[Surgical treatment of ventricular septal defect in infants: report of 230 cases].
To review the experience of surgical treatment of ventricular septal defect (VSD) in infants. 230 infants with VSD of less than 3 years old underwent surgical repair from Feb. 1990 to Dec. 1997. Their ages ranged from 3 to 36 months. Their weight was 3.2 to 15.5 kg. The number of patients with perimembranous VSD was 192, and that of subpulmonary VSD 36. Two patients had multiple VSDs. 150 patients (65.2%) had moderate or severe pulmonary hypertension before operation. Thirteen patients died during hospitalization period, with a hospital mortality of 5.65%. The main causes of death were pulmonary hypertensive crisis and arrhythmia. The leading complications were pulmonary infections, arrhythmia and pulmonary hypertensive crisis. Surgical treatment of VSD in infancy may have a satisfactory outcome, it standardized surgical techniques and the improved perioperative management are used.


Genomic and evolutionary aspects of Mimivirus.
We recently described a giant double stranded DNA virus called Mimivirus, isolated from amoebae, which might represent a new pneumonia-associated human pathogen. Its unique morphological and genomic characteristics allowed us to propose Mimivirus as a member of a new distinct Nucleocytoplasmic Large DNA viruses family, the Mimiviridae. Mimivirus-specific features, namely its size and its genomic complexity, ranged it between viruses and cellular organisms. This paper reviews our current knowledge on Mimivirus structure, life cycle and genome analysis and discusses its putative evolutionary origin in the tree of species of the three domains of life.


Aggravation of acute ischemic stroke by hyperthermia is related to an excitotoxic mechanism.
To examine whether hyperthermia aggravates cerebral injury in acute ischemia by an excitotoxic mechanism, we studied the relationship between body temperature on admission and CSF concentrations of neuroexcitatory amino acids in 128 patients with acute ischemic stroke of less than 24 h duration. Stroke worsening was defined as the percent change between the Canadian Stroke Scale (CSS) at 48 h and the CSS on admission. Infarct volume was measured on days 4-7 on cranial computed tomography. Excitatory amino acids were analyzed using HPLC. Glutamate concentration [median (min.-max.)] was 11 (2-19) micromol/l in hyperthermic patients (body temperature >37.5 degreesC) and 5 (2-22) micromol/l in normothermic patients (p < 0.0001). Glycine concentration in hyperthermic and normothermic patients was 16 (3-21) micromol/l and 9 (3-50) micromol/l, respectively (p < 0.0001). Glutamate was significantly higher in patients with hyperthermia only during the first 12 h after the onset of symptoms. The CSF concentrations of glutamate (r = 0.52; p < 0.0001) and glycine (r = 0.62; p < 0.0001) correlated with body temperature. Body temperature was significantly related to stroke worsening and infarct size, but this effect was dependent on the glutamate effect. Glutamate and glycine release during the acute phase of cerebral ischemia could be responsible for the increased brain damage in hyperthermia.


Purification and characterization of an antitumor polysaccharide from Portulaca oleracea L.
In the present study, we purified a unique polysaccharide component (POP) from Portulaca oleracea and found that it had pronounced anti-tumor effects in vivo model. Tumor weight, immune organ index and T lymphocyte subsets were employed to detect the immunoregulatory and antitumor effects of POP after administration. Hematological and biochemical analyses were also investigated in order to evaluate the toxicological aspects related to POP treatment. POP could significantly inhibit the growth of transplantable sarcoma 180 and potentiate the animal's immune responses including an increase in the number of white blood cell (WBC) and CD4(+) T-lymphocytes, as well as the ratio of CD4(+)/CD8(+). Furthermore the serum aspartate transanimase (AST), alanine transaminase (ALT), urea nitrogen (BUN), and creatinine levels in S180-bearing mice were significantly reversed by POP. Considering all these results, it is suggested that the anti-tumor effect elicited by POP could be associated with its immunostimulating properties.


Effectiveness of confidential unit exclusion in screening blood donors of the regional blood bank in Londrina, Paraná State.
For transfusion purposes, blood donors must be accepted both in clinical and serological evaluations and must not have excluded their own donation using the confidential unit exclusion. The objective of this study was to verify whether blood donors who choose self exclusion are more likely to be positive in serological tests than donors who do not. A cross-sectional analysis was carried out of 51,861 consecutive whole blood donations from January 2004 to December 2008 at a public blood bank in Londrina, Southern Brazil. Self exclusion was chosen in 1672 (3.2%) donations, most frequently by first-time blood donors (p-value < 0.0001), by blood donors from external collections (p-value < 0.0001), by men (p value < 0.0001) and by under 30-year-old donors (p-value < 0.0001). The frequency of positive serology was 5.3% in the group that chose self exclusion and 3.5% in the group that did not choose self exclusion (p-value < 0.0001). These results show that confidential unit exclusion used in this blood bank is effective and is inexpensive. However, the diagnostic power to detect blood-borne infections was low and resulted in the discard of a high number of blood bags without any direct or indirect serologic markers of pathogens. The use of confidential unit exclusion could be replaced with molecular tests to screen blood donors.


Prognostic value and time course evolution left ventricular global longitudinal strain in septic shock: an exploratory prospective study.
Our main objective was to describe the course of GLS during the first days of septic shock and to assess the agreement between GLS values and longitudinal strain measured in apical four chambers. A prospective observational single centre study was conducted at the Nimes University Hospital's ICU. All patients admitted for a diagnosis of septic shock without pre-existing heart disease were eligible. Echocardiography (LVEF and GLS) was performed on the first day, and repeated once between day 3 and day 5 then once between day 6 and day 8. We enrolled 40 consecutive patients. Four patients were excluded. In overall population, GLS at T1 was impaired (- 11.0%, IQR(interquartile range) [- 15; - 10]). On T2 exams, a significant improvement of the GLS (- 11% vs - 16% p = 0.02) was observed whereas LVEF remained stable over time. A good agreement between GLS and longitudinal strain measured on a four chambers view was found. Based on the Bland and Altman method, the mean of differences for T1 exams was 0.1 (95% CI [- 0.6; 0.8]) with limits of agreement ranging from - 4 to 4. Myocardial strain is depressed at the early phase of septic shock and improves over time. A single measurement of LS4C view appears sufficient at bedside.


Drugs involved in drug-facilitated crimes: part I: alcohol, sedative-hypnotic drugs, gamma-hydroxybutyrate and ketamine. A review.
In recent years, there has been a notable increase in the number of reports of drug-facilitated crimes (DFCs). Usually, individuals report that they were robbed or assaulted while incapacitated by drugs. Most often, these cases have involved drugs that have the ability to produce an effect that leaves the victim in a semiconscious or unconscious state. It is reasonable to assume that the purpose of drug-induced incapacitation is probably largely unchanged with time. This covers the full range of property offences (particularly theft) and crimes against the person. What have changed are the drugs themselves: the number; type; their accessibility; effects and detection. The purpose of this review is to explore the different aspects related to the involvement and use of ethanol, sedative-hypnotics drugs, gamma-hydroxybutyrate (GHB) and ketamine in DFCs or offences, which may help people working in this field to expand their knowledge for better understanding of the nature of these crimes or offences.


Trehalose protects against cisplatin-induced cochlear hair cell damage by activating TFEB-mediated autophagy.
Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Unfortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calcineurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.


Inoculation with enterococci does not affect colon inflammation in the multi-drug resistance 1a-deficient mouse model of IBD.
Intestinal bacteria are thought to play a role in the pathogenesis of human inflammatory bowel disease (IBD). We investigated whether oral inoculation with specific intestinal bacteria increased colon inflammation in the multi-drug resistance 1a-deficient (Mdr1a (-/-) ) mouse model of IBD. Five-week-old Mdr1a (-/-) mice (FVB background) and FVB mice were randomly assigned to one of two treatment groups (Control or Inoculation, n = 12 per group). All mice were fed AIN-76A rodent diet, and mice in the Inoculation groups also received a single oral bacterial inoculation consisting of twelve cultured Enterococcus species combined with conventional intestinal flora obtained from the gastrointestinal tract of healthy mice (EF.CIF). Body weight, food intake, and disease activity index (DAI) were assessed throughout the study, and at 21 or 24 weeks of age, inflammation was assessed post-mortem by determining colon length and histological injury score (HIS), and plasma serum amyloid A (SAA). Mdr1a (-/-) mice consumed more food than FVB mice at 13 weeks of age (P < 0.05). There was also a significant effect of genotype on body weight, with Mdr1a (-/-) mice weighing less than FVB mice throughout the study (P < 0.05) regardless of treatment, but there was no effect of inoculation on body weight (P > 0.25). Colon HIS of Mdr1a (-/-) mice was significantly higher than that of FVB mice in the Control (9.3 ± 4.7 (mean ± SD) vs. 0.58 ± 0.51; P < 0.001) and Inoculation (6.7 ± 5.1 vs. 0.92 ± 0.39; P < 0.001) groups. There was no difference in colon HIS of Mdr1a (-/-) mice in the Control group compared with Mdr1a (-/-) mice in the Inoculation group (P = 0.25), nor was there any difference in within-group variation of colon HIS in these two Mdr1a (-/-) groups. DAI was higher in Mdr1a (-/-) mice than in FVB mice, but there was no effect of treatment in either strain, nor were there any differences in colon length or plasma SAA. Inoculation of Mdr1a (-/-) mice with the EF.CIF inoculum described here does not increase colon inflammation or reduce the observed variability of inflammation.


The role of pediatric surgery in the medical school curriculum.
In most medical schools, exposure to pediatric surgery is presented as a subspecialty elective. We have offered it as an integral part of the surgical clerkship for 10 years in the belief that it provides an excellent educational environment. To confirm this concept, the quizzes (Q), final examinations (FE), and grades of students assigned to the pediatric surgical service were prospectively studied. All students (N = 139) in the surgical clerkship entered the study. Thirty-two students were randomly selected and assigned to the surgical service of a major pediatric hospital (P-Surg) for 50% of their clerkship. The other students (N = 107) were assigned to a variety of adult surgical services (G-Surg) and served as the control group. All students attended the same seminars, used the same educational materials, were examined with the same test items, and were evaluated by the same oral examiners. Test items were electronically scored and the database was analyzed on an IBM computer. The statistical analysis was performed using a Student's t test and chi 2 analysis. There was no significant difference in the demonstrated cognitive performance and grades awarded to the two groups of students. We conclude that a pediatric surgical service provides an atmosphere that is educationally comparable to the adult general surgical service.


Endovascular aortic aneurysm repair with the talent stent-graft: outcomes in patients with large iliac arteries.
The purpose of this study is to report outcomes following endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) in patients with ectatic common iliac arteries (CIAs). Of 117 AAA patients treated by EVAR between 1998 and 2005, 87 (74%) had CIAs diameters <18 mm and 30 (26%) patients had one or more CIA diameters >18 but <25 mm. All patients were treated with Talent stent-grafts, 114 bifurcated and 3 AUI devices. Departmental databases and patient records were reviewed to assess outcomes. Technical success, iliac-related outcome, and iliac-related reintervention (IRSI) were analyzed. Patients with EVAR extending into the external iliac artery were excluded. Median (range) follow-up for the study group was 24 (1-84) months. Initial technical success was 98% for CIAs <18 mm and 100% for CIAs >/=18 mm (p = 0.551). There were three distal type I endoleaks (two in the ectatic group) and six iliac limb occlusions (one in an ectatic patient); there were no statistically significant differences between groups (p = 0.4). There were nine IRSIs (three stent-graft extensions, six femorofemoral crossover grafts); three of these patients had one or both CIAs >/=18 mm (p = 0.232). One-year freedom from IRSI was 92% +/- 3% and 84% +/- 9% for the <18-mm and >/=18-mm CIA groups, respectively (p = 0.232). We conclude that the treatment of AAA by EVAR in patients with CIAs 18-24 mm appears to be safe and effective, however, it may be associated with more frequent reinterventions.


SGLT2 Inhibitors Improve Cardiac Failure by Reducing Whole-Body Oxygen Demand: A Hypothesis.
Beyond the effects of lowering glycated hemoglobin, recent evidence for sodium-glucose cotransporter 2 (SGLT2) inhibitors has revolutionarily impacted the management of patients with heart failure. However, the mechanism of SGLT2 inhibitors that can explain the following features has not been clarified. First, SGLT2 inhibitors significantly reduced the risk of heart failure in the early stage. Second, SGLT2 inhibitors are effective in treating heart failure without increasing cardiac output. Third, the effects of SGLT2 inhibitors are incremental and complementary to those of conventional therapies for heart failure. Fourth, SGLT2 inhibitors can improve prognosis in patients with heart failure independent of the ejection fraction. Fifth, SGLT2 inhibitors show consistent effects on heart failure, irrespective of etiology. Based on the perspective of Guyton's physiology and clinical experiences that SGLT2 inhibitors reduced oxygen consumption of the whole body, we provided a demand-reducing theory that SGLT2 inhibitors alleviate the imbalance between oxygen demand and supply not by increasing cardiac output but by reducing oxygen consumption of the whole body, which can explain several unique characteristics of SGLT2 inhibitors.


Early-stage mycosis fungoides variants: case-based review.
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. The diagnosis of classic MF is based on a combination of clinical presentation, histopathology, and T-cell monoclonality detected by molecular studies. However, the diagnosis can be difficult in cases of early MF because of the subtle nature of histologic findings and, in cases of variants of MF, because of the unusual clinical and/or pathologic features. In this review, we presented the most frequent variants of MF at early stage including hypopigmented, folliculotropic, pagetoid reticulosis, unilesional, granulomatous, and ichthyosis forms. This case-based clinicopathologic review provides the notion that a comprehensive clinicopathologic correlation is of substantial importance to render the diagnosis of MF. In addition, we discuss the role of molecular studies, which are highly sensitive and recently more applicable to routinely processed skin biopsy specimens in the diagnosis of MF.


Multilevel depth-wise context attention network with atrous mechanism for segmentation of COVID19 affected regions.
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) also named COVID-19, aggressively spread all over the world in just a few months. Since then, it has multiple variants that are far more contagious than its parent. Rapid and accurate diagnosis of COVID-19 and its variants are crucial for its treatment, analysis of lungs damage and quarantine management. Deep learning-based solution for efficient and accurate diagnosis to COVID-19 and its variants using Chest X-rays, and computed tomography images could help to counter its outbreak. This work presents a novel depth-wise residual network with an atrous mechanism for accurate segmentation and lesion location of COVID-19 affected areas using volumetric CT images. The proposed framework consists of 3D depth-wise and 3D residual squeeze and excitation block in cascaded and parallel to capture uniformly multi-scale context (low-level detailed, mid-level comprehensive and high-level rich semantic features). The squeeze and excitation block adaptively recalibrates channel-wise feature responses by explicitly modeling inter-dependencies between various channels. We further have introduced an atrous mechanism with a different atrous rate as the bottom layer. Extensive experiments on benchmark CT datasets showed considerable gain (5%) for accurate segmentation and lesion location of COVID-19 affected areas.


Cloning, tissue expression and metal inducibility of an ubiquitous metallothionein from Panulirus argus.
Invertebrate metallothioneins (MT) have mainly been reported in digestive tissues, but data about the existence of a ubiquitous isoform expressed also in nervous tissue, are not available. Here we report the identification of a new metallothionein gene (MTPA) from the lobster Panulirus argus, putatively encoding a 59 residue polypeptide including 19 Cys. Tissue specific analysis indicated that MTPA is ubiquitously expressed in the hepatopancreas, intestine, nervous tissue and muscle, with the highest levels in the hepatopancreas and the lowest in muscle and nervous tissue. In addition, our data showed that MTPA is differentially regulated by metals: tissue explants exposed to Cd exhibited increased MTPA mRNA levels in all cases, except in muscle, with the highest effects in the nervous tissue, while Zn was effective only in the hepatopancreas. Interestingly, Cu showed no effects in any of the analyzed tissues. Taken together, these results suggest that MTPA in the hepatopancreas likely plays an important role in Cd detoxification and Zn homeostasis. The potent Cd-inducibility of MTPA in the nervous tissue might suggest a key function of this protein in protecting this highly sensitive tissue from cadmium-induced neurotoxicity.


BCOR-CCNB3 sarcoma with concurrent RNF213-SLC26A11 gene fusion: a rare sarcoma with altered histopathological features after chemotherapy.
Chemotherapy is a common approach for cancer treatment, but intrinsic genetic mutations in different individuals may cause different responses to chemotherapy, resulting in unique histopathological changes. The genetic mutation along with the distinct histopathological features may indicate new tumor entities. BCOR-CCNB3 sarcomas is a kind of Ewing-like sarcomas (ELS) occurring mostly in bone and soft tissues. No gene fusion other than BCOR-CCNB3 has been found in this type of tumor. We herein report a case of 17-year-old male patient, presented with a mass on his left shoulder that was diagnosed as undifferentiated small round cell sarcoma according to core biopsy. The patient received 5 courses of preoperational chemotherapy, and the tumor was resected and analyzed. Primitive small round cells and larger myoid cells in the resected tumor tissue but not in biopsy were observed, and arterioles stenosis and occlusion were also detected, indicating a dramatic change of histopathological features of this tumor. In addition, the immunohistochemical results showed the altered staining patterns of BCOR, bcl2, CyclinD1, TLE1, AR, SMA, CD117, STAB2, CD56, and CD99 in tumor tissues after chemotherapy. Notably, RNA sequencing revealed a RNF213-SLC26A11 fusion in the tumor sample. The BCOR-CCNB3 sarcoma with RNF213-SLC26A11 fusion may indicate a subset of tumors that undergo histopathological changes in response to chemotherapy. More similar cases in the future may help to clarify the clinical meanings of RNF213-SLC26A11 fusion in BCOR-CCNB3 sarcomas and the underlying mechanisms.


Sparse group selection and analysis of function-related residue for protein-state recognition.
Machine learning methods have helped to advance wide range of scientific and technological field in recent years, including computational chemistry. As the chemical systems could become complex with high dimension, feature selection could be critical but challenging to develop reliable machine learning based prediction models, especially for proteins as bio-macromolecules. In this study, we applied sparse group lasso (SGL) method as a general feature selection method to develop classification model for an allosteric protein in different functional states. This results into a much improved model with comparable accuracy (Acc) and only 28 selected features comparing to 289 selected features from a previous study. The Acc achieves 91.50% with 1936 selected feature, which is far higher than that of baseline methods. In addition, grouping protein amino acids into secondary structures provides additional interpretability of the selected features. The selected features are verified as associated with key allosteric residues through comparison with both experimental and computational works about the model protein, and demonstrate the effectiveness and necessity of applying rigorous feature selection and evaluation methods on complex chemical systems.


Melatonin activates brain dopaminergic systems in the eel with an inhibitory impact on reproductive function.
In the eel, a deficit in gonadotrophin-releasing hormone (GnRH) and a strong dopaminergic (DA) inhibition are responsible for the blockade of gonad development if silver eels are prevented from their reproductive migration. Environmental factors that eels encounter during their oceanic reproductive migration are thought to play an important role in the stimulation of eel pubertal development. We investigated the potential role of melatonin, a known mediator of the effects of external factors on reproductive function in vertebrates. We demonstrated that a long-term melatonin treatment increased brain tyrosine hydroxylase (TH, the rate limiting enzyme of DA synthesis) mRNA expression in a region-dependent way. Melatonin stimulated the dopaminergic system of the preoptic area, which is involved in the inhibitory control of gonadotrophin [luteinising hormone (LH) and follicle-stimulating hormone (FSH)] synthesis and release. Moreover, we showed that the increased TH expression appeared to be consistent with melatonin binding site distribution as shown by 2[(125)I]-melatonin labelling studies. On the other hand, melatonin had no effects on the two eel native forms of GnRH (mGnRH and cGnRH-II) mRNA expression. Concerning the pituitary-gonad axis, we showed that melatonin treatment decreased both gonadotrophin beta-subunit (LHbeta, FSHbeta) mRNA expression and reduced sexual steroid (11-ketotestosterone, oestradiol) plasma levels. This indicates that melatonin treatment had a negative effect on eel reproductive function. To our knowledge, the results of the present study provide the first evidence that melatonin enhances TH expression in specific brain regions in a non-mammalian species. By this mechanism melatonin could represent one pathway by which environmental factors could modulate reproductive function in the eel.


The painful eye: neuro-ophthalmic causes.
A physician should have a better appreciation of diseases that can cause significant ocular morbidity and, in some cases, death. This article describes some of the painful eye syndromes associated with ocular, orbital, and intracranial disease. Differential diagnosis, clinical findings, laboratory investigation, and treatment are reviewed.


Higher odds of abortion in dairy cows hoof trimmed late in gestation.
Until now, it is unknown whether hoof trimming late in gestation is associated with increased risk of abortion in dairy cows. Using data from 1,476,013 pregnancies in Danish dairy cows, the objective of the present study was to evaluate risk factors for abortion in cows hoof trimmed during pregnancy. Odds of abortion was lower in first parity cows, lower in Jersey cows compared to other breeds, and higher in cows pregnant with twins. Odds of abortion was 2.4 times higher in cows hoof trimmed within the last four weeks before end of pregnancy. Hoof trimming of cows in late gestation should be done with caution.


Isolation and purification of calcium-binding proteins from bovine neurohypophyses.
An acidic calcium-binding protein was isolated from the soluble fraction of the homogenate of ox neurohypophyses. The protein has a molecular weight of 35 000 and a subunit weight of 15 000. The purification procedure involved ammonium sulphate fractionation, DEAE-cellulose chromatography and gel filtration on Sephadex G-100 and Sephadex G-50. Conventional and sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated it to be a protein distinct from the S-100 protein and the soluble hormone-binding proteins (neurophysins) abundant in the neurohypophysis. This appears to be the only Ca2+-binding protein in the soluble part of the homogenate, with an apparent Kdiss for Ca2+ of 1.1 X 10(-5) M (at 22 degrees C) and a binding capacity of 2 mol of calcium per mol of protein. Two different Ca2+-binding proteins of molecular weights 16 500 and 68 000, respectively, were identified in the sodium-deoxycholate-soluble proteins from an ox neurohypophysial microsome fraction. One of them (the former) has been isolated in high purity by DEAE-cellulose chromatography and gel filtration on Sephadex G-200. This protein binds 4 mol of calcium per mol of protein with an apparent Kdiss of 1.0 X 10(-5) M (at 22 degrees C). The sodium-deoxycholate-insoluble proteins from the microsomal fraction also have Ca2+-binding components. The soluble Ca2+-binding protein has properties similar to and may be identical to Ca2+-binding proteins which have been isolated from bovine brain and have been demonstrated to be modulators of brain cyclic nucleotide phosphodiesterase and of actinomyosin ATPase. It also resembles Ca2+-binding proteins isolated from bovine adrenals and the electroplax from electrophorus electricus.


Patterns of seed germination in Californian serpentine grassland species.
Germination of nine Californian serpentine annual species and one perennial grass was examined as a function of soil and litter cover and seasonal timing of rainfall. Germination responses varied with the date of moisture application, and the patterns of variation differed among species. Germination occurred in waves over time, but in most of the species, virtually all the seeds had germinated by December. These results indicate that yearly climatic variation can affect species composition and competitive relationships among species through the germination process. Soil and litter cover produced little or no effect except for the smallest-seeded species.


Short-term effects of menthol on walking dyspnoea in patients with COPD: a randomised, single blinded, cross-over study.
Chewing menthol gum prior to exercise is a safe, easy-to-implement, low-cost, non-pharmacologic intervention that provides a reduction in dyspnoea in a third of patients and decreases the perception of discomfort during exercise in two-thirds of patients https://bit.ly/3FoFHp1.


Rapid diagnosis of adenoviral keratoconjunctivitis by a fully automated molecular assay.
To establish and evaluate a new test system for rapid detection and diagnosis of adenoviral keratoconjunctivitis. After establishment of the molecular assay, 52 conjunctival smears were studied. Samples were derived from patients with a clinical presentation compatible with keratoconjunctivitis. A molecular assay for detection of human adenovirus (HAdV) based on automated nucleic acid extraction and real time polymerase chain reaction was established and evaluated. The new assay included a heterologous internal control. Statement about the presence or absence of adenoviral DNA in the specimen. The amplification efficiency was found to be 100%. The detection limit was calculated to be 116 copies per LightCycler capillary. When clinical specimens were tested, 15 of 52 conjunctival smears were found to be positive for HAdV DNA. The internal control was detected in all samples. The new molecular assay proved to be suitable for rapid diagnosis of adenoviral keratoconjunctivitis in the routine diagnostic laboratory.


Mechanical degradation of porous titanium with entangled structure filled with biodegradable magnesium in Hanks' solution.
The degradation behavior of the porous titanium with entangled structure filled with biodegradable magnesium (p-Ti/Mg) in Hanks' solution was investigated. It was found that the p-Ti/Mg composite had higher strength than pure magnesium and porous titanium with entangled structure (p-Ti). Although the magnesium in p-Ti/Mg was completely dissolved in Hanks' solution after immersion for 104 h, the rest of the sample still maintained strength of about 86 MPa. Moreover, the produced porousness (due to magnesium-degradation) could provide channels for the ingrowth and transportation of bone cells. However, the high corrosion rate of p-Ti/Mg is still a problem when used as a candidate biomedical material, which needs further improvement.


Ultrasound Assessment of Diaphragmatic Motion in Subjects With ARDS During Transpulmonary Pressure-Guided PEEP Titration.
We aimed to investigate the effects of incremental PEEP titration in patients with ARDS on regional diaphragmatic motion with bedside ultrasound. Dorsal diaphragmatic excursion (DDE) and ventral diaphragmatic excursion (VDE) were measured using anatomic M-mode ultrasonography of the right hemidiaphragm as PEEP was randomized to -6, -3, +3, and +6 cm H2O from baseline to achieve a positive transpulmonary pressure. Inter-operator variability of DDE was assessed in 10 separate subjects. A total of 14 subjects ventilated for ARDS were enrolled. Subjects had a mean age of 54 ± 12 y, mean PaO2 /FIO2 = 137 ± 54 mm Hg, and mean sequential organ failure assessment (SOFA) score = 14 ± 1). Transpulmonary pressure, DDE, and DDE/VDE ratio increased with incremental PEEP titration (-1.15 cm H2O vs 3.63 cm H2O, P < .001; 4.9 mm vs 8.2 mm, P < .001; and 62% vs 93%, P < .001, respectively). When transpulmonary pressure became positive, a visual increase in DDE and DDE/VDE ratio 0.60 to 0.93 was observed (from 0.48 cm to 0.82 cm, R2 = 0.87, P = .02; and R2 = 0.93, P = .006, respectively). There was high agreement in DDE measurements between 2 ultrasonographers (intra-class correlation 0.987, P < .001). DDE was affected by incremental PEEP titration toward a positive transpulmonary pressure. The ultrasound assessment using anatomic M-mode allowed for specific measurement of regional diaphragmatic excursion. This pattern of motion in the dependent regions of the diaphragm during PEEP titration in subjects with ARDS achieving a positive transpulmonary pressure may reflect a potential target for future studies in the bedside assessment for lung recruitment. (Clinical Trials.gov registration NCT02463773.).


Sex difference in cold perception and shivering onset upon gradual cold exposure.
To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (TE) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1-2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher TE than men (11.3 ± 1.8 °C for women vs 9.6 ± 1.8 °C for men, P = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher TE than men (18.3 ± 3.0 °C for women vs 14.6 ± 2.6 °C for men, P < 0.001). This study demonstrates a sex difference in response to cold exposure: women require shivering as a source of heat production earlier than men. This difference could be important and sex should be considered when using cooling protocols in physiological studies.


gVARVI: A graphical software tool for the acquisition of the heart rate in response to external stimuli.
At present, tools capable of acquiring heart rate data can be found both in commercial and research fields. However, these tools do not allow users to manage experiments comprising sequences of activities or to store the information needed to perform heart rate variability analysis across different activities. One exception is VARVI, a simple software tool developed previously in our research group that does not have a graphical user interface and it works only with visual stimuli. In this paper, we present gVARVI, a software tool aimed at obtaining heart rate data signals while the user is either receiving a sequence of external stimuli or performing a sequence of actions (an activity). gVARVI is an open source application developed in Python programming language. It can acquire heart rate data by means of a wireless chest strap using either Bluetooth or ANT+ protocols. Users can define activities of different types (video, sounds, pictures or keyboard controlled actions) which will associate contextual information to the heart rate data. gVARVI allows users to preview this data or to store it to be used for heart rate variability studies. Our tool was validated by 15 researchers, who worked with the application and filled in a usability questionnaire. The outcome of the usability test was satisfactory, giving a mean score of 4.75 in a 1-5 scale (1 - strongly disagree, 5 - strongly agree). Participants also contributed with valuable comments, which we used to include new features in the last version of our tool. gVARVI is an open source tool that offers new possibilities to both physicians and clinicians to perform heart rate variability studies. It allows users to acquire heart rate data including information on the activity performed by subjects while recording. In this paper, we describe all the functionalities included in gVARVI, and a complete example of use is provided.


Dynamic modeling in ovarian cancer: an original approach linking early changes in modeled longitudinal CA-125 kinetics and survival to help decisions in early drug development.
Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients. The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations. The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance. We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.


Extensive pathological analysis of selected melanoma sentinel lymph nodes: high metastasis detection rates at reduced workload.
Extensive pathological workup of sentinel lymph nodes (SLNs) in melanoma detects more patients with metastasis-positive SLNs than do routine protocols, but at the cost of high laboratory workloads. We aimed to design a protocol that reduced this workload without compromising metastasis detection. We analyzed 920 SLNs from 321 consecutive patients with melanoma by complete step sectioning and immunohistochemistry. We designed different models to theoretically reduce the number of histological sections examined and compared the results from these simulations with results obtained with our extended protocol, with the restricted national Danish protocol, and with the protocol recommended by the European Organization for Research and Treatment of Cancer (EORTC). The extended protocol increased the metastasis detection rate by 22% (95% confidence interval, 11-34; 30.8% vs. 25.2%, P < .0001) compared with the national Danish protocol, and it had a similar rate to that reported by the EORTC (30.8% vs. 29.4%, P = .6229). The workload associated with complete step sectioning could be reduced by 40% by focusing step sectioning on the SLNs with the highest gamma counts, while examining SLNs with lower gamma counts with one to three central sections. The false-negative rate for detecting metastases with this reduced protocol was 6% compared with complete step sectioning. Combining complete step sectioning of SLNs with immunohistochemistry ensures high metastasis detection rates. Workloads can be markedly reduced with only a slight increase in the false-negative rate by focusing analysis on the SLNs most likely to contain metastases, i.e., those with the highest gamma counts.


Acinic cell carcinoma on the lower lip resembling a mucocele.
A 64-year-old woman presented with a 2-week history of an asymptomatic mass involving the lower lip. Histopathological examination showed a well-circumscribed tumour composed of many lobules separated by thin, fibrous connective tissue. Individual lobules were composed of round or polyhedral tumour cells, which had a characteristic finely granular and vacuolated cytoplasm and eccentric hyperchromatic nuclei. Positive staining was observed with Periodic acid-Shiff, and immunohistochemistry for cytokeratin, alpha-1 antitrypsin, and S-100 protein resulting in a final diagnosis of acinic cell carcinoma. Acinic cell carcinoma represents a well-established, although uncommon, entity in the classification of neoplasms of salivary gland origin. The parotid salivary gland is the most frequent site of acinic cell carcinoma, whereas the lip is a particularly unusual site. The unusual presentation of this tumour may lead to confusion with a mucocele. Given these findings, we suggest that acinic cell carcinoma should be considered in the differential diagnosis of any mucocele-like mass on the lower lip.


Reliability and Validity of the Child and Adolescent Behavior Assessment (CABA): A Brief Structured Scale.
Use of valid, affordable, accessible, and brief measures facilitates the assessment of mental health outcomes. The Child and Adolescent Behavior Assessment Scale, a brief, structured scale, assesses problem behavior through patient and/or informant report. The purpose of this paper is to illustrate the scale's psychometric properties. In the cross-sectional study presented, a large national sample of youth (aged 5-18) admitted for psychiatric treatment (N = 32,689) was examined. The two major domains of problem behavior assessed were Internalizing and Externalizing. Reliability was good to excellent with alpha levels ranging from 0.874 to 0.917. Additional items measured Risk Behavior (α = 0.648). Subscale total scores correlated well with the Brief Psychiatric Rating Scale for Children, 9-item version (BPRS-C-9). Exploratory and confirmatory factor analyses supported the three-factor, multidimensional model of problem behavior as satisfactory for child and adolescent use, although further research is required to refine some items for clarity and improved model fit.


A new laser pain threshold model detects a faster onset of action from a liquid formulation of 1 g paracetamol than an equivalent tablet formulation.
To discover whether a new infra-red laser method could detect a change in pain threshold after as mild an analgesic as paracetamol and whether an effervescent liquid formulation produced a faster onset of action than tablets. This double-blind, placebo controlled randomized study used a portable, infra-red laser to measure "first pain" thresholds on the nondominant forearm in 12 normal volunteers before and after 1 g of paracetamol or placebo. The mean of six recordings was determined three times before dosing, the first being used as a familiarization procedure, and 14 times after dosing. We detected a small (2%), statistically significant difference in pain threshold between a liquid formulation of paracetamol and placebo at 30 and 60 min (P = 0.004 and P = 0.001), but not between tablets and placebo. Liquid also increased the threshold significantly compared with tablets at 60 min (P = 0.01). To detect such a small increase in pain threshold requires a highly consistent measure and the coefficient of variation was 2% for the study overall, surprisingly low for a subjective phenomenon. The reasons for this include minimizing reflectance by blacking the skin, using a nonhairy site, averaging six data points at each sample time and controlling closely the ambient conditions and the subjects' preparation for studies.


Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks.
Epithelial-mesenchymal transition (EMT) is a key event preceding tumor cell metastasis that increases cell invasiveness and cancer stem cell (CSC) populations. Studies suggest that genes used in generating circadian rhythms also serve in regulating EMT. To test the role of circadian clocks in cellular EMT events two cancer cell lines were compared, one that has a well-established circadian clock, C6 from rat glioma, and one that does not, MCF-7 from human breast tumor. MCF-7 tumorsphere cultures were tested for evidence of circadian rhythms because of previously reported circadian rhythm enhancement in C6 tumorspheres shown by elevated rhythm amplitude and increased expression of circadian clock gene Per2. Bioluminescence imaging of Per2 gene expression in MCF-7 tumorspheres revealed a previously unconfirmed circadian clock in this important cancer research model. Inducing CSC generation through EMT in C6 and MCF-7 monolayer cultures revealed circadian oscillations in the size of the post-EMT CSC population, confirming that circadian rhythms are additional processes controlling this stage of cancer progression. EMT was verified by distinct cellular morphological changes and expression of stem cell proteins OCT4, nestin, MSI1, and CD133 along with EMT-related proteins ZEB1, vimentin, and TWIST. Quantifying single-cell events and behaviors through time-lapse imaging indicated the post-EMT population size was determined largely by circadian rhythms in epithelial-like cancer cells undergoing EMT. We then identified a specific phase of the circadian rhythm in Per2 gene activation as a potential target for therapeutic treatments that may suppress EMT, minimize CSCs, and limit metastasis.


Successful removal of traumatic tattoos in Asian skin with a Q-switched alexandrite laser.
Traumatic tattoos result from mechanical penetration of the skin by foreign-body particles associated with puncture, abrasive, or explosive trauma. Until the recent development of the Q-switched lasers, it was not possible to remove tattoo pigments without scar and pigmentary changes. The objective of this study was to determine the effectiveness of the Q-switched alexandrite laser (wavelength, 755 nm; pulsewidth, 100 ns), in treating the 27 cases of Asian skin with 36 traumatic tattoos and to observe any side effects such as scarring or pigmentary change. The results of treatments on 16 patients with 19 penetrant tattoos, 10 patients with 16 abrasive tattoos and 1 patient with bomb explosion were clinically analyzed. Greater than 76% removal of tattooed pigments required an average of 1.7 treatment sessions in penetrant tattoos in contrast with 2.4 sessions in abrasive tattoos. The excellent removal of traumatic tattoos required 7.5 J/cm2 except the scarred region of one explosive tattoo and one abrasive tattoo on soil. There were no permanent side effects such as scar or permanent pigmentary changes. In conclusion, the Q-switched alexandrite laser is a safe and highly effective modality for removal of various traumatic tattoos without scar or permanent pigmentary change in Asian skin.


Targets to prevent prolonged length of stay after endovascular aortic repair.
Endovascular aneurysm repair (EVAR) is a commonly performed vascular operation. Yet, postoperative length of stay (LOS) varies greatly, even within institutions. The present study reviewed the morbidity, mortality, and the financial effect of increased LOS to establish modifiable factors associated with prolonged hospital LOS, with the goal of improving quality. The Society for Vascular Surgery Vascular Quality Initiative database was used to identify all patients undergoing primary, elective EVAR at a single institution between January 1, 2011, and May 28, 2014. Preoperative patient characteristics, intraoperative details, postoperative factors, long-term outcomes, and cost data were reviewed using an Institutional Review Board-approved prospectively collected database. Multivariate analysis was used to determine statistical difference between patients with LOS ≤2 days and >2 days. Complete 30-day variable and cost data were available for 138 patients with an average follow-up of 12 months; of these, 46 (33%) had a LOS >2 days. Variables determined to be statistically significant predictors of prolonged LOS included aneurysm diameter (P = .03), American Society of Anesthesiologists Physical Status Classification score (P < .001), thromboembolectomy (P = .01), and increased postoperative cardiac (P < .001) and renal (P = .01) complications. Specifically, modifiable risk factors that contributed to increased LOS included performance of a concomitant procedure (P < .001), increased volume of iodinated contrast (P = .05), increased volume of intraoperative crystalloid (P = .05), placement in an intensive care unit (P < .001), return to the operating room (P < .001), and the use of vasoactive medications (P < .001). Hospital charges ($102,000 ± $41,000 vs $180,000 ± $73,000; P = .01) and costs ($27,000 ± $10,000 vs $45,000 ± $19,000 P = .01) were significantly higher in patients with prolonged LOS; however, there was no difference in physician charges ($8000 ± $5700 vs $12,000 ± $12,000; P = .09). Increased LOS after EVAR was associated with an increase in mortality at 1 month (0% vs 4% P = .05) and 12 months (3% vs 13% P = .03). This study highlights several modifiable risk factors leading to increased LOS after EVAR, including performance of concomitant procedures, admission to the intensive care unit, and postoperative renal and cardiac complications. Further, increased LOS was associated with increased charges, costs, morbidity, and mortality after EVAR. This study highlights specific areas of focus for decreasing LOS after EVAR and, in turn, improving quality in vascular surgery.


Intentionally Created Localized Bridges for Electron Transport Through Graphene Monolayer Between Two Metals.
Monolayer graphene (1LG) is frequently unpredictably modified by supporting material so that it limits development of devices. Van der Waals interaction is dominant in the models describing the in-plane processes, including the electrical charge transport. However, the current flow perpendicular to the plane of the graphene is still less understood. This report analysed specific aspect of the perpendicular current and disclosed an original way to create transport bridges perpendicular to the plane across the 1LG. The most extraordinary finding is that the electron transport between two parallel metal surfaces can be shut down and opened if the metals are separated by the 1LG. The electron transmission can be intentionally varied in this metal - 1LG - metal (M-G-M) system by pressure. In the experimental study the AFM force curve and tunnelling current measurements were combined when the external load force (0 - 1200 nN) and electrical potential (-1.5 V - +1.5 V) were used. It is proved that for low voltages (< ±9 mV) a bridge is opened perpendicular to the graphene across the M-G-M systems by the external force, if the compression dependent Fermi level crosses electronic states in the interfaces and graphene. The localised bridges with diameter about 10 - 40 nm can be opened and kept continuously by the stabilised force in separated points of the system. However, the predictable changes can be produced in the system if the voltage and the force exceeded critical magnitudes. A combined model was proposed acceptable to explain the bridging and predictably modify the characteristics.


The survival of adenovirus in multidose bottles of topical fluorescein.
To determine if common ocular adenovirus serotypes survive in vitro in multidose bottles of topical fluorescein (Fluress; Pilkington Barnes Hind, Inc, Sunnyvale, California). Clinical isolates of adenovirus types 8 and 19 were inoculated separately into 10 bottles each of Fluress and maintained at room temperature (25 C). All bottles were titered for adenovirus on A549 cell monolayers at 0, 7, 14, 21, 28, and 49 days. Adenovirus was recovered from Fluress for up to 21 days for adenovirus type 19 and 28 days for adenovirus type 8. A multidose bottle of Fluress contaminated with adenovirus can be a potential source of adenoviral transmission in an ophthalmic office setting.


The Prevalence of Sjögren's Syndrome in Rheumatoid Arthritis Patients and Their Clinical Features.
To estimate the prevalence of Sjögren's syndrome (SS) in patients with rheumatoid arthritis (RA) and to compare the clinical features of RA patients with and without SS. We conducted a retrospective study of RA patients who visited a rheumatology clinic in a tertiary referral hospital in Korea between May 20 and July 22, 2016. All patients fulfilled the classification criteria for RA, and the diagnosis of SS was made clinically by rheumatologists and according to the 2002 American-European Consensus Group (AECG), 2012 American College of Rheumatology (ACR), and 2016 ACR/European League Against Rheumatism (EULAR) classification criteria. The prevalence was estimated as the number of SS patients within the total number of RA patients. The disease activity and treatment pattern of RA were compared between patients with and without SS. Among 827 RA patients, 72 patients (8.7%) were diagnosed with SS by a rheumatologist, though only 60 patients (7.3%) satisfied the 2002 AECG classification criteria for SS. Fifty-two patients (6.3%) and 56 patients (6.8%) fulfilled the 2012 ACR and 2016 ACR/EULAR classification criteria, respectively. The prevalence of SS in RA patients was 10.5%, 17.0%, and 67.6% in rheumatoid factor, antinuclear antibody (≥ 1:80), and anti-Ro antibody positive patients, respectively. The prevalence of SS among RA patients was 8.7% according to rheumatologists' diagnosis. The presence of SS did not affect the treatment patterns of RA patients. However, the autoantibody profiles and demographics of RA patients with SS differed from those of patients without SS.


Toward the experimental codon reassignment in vivo: protein building with an expanded amino acid repertoire.
The high precision and fidelity of the genetic message transmission are ensured by numerous proofreading steps, from DNA replication and transcription to protein translation. The key event for translational fidelity is the proper codon assignment for 20 canonical amino acids. An experimental codon reassignment is possible for noncanonical amino acids in vivo using artificially constructed expression hosts under efficient selective pressure. However, such amino acids may interfere with the cellular metabolism and thus do not belong to the 'first' or 'restricted' part of the universal code, but rather to a second or 'relaxed' part, which is limited mainly by the downstream proofreading in the natural translational machinery. Correspondingly, not all possible alpha-amino acids can be introduced into proteins. The aim of this study is to discuss biological and evolutionary constraints on possible candidates for this second coding level of the universal code. Engineering of such a 'second' code is expected to have great academic as well as practical impact, ranging from protein folding studies to biomedicine.


Nurses' characteristics and practice environments: Comparison between clusters with different attitude and utilisation profiles regarding nursing diagnosis.
To identify clusters of nurses in relation to the utilisation and attitude towards nursing diagnosis and to compare their profiles considering demographics, professional characteristics and nursing practice environments. Nursing diagnosis has benefits for both patients and nurses, and the attitude of nurses towards nursing diagnosis has been proposed as a determinant of its use. Therefore, an adequate understanding of nurses' attitude and utilisation profiles regarding nursing diagnosis is essential for the nursing managers who want to adopt nursing diagnosis as a practice framework. A cross-sectional survey design was used. A sample of 239 nurses working in the Catalan primary health care system were categorised into clusters with similar attitude and utilisation profiles, which were compared with each other a posteriori. Nursing managers were grouped into more positive attitude clusters than clinical nurses. Nurses working in supportive nursing practice environments were classified into more positive attitude and higher utilisation clusters. The field of work and nursing practice environments were found as differential factors in profiles of nurses with different attitudes towards and/or utilisation of nursing diagnosis. The promotion of supportive nursing practice environments could enhance the implementation and maintenance of nursing diagnosis as a practice framework in primary health care.


Orphaned and vulnerable to infection, undernutrition and early death: increasing threats to infants and children.
Infants and young children in Guinea-Bissau who were made motherless had much higher mortality rates than a control group of subjects. Child mortality was higher in rural than urban children and was highest under 2 y of age and within 6 mo of their mothers' deaths. The authors of this study, which appears elsewhere in this issue, suggest that premature weaning may contribute to this excess mortality. There are many causes of maternal mortality that can lead to motherlessness among infants and children, particularly in developing countries. Multifaceted approaches to the care of these children are needed to lessen their excessive mortality. Paediatricians have a potentially very important role in preventing this burden of childhood ill-health and deaths.


Socioeconomic inequalities in cervical precancer screening among women in Ethiopia, Malawi, Rwanda, Tanzania, Zambia and Zimbabwe: analysis of Population-Based HIV Impact Assessment surveys.
We examined age, residence, education and wealth inequalities and their combinations on cervical precancer screening probabilities for women. We hypothesised that inequalities in screening favoured women who were older, lived in urban areas, were more educated and wealthier. Cross-sectional study using Population-Based HIV Impact Assessment data. Ethiopia, Malawi, Rwanda, Tanzania, Zambia and Zimbabwe. Differences in screening rates were analysed using multivariable logistic regressions, controlling for age, residence, education and wealth. Inequalities in screening probability were estimated using marginal effects models. Women aged 25-49 years, reporting screening. Self-reported screening rates, and their inequalities in percentage points, with differences of 20%+ defined as high inequality, 5%-20% as medium, 0%-5% as low. The sample size of participants ranged from 5882 in Ethiopia to 9186 in Tanzania. The screening rates were low in the surveyed countries, ranging from 3.5% (95% CI 3.1% to 4.0%) in Rwanda to 17.1% (95% CI 15.8% to 18.5%) and 17.4% (95% CI 16.1% to 18.8%) in Zambia and Zimbabwe. Inequalities in screening rates were low based on covariates. Combining the inequalities led to significant inequalities in screening probabilities between women living in rural areas aged 25-34 years, with a primary education level, from the lowest wealth quintile, and women living in urban areas aged 35-49 years, with the highest education level, from the highest wealth quintile, ranging from 4.4% in Rwanda to 44.6% in Zimbabwe. Cervical precancer screening rates were inequitable and low. No country surveyed achieved one-third of the WHO's target of screening 70% of eligible women by 2030. Combining inequalities led to high inequalities, preventing women who were younger, lived in rural areas, were uneducated, and from the lowest wealth quintile from screening. Governments should include and monitor equity in their cervical precancer screening programmes.


[Applying photocclusion method to study occlusion mechanics on wedge shaped teeth defect with computer assisting].
Study the occlusal force of wedge shaped teeth defect and its relation with the clinical condition. Use the method of clinical examination and plaster model measurement to decide the parameters of axial gradient degree of the teeth, abrasion index, missing teeth number and so on; Adopt the computer image processing technology and program to analyse the photocclusion sheet, take the date and image information of occlusion force, areas, and occlusal stress of wedge shaped teeth defect. The occlusion contact data and graph of wedge-shaped teeth defect had the features of trauma occlusion. 42.97% of them has the larger axial gradient degree, 96.09% of them has abration in different classes, 46.29% missing the front teeth and 57.03% missing the buccal teeth. Occlusal contact force increase took up 78.91% in the wedge shaped teeth defect. It can be concluded that the not uniformly distributed occlusal force produced from the larger axial gradient degree, the defect of dentition, and the abrasion of teeth, may be the important factors which cause wedge shaped teeth defect.


A rare case of insulinoma presented with neurological manifestations: A case report.
Insulinoma is a rare, most commonly benign tumor with several manifestations that may be misattributed to psychiatric, cardiac, or neurological disorders. In this report, we describe the case of a 47-year-old woman who presented with neurological manifestations, including seizures, that were misdiagnosed initially as seizures due to small vessel ischemic disease and managed accordingly with various antiepileptic drugs without any benefit. An endocrinologist's assessment suggested measuring the levels of glucose, insulin, and C-peptide. The results were abnormal. Subsequently, an enhanced-contract CT scan followed by an MRI of the abdomen was requested, and it revealed a well-delineated lesion measuring about (3,2 × 2,1 × 2,2) cm located in the tail of the pancreas. On laparoscopic visualization, a partial pancreatectomy was accomplished using a stapler. Histopathology of the surgical specimen revealed a benign insulinoma with free margins. The follow-up after three months demonstrated that the patient was doing well. Although insulinoma is mostly benign, conservative surgery such as enucleation or partial pancreatectomy is usually the cornerstone of treatment. If other indicators such as large size, multiplicity, proximity to the major pancreatic duct, association with MEN1, and malignancy were present, radical resection was considered. A high index of suspicion is requested to establish the diagnosis of insulinoma, especially when presenting with severe neurological symptoms like seizures and coma. It should be kept in mind that insulinoma is the most common cause of hypoglycemia associated with endogenous hyperinsulinism.


Computational Approaches: Drug Discovery and Design in Medicinal Chemistry and Bioinformatics.
To date, computational approaches have been recognized as a key component in drug design and discovery workflows [...].


Immunological features of a lung cancer patient achieving an objective response with anti-programmed death-1 blockade therapy.
The role of immune checkpoint inhibitors in metastatic lung cancer has been established in recent years and the pretherapeutic profiles of the tumor microenvironment in responders have been increasingly reported. The role of salvage surgery and the immune profiles of the posttherapeutic specimens in patients achieving an objective response have rarely been studied. We report a case of metastatic lung cancer treated by anti-programmed death-1 Ab followed by surgical resection. The immune status of the tumor was assessed, showing germinal center formation, memory B cell infiltration, and a high frequency of interferon gamma -secreting T cells.


Biliary extracorporeal shock wave lithotripsy in the treatment of an impacted stone in bile duct diverticulum.
A calcified, retained stone impacted in a diverticulum of the distal common bile duct was successfully treated with biliary extracorporeal shock wave lithotripsy (BESWL). The stone fragments spontaneously passed within 1 week of lithotripsy treatment without the aid of further intervention. This case is unusual in that the stone lodged in a bile duct diverticulum proved inaccessible at the time of surgical exploration.


Reengineering the specificity of a serine active-site enzyme. Two active-site mutations convert a hydrolase to a transferase.
Two residues are known to play important catalytic roles in fatty acyl-thioester hydrolase, thioesterase II: Ser-101, the site of a covalent acyl-enzyme intermediate, and His-237 which is within hydrogen bonding distance of Ser-101 and facilitates catalysis by increasing the nucleophilicity of this residue. In this study we have examined the effect of mutations at these two residues on the ability of the enzyme to function as a hydrolase and, in the presence of a thiol acceptor, as an acyltransferase. In the hydrolase reaction kcat values for the wild-type, H237R, S101C, and S101C, H237R thioesterase enzymes were 0.11, < 0.002, 0.10, and < 0.002 s-1, respectively, and at steady state, the proportion of each enzyme present as the covalent acyl-enzyme intermediate was 11, 91, 71, and 100%, respectively. In the acyltransferase reaction no activity could be detected for the wild-type or H237R enzymes but the specific activities of the S101C and S101C/H237R thioesterases were 170 and 1300 nmol/min/mg of protein, respectively. From this data we conclude the following: the wild-type enzyme functions exclusively as a hydrolase. The H237R mutant acts ineffectively as a hydrolase primarily because the deacylation reaction is drastically retarded. The S101C enzyme functions well as a hydrolase, even though the rate of deacylation is adversely affected, and this enzyme can also perform as an acyltransferase. Mutation of both catalytic residues leads to a complete loss of hydrolase activity and the S101C,H237R mutant functions as an effective acyltransferase exhibiting kcat values higher then those of the wild-type enzyme acting as a hydrolase. This study reveals that, with only two amino acid replacements, an enzyme capable of functioning exclusively as a hydrolase can be converted into an equally active enzyme performing solely as an acyltransferase.


Adaptive slice-specific z-shimming for 2D spoiled gradient-echo sequences.
To reduce the misbalance between compensation gradients and macroscopic field gradients, we introduce an adaptive slice-specific z-shimming approach for 2D spoiled multi-echo gradient-echoe sequences in combination with modeling of the signal decay. Macroscopic field gradients were estimated for each slice from a fast prescan (15 seconds) and then used to calculate slice-specific compensation moments along the echo train. The coverage of the compensated field gradients was increased by applying three positive and three negative moments. With a forward model, which considered the effect of the slice profile, the z-shim moment, and the field gradient, R2∗ maps were estimated. The method was evaluated in phantom and in vivo measurements at 3 T and compared with a spoiled multi-echo gradient-echo and a global z-shimming approach without slice-specific compensation. The proposed method yielded higher SNR in R2∗ maps due to a broader range of compensated macroscopic field gradients compared with global z-shimming. In global white matter, the mean interquartile range, proxy for SNR, could be decreased to 3.06 s-1 with the proposed approach, compared with 3.37 s-1 for global z-shimming and 3.52 s-1 for uncompensated multi-echo gradient-echo. Adaptive slice-specific compensation gradients between echoes substantially improved the SNR of R2∗ maps, and the signal could also be rephased in anatomical areas, where it has already been completely dephased.


Effects of pelvic organ prolapse ring pessary therapy on intravaginal microbial flora.
The purpose of this paper is to report our evaluation of changes in intravaginal microbial flora after ring pessary therapy for pelvic organ prolapse (POP) using conventional and our clone library method. Thirteen patients with POP who were fitted with a ring pessary participated in this longitudinal study that incorporates data from before and 1 month after beginning ring pessary therapy. Changes in intravaginal microbial flora were evaluated by conventional methods, i.e., vaginal pH, lactobacillary grade (LAC grade), Nugent score, and culture-based bacterial detection methods. In addition, we performed our clone library method using 16S ribosomal RNA (rRNA) sequencing of vaginal fluid. Conventional methods revealed that most patients had abnormal intravaginal microbial flora. Mean numbers of detected bacterial species by the culture-based and our clone library method were 3.1 (1-6) and 11.8 (1-25), respectively. Our clone library method showed that Lactobacillus spp. increased in four and decreased in two cases after ring pessary therapy but reappeared after therapy in two cases; no Lactobacillus spp. were detected in five cases. Our study showed that ring pessary therapy did not always disturb intravaginal microbial flora, especially for patients with Lactobacillus spp. prior to ring pessary insertion. Anaerobic circumstances in the vagina after therapy seem to have induced the growth of anaerobic bacteria.


Outcomes of Patients With a History of Coronary Artery Bypass Grafting Who Underwent Orbital Atherectomy for Severe Coronary Artery Calcification.
We assess the angiographic and clinical outcomes of patients with a history of coronary artery bypass graft (CABG) surgery who underwent orbital atherectomy for the treatment of severely calcified coronary lesions. The presence of severe coronary artery calcification (CAC) increases the complexity of percutaneous coronary intervention (PCI) and is associated with worse clinical outcomes. Patients with a history of CABG who undergo PCI often have comorbidities and are at higher risk for ischemic complications. Of the 458 patients who underwent orbital atherectomy, 77 patients (17%) had a history of CABG and 381 (83%) did not. The primary endpoint was rate of 30-day major adverse cardiac and cerebrovascular events (MACCE), comprised of cardiac death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke. The CABG group had a higher prevalence of hypertension, chronic renal insufficiency, history of PCI, and unstable angina. The primary endpoint was similar in the CABG and non-CABG groups (1% vs 2%; P=.56), as were the individual endpoints of cardiac death (0% vs 2%; P=.27), MI (1% vs 1%; P=.85), TVR (0% vs 0%; P>.99), and stroke (0% vs 0%; P=.65). The rates of angiographic complications and stent thrombosis were similarly low in both groups. Despite a higher-risk baseline profile, patients with a history of CABG had similar angiographic and clinical outcomes compared with patients who had no previous history of CABG. Further studies are needed to clarify the role of orbital atherectomy in these patients.


Effects of dietary restriction on insulin resistance in obese mice.
In many cases, development of insulin resistance has been linked to obesity and may contribute to mechanism of aging. The role of diet, irrespective of degree of obesity, in modulating insulin resistance and development of age degeneration disease remains uncertain. Lowered blood glucose levels are commonly associated with diet restriction (DR), which is an intervention shown to successfully retard aging and age associated disease. The effects of DR on blood glucose and insulin resistance were measured in yellow obese (A(vy)/A), lean black (a/a) mice and in another common inbred strain (B6C3F1) (at three different ages). The yellow obese mice become diabetic as a result of an insulin receptor defect which is not clearly understood. Insulin responses and radioinsulin binding were assayed in yellow obese and lean black mice fed either ad libitum (AL) or DR diets (YAL, BAL, YDR and YAL, respectively) at four different circadian intervals. The B6C3F1 controls were fed either AL (CAL) or DR (CDR) and measures were made at six circadian stages and three different ages. Within 23 days, DR produced a significant loss in body weight and a time-dependent 22-55% reduction in basal blood glucose levels in the yellow obese mice. Additionally, exogenous insulin produced circadian stage dependent (at the time of food intake) reductions in blood glucose in the YDR animals that were not present in YAL animals. (125)I-Insulin binding in liver was increased nearly 2-fold in YDR and BDR mice during the time of day that animals were active and eating. (125)I-Insulin binding was two-fold-higher in CDR mice at 4, 12 and >24 months of age. Binding decreased as a function of age in both the CAL and CDR animals. However, even in the >24 month group the CDR animals were found to have levels of binding that were as high as those found in younger CAL liver. The mechanism of action appears to be through resolution of insulin resistance by modulating an insulin receptor defect.


Endoscopic diagnosis and management of tropical parasitic infestations.
Biliary parasitosis is one of the common causes of biliary obstruction in developing countries and can often be confused with stone disease. With increased worldwide travel and immigration, these conditions are not limited to the developing countries alone. Ascariasis, hydatid liver disease, clonorchiasis, and fascioliasis are the commonly encountered parasitic infestations of the biliary tract usually presenting with biliary colic or cholangitis. Endoscopy has an important role in the diagnosis and emergent management of these conditions and in elective endoscopic therapy of associated complications. Endoscopic sphincterotomy and bile ductal clearance, along with pharmacotherapy, are the mainstays of treatment.


The bacterial epigenome.
In all domains of life, genomes contain epigenetic information superimposed over the nucleotide sequence. Epigenetic signals control DNA-protein interactions and can cause phenotypic change in the absence of mutation. A nearly universal mechanism of epigenetic signalling is DNA methylation. In bacteria, DNA methylation has roles in genome defence, chromosome replication and segregation, nucleoid organization, cell cycle control, DNA repair and regulation of transcription. In many bacterial species, DNA methylation controls reversible switching (phase variation) of gene expression, a phenomenon that generates phenotypic cell variants. The formation of epigenetic lineages enables the adaptation of bacterial populations to harsh or changing environments and modulates the interaction of pathogens with their eukaryotic hosts.


Non-coding RNAs and gastrointestinal cancers prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.
Provide an overview and a systematic evaluation of the evidence quality on the association between non-coding RNAs (ncRNAs) and prognosis value for gastrointestinal cancers (GICs). We searched the literature from three electronic databases: Pubmed, Embase, and Web of science, then carefully screened and extracted the primary information and results from the included articles. We use A measurable systematic review and meta-analysis evaluation tool (AMSTAR2) to evaluate the quality of methodology and then use the Grading of Recommendations Assessment 2, Development and Evaluation guideline (GRADE) make sure the reliability of the meta-analysis. Overall, 182 meta-analyses from 58 studies were included in this study. Most of these studies are of low or very low quality. Using the scoring tool, we found that only two meta-analyses were rated as high reliability, and 17 meta-analyses were rated as medium reliability. Although ncRNA has good prognostic value in some studies, only a tiny amount of evidence is highly credible at present. More research is needed in the future. CRD42022382296.


Factors affecting access to head and neck cancer care after a natural disaster: a post-Hurricane Katrina survey.
Our aim was to survey the factors affecting access to cancer care in patients with head and neck cancer after Hurricane Katrina. In this cross-sectional survey, 207 patients with head and neck cancer were identified post-Hurricane Katrina, but only 83 patients completed the questionnaires and were analyzed. Clinical, demographic, and socioeconomic data were recorded. Chi-square test and t test were used for comparisons. Patients who felt that there was a lack of access to cancer care would have sought treatment earlier had they had better access to cancer care (chi-square[1] = 32; p < .0001). Patients who felt that there was a lack of access to cancer care also had difficulty receiving treatment (chi-square[1] = 48; p < .0001). Availability of transportation affected access to cancer care in patients with early-stage cancers (chi-square[1] = 4; p < .035). In the postdisaster environment, patients who felt the lack of access to cancer care post-Hurricane Katrina would have sought treatment earlier with better access to cancer care. These patients also reported difficulty obtaining cancer treatment. Availability of transportation affected access to cancer care in patients with early-stage cancers. Clinical, demographic, and socioeconomic factors did not influence access to cancer care.


Unreprogrammed H3K9me3 prevents minor zygotic genome activation and lineage commitment in SCNT embryos.
Somatic cell nuclear transfer (SCNT) can be used to reprogram differentiated somatic cells to a totipotent state but has poor efficiency in supporting full-term development. H3K9me3 is considered to be an epigenetic barrier to zygotic genomic activation in 2-cell SCNT embryos. However, the mechanism underlying the failure of H3K9me3 reprogramming during SCNT embryo development remains elusive. Here, we perform genome-wide profiling of H3K9me3 in cumulus cell-derived SCNT embryos. We find redundant H3K9me3 marks are closely related to defective minor zygotic genome activation. Moreover, SCNT blastocysts show severely indistinct lineage-specific H3K9me3 deposition. We identify MAX and MCRS1 as potential H3K9me3-related transcription factors and are essential for early embryogenesis. Overexpression of Max and Mcrs1 significantly benefits SCNT embryo development. Notably, MCRS1 partially rescues lineage-specific H3K9me3 allocation, and further improves the efficiency of full-term development. Importantly, our data confirm the conservation of deficient H3K9me3 differentiation in Sertoli cell-derived SCNT embryos, which may be regulated by alternative mechanisms.


A new species of Suwallia (Plecoptera: Chloroperlidae) from China.
A new species of the genus Suwallia, S. wolongshana sp. nov. is described and illustrated from specimens collected in Sichuan Province, China. The new species is characterized by the two sclerotized bands between the hemitergal processes. The new species is the fourth recorded species of Suwallia from China.


Antibody deficiency with normal immunoglobulins in a child with hypoplastic anemia.
We report a young child with hypoplastic anemia and antibody deficiency with normal serum immunoglobulin levels. Studies of antibody responses to bacteriophage phi X 174 revealed an amnestic response but was predominantly limited to IgM. A similar response was observed following booster tetanus toxoid immunization. Analysis of in vitro pokeweed mitogen-induced immunoglobulin synthesis by the patient's B cells suggested an intrinsic B-cell defect.


Expression of SOX10 in Salivary Gland Oncocytic Neoplasms: A Review and a Comparative Analysis with Other Immunohistochemical Markers.
We evaluated SOX10 (SRY-related HMG-box 10) in differentiating acinic cell carcinoma (AciCC) from other salivary gland neoplasms with oncocytic features on fine-needle aspiration cell blocks (FNA CB) and compared its performance to DOG1 (discovered on gastrointestinal stromal tumor 1). 35 FNA CB of oncocytic salivary gland neoplasms, i.e. 13 cases of AciCC, 16 of Warthin tumor (WT), 3 of mucoepidermoid carcinoma (MEC) and 3 of oncocytoma (ONC), and 75 salivary gland resections, i.e. 26 AciCC, 7 WT, 36 MEC, 3 ONC, 2 mammary analog secretory carcinomas (MASC) and 1 papillary cystadenoma were stained for SOX10 and DOG1. None of the benign oncocytic neoplasms were immunoreactive for SOX10 on CB or resection, similar to DOG1. On CB, 61.5 and 77% of AciCC were positive for SOX10 and DOG1, respectively. All surgically resected AciCC cases were positive for SOX10 and DOG1; other malignant oncocytic lesions such as MEC and MASC demonstrated variable SOX10 and DOG1 staining. The use of SOX10 may increase the diagnostic accuracy of oncocytic lesions on FNA. In this context, SOX10 is equivalent to DOG1 in ruling out benign lesions such as WT and ONC; however, negative results for SOX10 as well as DOG1 do not favor a benign diagnosis since MEC is often negative for both markers.


Mutational landscape of nasopharyngeal carcinoma based on targeted next-generation sequencing: implications for predicting clinical outcomes.
The aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS). A total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell's concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan-Meier curves and log-rank tests. The twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts. In this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.


Biomechanical properties of infantile hemangiomas: clinical stage and effect of age.
Infantile hemangiomas (IHs) are benign vascular neoplasms with rapid capillary proliferation shortly after birth and slow involution with diminishing capillary proliferative activity, fibrosis, and fatty replacement over 7-10 years. Hemangiomas and contralateral control sites in 88 subjects were measured using a suction device, 6-mm probe and 200 mbar negative pressure. Mechanical properties were assessed vs. controls and effects of body site, depth, clinical stage, histology diagnosis, and time. Biological elasticity, overall elasticity, net elasticity, total recovery, and elastic recovery were lower for IH vs. controls (P < 0.001). IH total deformation, elastic deformation, viscoelastic creep, and residual deformation were higher than controls (P < 0.001). Involuting IHs had lower viscoelasticity than proliferating and stable lesions (P < 0.001) and lower viscoelastic creep than stable IHs (P = 0.04). IH viscoelasticity was higher at 2.3 than 12.9, 23.7, and 61.0 months and at 4.9 and 8.1 than 61.0 months. IH elastic recovery varied by body site with larger differences vs. control for abdomen and leg. Elastic recovery differences from control were smaller at younger vs. older ages. Measurement of biomechanical properties may be useful to characterize IH progression and treatment response in clinical settings.


Knee joint stabilization therapy in patients with osteoarthritis of the knee: a randomized, controlled trial.
To investigate whether an exercise program, initially focusing on knee stabilization and subsequently on muscle strength and performance of daily activities is more effective than an exercise program focusing on muscle strength and performance of daily activities only, in reducing activity limitations in patients with knee osteoarthritis (OA) and instability of the knee joint. A single-blind, randomized, controlled trial involving 159 knee OA patients with self-reported and/or biomechanically assessed knee instability, randomly assigned to two treatment groups. Both groups received a supervised exercise program for 12 weeks, consisting of muscle strengthening exercises and training of daily activities, but only in the experimental group specific knee joint stabilization training was provided. Outcome measures included activity limitations (Western Ontario and McMaster Universities Osteoarthritis Index - WOMAC physical function, primary outcome), pain, global perceived effect and knee stability. Both treatment groups demonstrated large (∼20-40%) and clinically relevant reductions in activity limitations, pain and knee instability, which were sustained 6 months post-treatment. No differences in effectiveness between experimental and control treatment were found on WOMAC physical function (B (95% confidence interval - CI) = -0.01 (-2.58 to 2.57)) or secondary outcome measures, except for a higher global perceived effect in the experimental group (P = 0.04). Both exercise programs were highly effective in reducing activity limitations and pain and restoring knee stability in knee OA patients with instability of the knee. In knee OA patients suffering from knee instability, specific knee joint stabilization training, in addition to muscle strengthening and functional exercises, does not seem to have any additional value. Dutch Trial Register (NTR) registration number: NTR1475.


Serum lysophospholipase D/autotaxin may be a new nutritional assessment marker: study on prostate cancer patients.
It is now established that the bioactive lipid lysophosphatidic acid (LPA) contributes to cancer initiation, progression and metastasis, including those of prostate cancer. LPA is produced in the serum and plasma mainly by conversion from lysophospholipids through the action of lysophospholipase D (lysoPLD), which is identical to the soluble form of autotaxin (ATX) originally isolated as a tumour cell motility-stimulating factor. In this study, we evaluated the usefulness of lysoPLD/ATX activity as a diagnostic marker. The serum lysoPLD activity, assessed by measuring choline liberation from the substrate lysophosphatidylcholine, was measured in patients with prostate cancer and compared with the concentrations of prostate-specific antigen (PSA) and conventional nutritional assessment markers. The serum lysoPLD activity in prostate cancer patients was not statistically different from that in the controls. Consistent with this, there was no correlation between the serum lysoPLD activity and the serum PSA concentrations. However, the lysoPLD/ATX activity did decrease after operation in the prostate cancer patients and seemed to reflect the postoperative damage or the nutritional status. We postulate that while the serum lysoPLD/ATX may not be a marker of prostate cancer, it promises to instead be a new marker of nutritional status.


Driving Natural Killer cells toward the melanoma tumor battlefield: Autophagy as a valuable therapeutic target.
Natural Killer (NK) cell-based cancer immunotherapies were often disappointing in the clinic mostly due to insufficient NK cell infiltration into tumors. We found that targeting autophagy induced a massive infiltration of NK cells into melanoma tumors. These findings highlight autophagy inhibition as a cutting-edge approach to fully exploit the anti-tumor properties of NK cells in a wide variety of cancer patients.


Modular Regiodivergent Synthesis of Benzo-Fused Isocoumarins by a Cyclopropane Aromatization Strategy.
Reported herein is an electrophile-modulated aromatization reaction of highly functionalized cyclopropanes to structurally diverse benzoisocoumarins featuring concurrent formation of the benzenoid and α-pyrone rings under mild conditions. An aromatization reaction of the proposed benzonorcaradiene intermediates prepared independently revealed a crucial role of the neighboring olefinic substituents in determining whether the cyclopropane ring expansion is followed by a 1,2-shift of the ester group.


Gene cloning, heterologous overexpression and optimized refolding of the NAD-glutamate dehydrogenase from Haloferax mediterranei.
The NAD-dependent glutamate dehydrogenase (GDH) gene from the halophilic archaeon Haloferax mediterranei has been cloned. The analysis of the nucleotide sequence revealed an open reading frame of 1323 bp that encodes a NAD-GDH. The amino acid sequence displayed high homology with those from other sources, especially the highly conserved residues involved in 2-oxoglutarate binding. The expression of this gene in Escherichia coli, the refolding and further characterization, yielded a fully active NAD-GDH with the same features than those found for the wild-type enzyme. This halophilic NAD-GDH showed a highly dependence on salts for both stability and activity, being essential for the refolding of the recombinant enzyme.


Cysteine adducts of human haemoglobin measured by isoelectric focusing in polyacrylamide gels with a non-linear pH gradient.
The in vitro formation of adducts from human haemoglobin formed by alkylation with methyl-methanesulphonate, dimethyl sulphate and iodoacetamide was determined with isoelectric focusing in ultra-thin polyacrylamide gels with a non-linear pH gradient. The most important adduct seen in the gels was identified as HbA alkylated at the beta-93 cysteine. Influences of the chemical nature of the alkylating agents and of the biological environment are discussed. The method is suggested to be applicable to monitoring the biological effects of low, long-term exposure to mixtures of alkylating agents or of exposure to unknown compounds.


Role of oxidative stress and low-grade inflammation in letrozole-induced polycystic ovary syndrome in the rat.
The aims of the current study were to examine the effects of temporal changes in oxidative stress (OS) and low-grade inflammation in letrozole-treated rats and to correlate these changes with the development of polycystic ovary syndrome (PCOS)-like features. Rats were treated with letrozole for 7, 15 and 21 days to induce PCOS. On day 7 of the treatment, a significant increase in serum testosterone and high sensitive C-reactive protein (hsCRP), the low-grade inflammatory marker, was found in the letrozole treated rats compared to control rats. Moreover, a decreased immunoexpression of insulin receptor coincided with increased body weight. The strong correlation between the levels of hsCRP and lipid peroxidation (LPO) suggests simultaneous development of low-grade inflammation and OS in response to hyperandrogenism, and the role of OS in a formation of cystic follicles in the letrozole animal PCOS model. Therefore, the results of the present study suggest that OS and low-grade inflammation (hsCRP) are the major causes of PCOS induction in this model.


Requirement of SIRPα for protective immunity against Leishmania major.
Signal regulatory protein α (SIRPα) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Wild-type (WT) C57BL/6 mice are known to be resistant to Leishmania major infection. We here found that C57BL/6 mice that express a mutant version of SIRPα lacking most of the cytoplasmic region manifested increased susceptibility to L. major infection, characterized by the marked infiltration of inflammatory cells in the infected lesions. The numbers of the parasites in footpads, draining lymph nodes and spleens were also markedly increased in the infected SIRPα mutant mice, compared with those for the infected WT mice. In addition, soluble leishmanial antigen-induced production of IFN-γ by splenocytes of the infected SIRPα mutant mice was markedly reduced. By contrast, the ability of macrophages of SIRPα mutant mice to produce nitric oxide in response to IFN-γ was almost equivalent to that of macrophages from WT mice. These results suggest that SIRPα is indispensable for protective immunity against L. major by the induction of Th1 response.


The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: a report from the Childrens Cancer Group.
Childrens Cancer Group 123 was a trial of intensive multidrug chemotherapy as well as cranial irradiation and bulk disease irradiation in children with acute lymphoblastic leukemia with lymphomatous presentation (bulk disease and either T-cell phenotype, high white blood count, or absence of anemia), a poor prognostic group with an increased risk of central nervous system (CNS) and other extramedullary recurrence. Three hundred eight patients without CNS disease were randomized among three regimens: A--BFM chemotherapy (designed for high risk ALL patients) with 1800 cGy cranial irradiation; B--LSA2L2 chemotherapy (designed for non-Hodgkins lymphoma patients) with 1800 cGy cranial irradiation and 1500 cGy to nonabdominal bulk disease; C--Reg B without cranial irradiation. All patients received intrathecal methotrexate throughout therapy. Radiation treatment records were reviewed. With a minimum 52-month follow-up, Regimen B and C patients had 5-year actuarial CNS relapses of 7% and 17% (p = 0.01) and event-free survivals of 53% and 39% (p = 0.04). Patients with white blood count < 50,000/mm3 did not benefit from cranial irradiation. Regimen A patients had the same CNS relapse rate as Regimen B patients but an improved event-free survival. Regimen B and C patients with large mediastinal masses who received their assigned chest radiation had a lower event rate than those who did not (p = 0.06). Patients whose cranial fields did or did not encompass the entire meningeal surface had equivalent CNS relapse rates. Patients treated with LSA2L2 chemotherapy, a less than optimal regimen, benefited from cranial and mediastinal irradiation. Compliance with radiation volume guidelines was not essential for patients to receive the benefit of cranial irradiation.


NMR characterization of paclitaxel/poly (styrene-isobutylene-styrene) formulations.
TAXUStrade mark is a coronary drug-eluting stent system utilizing a formulation consisting of cellular-target drug paclitaxel and poly (styrene-isobutylene-styrene) (SIBS). The present study investigates the interaction and interfacial dynamics of paclitaxel incorporated in a nano-polymeric matrix system. Solution and solid-state CP/MAS NMR experiments were designed to characterize the microstructure of heterogeneous drug-polymer mixtures in terms of its composition, molecular mobility, molecular order, paclitaxel-SIBS molecular interactions, and molecular mobility of the drug in the polymer matrix. The NMR spectra demonstrated unchanged chemical shifts between the neat and incorporated paclitaxel, and suggested that the level of the interactions between paclitaxel and SIBS is limited to non-bonding interactions or physical interactions between paclitaxel and SIBS when mixed in solution under NMR detection. Carbon spin-lattice relaxation time and proton spin-lattice relaxation time in the rotating frame offer further confirmation that the mobility of paclitaxel is increased in the paclitaxel-SIBS mixture. The results also indicate that a change occurs from crystalline packing to amorphous packing in paclitaxel due to its intermolecular interaction with SIBS. Our studies were used in understanding the detailed structure, morphology, and molecular motion of paclitaxel in the paclitaxel-SIBS system and to probe chemical and physical heterogeneity down to the nanometer scale.


2D depiction of nonbonding interactions for protein complexes.
A program called the 2D-GraLab is described for automatically generating schematic representation of nonbonding interactions across the protein binding interfaces. The input file of this program takes the standard PDB format, and the outputs are two-dimensional PostScript diagrams giving intuitive and informative description of the protein-protein interactions and their energetics properties, including hydrogen bond, salt bridge, van der Waals interaction, hydrophobic contact, pi-pi stacking, disulfide bond, desolvation effect, and loss of conformational entropy. To ensure these interaction information are determined accurately and reliably, methods and standalone programs employed in the 2D-GraLab are all widely used in the chemistry and biology community. The generated diagrams allow intuitive visualization of the interaction mode and binding specificity between two subunits in protein complexes, and by providing information on nonbonding energetics and geometric characteristics, the program offers the possibility of comparing different protein binding profiles in a detailed, objective, and quantitative manner. We expect that this 2D molecular graphics tool could be useful for the experimentalists and theoreticians interested in protein structure and protein engineering.


Uapaca genus (Euphorbiaceae), a good source of betulinic acid.
Betulinic acid, isolated in substantial amounts from stem barks of five distinct species of Uapaca could be considered as an important chemotaxomic marker of the Uapaca genus. It inhibited Trypanosoma brucei GAPDH with an IC(50) value of 240 microM and has been shown to be a competitive reversible inhibitor (Ki=200+/-10 microM) of this enzyme with respect to its cofactor NAD(+).


Use of laser-induced breakdown spectroscopy for the determination of polycarbonate (PC) and acrylonitrile-butadiene-styrene (ABS) concentrations in PC/ABS plastics from e-waste.
Due to the continual increase in waste generated from electronic devices, the management of plastics, which represents between 10 and 30% by weight of waste electrical and electronic equipment (WEEE or e-waste), becomes indispensable in terms of environmental and economic impacts. Considering the importance of acrylonitrile-butadiene-styrene (ABS), polycarbonate (PC), and their blends in the electronics and other industries, this study presents a new application of laser-induced breakdown spectroscopy (LIBS) for the fast and direct determination of PC and ABS concentrations in blends of these plastics obtained from samples of e-waste. From the LIBS spectra acquired for the PC/ABS blend, multivariate calibration models were built using partial least squares (PLS) regression. In general, it was possible to infer that the relative errors between the theoretical or reference and predicted values for the spiked samples were lower than 10%.