at E15.5 and E18.5 between normal and knockout mutant mice of receptor tyrosine kinase-like orphan receptor (Ror) 2. In mice, BE and PD were large during the prenatal period and small after postnatal day 3, suggesting that the mandibular shape changes rapidly during the prenatal and early postnatal periods. In humans, BE of the mandibles peaked at 16-19 weeks of gestation, suggesting the time-dependent change in the mandibular shape. TPS and Procrustes analyses statistically separated the abnormal mandibles of the sutured or Ror2 mutant mouse fetuses from the normal mandible. These results suggest that TPS and Procrustes analyses are useful for assessing the morphogenesis and deformity of the mandible.


A coarse-grained elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations.
Normal mode analysis (NMA) methods are widely used to study dynamic aspects of protein structures. Two critical components of NMA methods are coarse-graining in the level of simplification used to represent protein structures and the choice of potential energy functional form. There is a trade-off between speed and accuracy in different choices. In one extreme one finds accurate but slow molecular-dynamics based methods with all-atom representations and detailed atom potentials. On the other extreme, fast elastic network model (ENM) methods with Cα-only representations and simplified potentials that based on geometry alone, thus oblivious to protein sequence. Here we present ENCoM, an Elastic Network Contact Model that employs a potential energy function that includes a pairwise atom-type non-bonded interaction term and thus makes it possible to consider the effect of the specific nature of amino-acids on dynamics within the context of NMA. ENCoM is as fast as existing ENM methods and outperforms such methods in the generation of conformational ensembles. Here we introduce a new application for NMA methods with the use of ENCoM in the prediction of the effect of mutations on protein stability. While existing methods are based on machine learning or enthalpic considerations, the use of ENCoM, based on vibrational normal modes, is based on entropic considerations. This represents a novel area of application for NMA methods and a novel approach for the prediction of the effect of mutations. We compare ENCoM to a large number of methods in terms of accuracy and self-consistency. We show that the accuracy of ENCoM is comparable to that of the best existing methods. We show that existing methods are biased towards the prediction of destabilizing mutations and that ENCoM is less biased at predicting stabilizing mutations.


Tissue plasminogen activator and plasminogen activator inhibitor-1 levels in patients with acute paraquat intoxication.
To investigate the effects of reactive oxygen species (ROS) on tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) plasma levels, and their possible implications on clinical outcome, we measured tPA and PAI-1 levels in 101 patients with acute paraquat (PQ) intoxication. The control group consisted of patients who ingested non-PQ pesticides during the same period. tPA and PAI-1 levels were higher in the PQ group than in the controls. PQ levels were significantly correlated with ingested amount, timelag to hospital, tPA level, and hospitalization duration. tPA levels were correlated with PAI-1, fibrin degradation product (FDP), and D-dimer. D-dimer levels were lower in the PQ group than in the controls. Univariate analysis indicated the following significant determinants of death: age, ingested amount, PQ level, timelag to hospital, serum creatinine, lipase, pH, pCO(2), HCO(3) (-), WBC, FDP, PAI-1, and tPA. However, multivariate analysis indicated that only PQ level was significant independent factor predicting death. In conclusion, tPA and PAI-1 levels were higher, while D-dimer levels were lower in the PQ group than in the controls, implying that ROS stimulate tPA and PAI-1, but PAI-1 activity overrides tPA activity in this setting. Decreased fibrinolytic activity appears to be one of the clinical characteristics of acute PQ intoxication.


Extrarenal handling of phosphate: effect of thyroparathyroidectomy, 1,25-dihydroxycholecalciferol, and dietary calcium.
It is known that 1,25-dihydroxycholecalciferol [1,25(OH)2D3] mobilizes inorganic phosphate (Pi) from gut and bone, thus increasing the entry of Pi into the extracellular space (ECS). In this work, we have investigated whether 1,25(OH)2D3 could also facilitate the net exit of Pi out of this pool into certain soft tissue and/or bone compartments in thyroparathyroidectomized (TPTX) rats. Sham-operated, TPTX, and TPTX rats treated with 1,25(OH)2D3 (26 pmol/day ip for 1 wk) were infused with a known amount of Pi over a given time. The amount of Pi excreted in the urine in excess of base-line values and the rise of the phosphatemia ([Pi]p) were measured. The difference between these two parameters corresponded to the net retention of infused Pi in the whole animal (RAPi) for a given rise in [Pi]p. The results show that RAPi was markedly diminished in TPTX as compared with sham-operated animals. This decrease could be corrected by 1,25(OH)2D3 treatment. Chronic reduction in the level of calcemia in TPTX 1,25(OH)2D3-supplemented rats as induced by decreasing dietary Ca intake also diminished RAPi. These effects could not be ascribed to the known actions of the experimental maneuvers on the renal excretion of Pi. Since infusions were chosen to obtain similar rises in [Pi]p and started from same levels of [Pi]p in animals of the same weight, the differences in RAPi were not due to variation of Pi retention in the ECS.(ABSTRACT TRUNCATED AT 250 WORDS)


Epitope mapping of HTLV envelope seroreactivity in LGL leukaemia.
Sera from approximately 50% of patients with large granular lymphocyte (LGL) leukaemia react with a recombinant human T-cell leukaemia/lymphoma virus (HTLV) transmembrane envelope protein, p21e. Two immunodominant epitopes within env p21e have been defined by reactivity against recombinant proteins GD21 and BA21. In this study sera from 41 patients with LGL leukaemia were examined for reactivity against these recombinant HTLV env proteins. Overall, 21/41 (51%) sera reacted to p21e. Only two sera reacted to GD21. The predominant immunoreactivity against p21e was directed against the BA21 epitope, with 19/41 (46%) sera being BA21 positive. Seroconversion to BA21 protein was also documented. PCR analyses confirmed the low incidence of protypical HTLV sequences (2/41, 5%). These data document an association between BA21 seroreactivity and LGL leukaemia. This finding raises the possibility that such BA21 seroreactivity could be due to cross-reactivity to a cellular or retroviral antigen sharing some amino acid homology with the transmembrane glycoprotein of HTLV.


Association of Accelerometer-Measured Sedentary Accumulation Patterns With Incident Cardiovascular Disease, Cancer, and All-Cause Mortality.
Background Emerging evidence suggests accruing sedentary behavior (SB) in relatively more prolonged periods may convey additional cardiometabolic risks, but few studies have examined prospective outcomes. We examined the association of SB accumulation patterns with incident cardiovascular disease (CVD), cancer, and all-cause mortality (ACM). Methods and Results Data were from 7671 EPIC-Norfolk (European Prospective Investigation Into Cancer and Nutrition-Norfolk) cohort middle- to older-aged adults who wore accelerometers on the right hip for 4 to 7 days. Cox proportional hazards regression modeled associations between 2 measures of SB accumulation and incident CVD, cancer, and ACM. These were usual SB bout duration (the midpoint of each individual's SB accumulation curve, fitted using nonlinear regression) and alpha (hybrid measure of bout frequency and duration, with higher values indicating relatively shorter bouts and fewer long bouts). Models were adjusted for potential confounders, then further for 24-hour time-use compositions. During mean follow-up time of 6.4 years, 339 ACM, 1106 CVD, and 516 cancer events occurred. Elevated rates of incident cancer and ACM were seen with more prolonged SB accumulation (lower alpha, higher usual SB bout duration) but not CVD. For usual SB bout duration and alpha, respectively, the confounder-adjusted hazard ratios per SD of the exposure were 1.12 (95% CI, 1.02-1.23) and 0.88 (95% CI, 0.79-0.98) with incident cancer and 1.16 (95% CI, 1.07-1.26) and 0.80 (95% CI, 0.72-0.89) with ACM (all P<0.05). Further adjustment for 24-hour time use weakened associations with ACM for usual bout duration (hazard ratio, 1.06; 95% CI, 0.97-1.16; P=0.209) and partially for alpha (hazard ratio, 0.87; 95% CI, 0.77-0.99; P=0.029). Conclusions Accruing SB in longer bout durations was associated with higher rates of incident cancer and ACM but not with incident CVD, with some evidence of direct SB accumulation effects independent of 24-hour time use. Findings provide some support for considering SB accumulation as an adjunct target of messaging to "sit less and move more."


Algorithm for the precise detection of single and cluster cells in microfluidic applications.
Recent advances in imaging flow cytometry and microfluidic applications have led to the development of suitable mathematical algorithms capable of detecting and identifying targeted cells in images. In contrast to currently existing algorithms, we herein proposed the identification and reconstruction of cell edges based on original approaches that overcome frequent detection limitations such as halos, noise, and droplet boundaries in microfluidic applications. Reconstructed cells are then discriminated between single cells and clusters of round-shaped cells, and cell information such as the area and location of a cell in an image is output. Using this method, 76% of cells detected in an image had an error <5% of the cell area size and 41% of the image had an error <1% of the cell area size (n = 1,000). The method developed in the present study is the first image processing algorithm designed to be flexible in use (i.e. independent of the size of an image, using a microfluidic droplet system or not, and able to recognize cell clusters in an image) and provides the scientific community with a very accurate imaging algorithm in the field of microfluidic applications. © 2016 International Society for Advancement of Cytometry.


[Peculiarities of the strategy for the treatment of elderly patients with duodenal ulcer and concomitant metabolic syndrome].
The study showed that ulcer disease in patients with metabolic syndrome is characterized by painless clinical course, bowel disorders in the form of constipation, enhanced appetite, unmotivated requirement for hypoglycemic therapy predisposition to complications along with activation of the inflammatory process in duodenal mucosa, high H. pylori count. The data obtained were used to develop the age-specific strategy for the treatment of elderly patients with duodenal ulcer and concomitant metabolic syndrome.


Atomically precise arrays of fluorescent silver clusters: a modular approach for metal cluster photonics on DNA nanostructures.
The remarkable precision that DNA scaffolds provide for arraying nanoscale optical elements enables optical phenomena that arise from interactions of metal nanoparticles, dye molecules, and quantum dots placed at nanoscale separations. However, control of ensemble optical properties has been limited by the difficulty of achieving uniform particle sizes and shapes. Ligand-stabilized metal clusters offer a route to atomically precise arrays that combine desirable attributes of both metals and molecules. Exploiting the unique advantages of the cluster regime requires techniques to realize controlled nanoscale placement of select cluster structures. Here we show that atomically monodisperse arrays of fluorescent, DNA-stabilized silver clusters can be realized on a prototypical scaffold, a DNA nanotube, with attachment sites separated by <10 nm. Cluster attachment is mediated by designed DNA linkers that enable isolation of specific clusters prior to assembly on nanotubes and preserve cluster structure and spectral purity after assembly. The modularity of this approach generalizes to silver clusters of diverse sizes and DNA scaffolds of many types. Thus, these silver cluster nano-optical elements, which themselves have colors selected by their particular DNA templating oligomer, bring unique dimensions of control and flexibility to the rapidly expanding field of nano-optics.