The efficacy and safety of adjunctive perampanel for the treatment of refractory focal-onset seizures in patients with epilepsy: A meta-analysis.
The last decade has seen an increase in the use of anti-seizure medications (ASMs); however, the burden of treating drug-resistant epilepsy has not fallen. We performed this meta-analysis to evaluate the optimal dose of Perampanel (PER) as a new adjunctive treatment for drug-resistant seizures. We searched for studies published from inception to February 1, 2021 from PubMed, Central Register of Controlled Trials (CENTRAL), and ScienceDirect. Research characteristics, patients' characteristics, and treatment regimen, concomitant ASMs, clinical outcomes were extracted. The practical outcome included a reduction in seizures frequency ≥50%, ≥75%, and ≥100% from baseline convulsive seizure frequency, and the safety outcome included the proportion of drug withdrawal and adverse reactions. Odds ratios (OR) for 95% confidence intervals (95% CI) were estimated by the inverse variance method. Four trials which enrolled 2187 participants (1569 in the PER group and 618 in the placebo group) were included. Results showed that 8 or 12 mg per day had the best effect on all three outcomes, with no significant difference between 8 and 12 mg per day (≥50% reduction, 35.5% vs 36.1%, P = .84; ≥75% reduction, 17.8% vs 19.1%, P = .64; seizure-free, 3.5% vs 3.7%, P = .85). In addition, 12-mg PER compared to 8 mg had a higher proportion of trial withdrawal (8.7% vs 17.0%; P < .00001) and treatment-emergent adverse event (TEAE) resulting in dose reduction/discontinuation (18.5% vs 32.0%; P < .00001). The adverse events (AEs) significantly associated with adjunctive PER were dizziness, somnolence, fatigue, and irritability. Adjunctive treatment of PER was associated with a more significant reduction in the frequency of seizures in patients with refractory epilepsy than placebo, but with a higher frequency of AEs. PER at a daily dose of 8 mg appears to have the best ratio between efficacy and tolerance in most study participants.


Membrane damage by Cerebratulus lacteus cytolysin A-III. Effects of monovalent and divalent cations on A-III hemolytic activity.
The effects of monovalent and divalent cations on the hemolytic activity of Cerebratulus lacteus toxin A-III were studied. The activity of cytolysin A-III is remarkably increased in isotonic, low ionic strength buffer, the HC50 (the toxin concentration yielding 50% lysis of a 1% suspension of erythrocytes after 45 min at 37 degrees C) being shifted from 2 micrograms per ml in Tris or phosphate-buffered saline to 20-30 ng per ml in sucrose or mannitol buffered with Hepes, corresponding to a 50-100-fold increase in potency. On the contrary, hemolytic activity decreases progressively as the monovalent cation concentration in the medium increases for Na+, K+, or choline salts. The divalent cations Ca2+ and Zn2+ likewise inhibit the cytolysin A-III activity, but more strongly than do the monovalent cations specified above. Zn2+ at a concentration of 0.3 mM totally abolishes both toxin A-III-dependent hemolysis of human erythrocytes and toxin-induced leakage from liposomes. The observation of similar effects in both natural membranes and artificial bilayers suggests an effect of Zn2+ on the toxin A-III-induced membrane lesion, especially since Zn2+ does not alter binding of the cytolysin. The dose-response curve for toxin A-III exhibits positive cooperativity, with a Hill coefficient of 2 to 3. However, analysis of toxin molecular weight by analytical ultracentrifugation reveals no tendency to aggregate at protein concentrations up to 2 mg per ml. These data are consistent with a post-binding aggregational step which may be affected by the ionic strength of the medium.


LRRC45 contributes to early steps of axoneme extension.
Cilia perform essential signalling functions during development and tissue homeostasis. A key event in ciliogenesis occurs when the distal appendages of the mother centriole form a platform that docks ciliary vesicles and removes CP110-Cep97 inhibitory complexes. Here, we analysed the role of LRRC45 in appendage formation and ciliogenesis. We show that the core appendage proteins Cep83 and SCLT1 recruit LRRC45 to the mother centriole. Once there, LRRC45 recruits the keratin-binding protein FBF1. The association of LRRC45 with the basal body of primary and motile cilia in both differentiated and stem cells reveals a broad function in ciliogenesis. In contrast to the appendage components Cep164 and Cep123, LRRC45 was not essential for either docking of early ciliary vesicles or for removal of CP110. Rather, LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organising centriolar satellites, establishing the transition zone and promoting the docking of Rab8 GTPase-positive vesicles. We propose that, instead of acting solely as a platform to recruit early vesicles, centriole appendages form discrete scaffolds of cooperating proteins that execute specific functions that promote the initial steps of ciliogenesis.


General dysplasia of the cerebral arteries with persistent primitive acoustic artery and giant aneurysm.
A case of cerebrovascular systemic dysplasia is presented. The anomalies were: persistent primitive acoustic artery, giant aneurysm of the left internal carotid artery, aneurysm of the basilar artery, and an arteriovenous fistula. A review of the literature shows that the association of multiple malformations of cerebral vessels with a persistent primitive acoustic artery has not previously been described. Impairment of embryonic development is suggested as the origin of the malformations.


Contemporary Role of Computed Tomography in Managing Pediatric Primary Spontaneous Pneumothorax.
The value of chest computed tomography (CT) in pediatric primary spontaneous pneumothorax (PSP) remains controversial. This study sought to evaluate the utility of CT scans in a contemporary cohort of children with PSP. An institutional review board approval was obtained for a retrospective review of all children (aged ≤18 y) who underwent video-assisted thoracoscopic surgery (VATS) for PSP between 2009 and 2019 at a university-affiliated pediatric hospital. Preoperative CT scans were evaluated for diagnostic accuracy of the CT of bleb disease. Thirty nine patients underwent VATS procedures for PSP, 34 (87%) of the patients were noted to have blebs. Twenty eight (72%) patients received preoperative CT scans with a 5.5:1 male to female ratio. On CT, 17 (61%) were diagnosed with blebs and all had blebs intraoperatively. CT did not identify disease in 11 patients, but seven had blebs intraoperatively. The positive and negative predictive values of preoperative CT for detecting ipsilateral bleb disease were 100% and 36%, respectively, with a sensitivity of 71%. Eleven patients had a contralateral disease on CT (39%). Five received elective contralateral VATS and three developed spontaneous PSP, with intraoperative blebs in all eight patients. Three never developed contralateral PSP. Six (21%) patients with no contralateral disease on CT developed spontaneous PSP with intraoperative blebs. The decision to operate for PSP should be made based on clinical findings rather than on the presence or absence of blebs identified by CT.


The structure of annelid and mollusc hemoglobins.
The polypeptide chain composition and the chemical properties of several annelid hemoglobins and chlorocruorins are presented. In agreement with earlier studies on the hemoglobin from Arenicola cristata (Waxman, L. (1971) J. Biol. Chem. 246, 7318-7327), nearly all of the pigments which have been examined consist of one or more different disulfide-linked polypeptide chains of 13,000 to 16,000 daltons, and the heme-protein stoichiometry suggests that more than one polypeptide is associated with each heme. Except for the prosthetic group, there is no outstanding chemical difference between the chlorocruorins and the hemoglobins, nor is ther any apparent differnce between those hemoglobins which show cooperative oxygen binding properties and those which do not. The results suggest that all these hemoglobins have similar structures. On the other hand, the polypeptide chains of mollusc hemoglobins have molecular weights of greater than 220,000. Each polypeptide binds many heme groups. Thus, annelids use small polypeptide chains while molluscs use giant polypeptides to carry O2.


Removal of centrosomal PP1 by NIMA kinase unlocks the MPF feedback loop to promote mitotic commitment in S. pombe.
Activation of the Cdk1/cyclin B complex, also known as mitosis-promoting factor (MPF), drives commitment to mitosis. Interphase MPF is inhibited through phosphorylation of Cdk1 by Wee1-related kinases. Because Cdc25 phosphatases remove this phosphate, Cdc25 activity is an essential part of the switch that drives cells into mitosis. The generation of a critical "trigger" of active MPF promotes a positive feedback loop that employs Polo kinase to boost Cdc25 activity and inhibit Wee1, thereby ensuring that mitotic commitment is a bistable switch. Mutations in the spindle pole body (SPB) component Cut12 suppress otherwise lethal deficiencies in Cdc25. Cut12 harbors a bipartite protein phosphatase 1 (PP1) docking domain. Mutation of either element alone suppressed the temperature-dependent lethality of cdc25.22, whereas simultaneous ablation of both allowed cells to divide in the complete absence of Cdc25. Late G2 phase phosphorylation between the two elements by MPF and the NIMA kinase Fin1 blocked PP1(Dis2) recruitment, thereby promoting recruitment of Polo to Cut12 and the SPB and elevating global Polo kinase activity throughout the cell. PP1 recruitment to Cut12 sets a threshold for Polo's feedback-loop activity that locks the cell in interphase until Cdc25 pushes MPF activity through this barrier to initiate mitosis. We propose that events on the SPB (and, by inference, the centrosome) integrate inputs from diverse signaling networks to generate a coherent decision to divide that is appropriate for the particular environmental context of each cell. PP1 recruitment sets one or more critical thresholds for single or multiple local events within this switch.


The thrombogenicity of human umbilical vein endothelial cell seeded collagen modules.
Modular tissue-engineered constructs are assembled from sub-mm sized cylindrical collagen gel modules which are covered with a surface layer of human umbilical vein endothelial cells (HUVEC). The resulting construct is permeated by a network of interconnected endothelial cell lined channels to facilitate blood perfusion and nutrient delivery. This design strategy relies critically on the endothelial cells' layer behaving in a non-thrombogenic manner on the module surface and the objective here was to characterize this thrombogenicity. HUVEC prolonged clotting times in whole blood-module mixtures, and enabled slightly heparinized whole blood perfusion of an assembled modular construct in vitro with no increase in platelet loss compared to background levels. Flow cytometry and scanning electron microscopy indicated that HUVEC seeded modules reduced platelet activation and deposition but not leukocyte activation, compared to collagen only modules. Plasma recalcification times on non-stimulated HUVEC were longer compared to stimulated HUVEC but not different than that on collagen only module films and were not prolonged by incubation with a tissue factor blocking antibody. Together these data suggest that a functional non-thrombogenic layer of EC was generated on the module surface and that this layer should be sufficient to maintain continuous blood flow through an engineered modular tissue. In/ex vivo studies are warranted to confirm this conclusion.


The use of footprint contact index II for classification of flat feet in a Nigerian population.
The objective index as developed by Qaura, Deodhar, and Jit, in 1980 was used to estimate the incidence of flat foot (pes planus) in 990 school pupils (532 females and 458 males) between the ages of 5 and 14 years. The ratio of contact area to the total area of the middle of the footprint (contact index 1) (4/10), usually measured with a planimeter, is accepted as the true representative of the condition of arches. In this field study, contact index II (ratio of contact width to the total width of the foot) which is simple, reliable, and correlates with contact index I has been used to assess flat foot. The mean for the contact index and standard deviation have been calculated. Feet have been considered as normal up to 1 SD around the mean value of the index and values greater or lesser than this have been considered abnormal. Furthermore, mean +/- 1 SD to 2 SD has been considered as possible flat foot, whereas mean +/- 3 SD and above has been taken as definite flat foot. On the whole, bilateral flat foot is not common among children of school age in Port Harcourt (0.60%). It is, however, more common in females (0.75%) than males (0.44%). Unilateral flat foot (2.22%) is found to be more common than bilateral flat foot. Early introduction to the use of shoes may predispose to flat foot. We were not in a position to say if any of the subjects found with flat foot would have a painful foot.(ABSTRACT TRUNCATED AT 250 WORDS)


A rapid removal of Phaeocystis globosa from seawater by peroxymonosulfate enhanced cellulose nanocrystals coagulation.
Cellulose nanocrystals (CNC) are recognized as promising bio-based flocculants for controlling harmful algal blooms (HABs). Due to the charge shielding effect in seawater and the strong mobility of algae cells, CNC can't effectively remove Phaeocystis globosa from seawater. To solve this problem, peroxymonosulfate (PMS) was used to enhance the coagulation of CNC for rapidly removal of P. globosa. The results showed that 91.7% of Chl-a, 95.2% of OD680, and 97.2% of turbidity of P. globosa were reduced within 3 h with the use of 200 mg L-1 of CNC and 20 mg L-1 of PMS. The removal of P. globosa was consisted of inactivation and flocculation. Notably, electron paramagnetic resonance (EPR) spectrums and quenching experiments revealed that the inactivation of P. globosa was dominated by PMS oxidation and 1O2. Subsequently, CNC entrained inactivated algal cells to settle to the bottom to achieve efficient removal of P. globosa. The content of total organic carbon (TOC) and chemical oxygen demand (COD) decreased significantly, indicating that a low emission risk of algal cell effluent was produced in the CNC-PMS system. In view of the excellent performance on P. globosa removal, we believe that the CNC-PMS system has great potential for HABs treatments.


The voltage-gated sodium channel NaV 1.9 in visceral pain.
Visceral pain is a common symptom for patients with gastrointestinal (GI) disease. It is unpleasant, debilitating, and represents a large unmet medical need for effective clinical treatments. Recent studies have identified NaV 1.9 as an important regulator of afferent sensitivity in visceral pain pathways to mechanical and inflammatory stimuli, suggesting that NaV 1.9 could represent an important therapeutic target for the treatment of visceral pain. This potential has been highlighted by the identification of patients who have an insensitivity to pain or painful neuropathies associated with mutations in SCN11A, the gene encoding voltage-gated sodium channel subtype 1.9 (NaV 1.9). Here, we address the role of NaV 1.9 in visceral pain and what known human NaV 1.9 mutants can tell us about NaV 1.9 function in gut physiology and pathophysiology.


The effects of the aminobisphosphonate alendronate on thyroid hormone-induced osteopenia in rats.
Hyperthyroidism, either endogenous or iatrogenic, leads to increased bone turnover and osteopenia. This study was conducted to examine (1) whether thyroid hormone excess in rats causes bone changes similar to those seen in patients with hyperthyroidism, and (2) the effects of the aminobisphosphonate alendronate on the thyroid hormone-induced bone changes. Sprague-Dawley male rats, divided into four groups, received L-thyroxine (T4) 250 micrograms/kg/day (+T4) or vehicle (-T4) subcutaneously six times per week and alendronate 1.75 mg/kg (+ALN) or vehicle (-ALN) orally twice a week. Rats were sacrificed after 3 weeks of treatment, blood samples were analyzed for serum T4, triiodo-L-thyronine (T3), and osteocalcin, and the proximal tibiae were processed for histomorphometric analysis. Serum T4 and T3 levels measured 20-24 hours after the last injection were 2 to 2.5-fold higher in +T4 groups than in -T4 groups. Serum osteocalcin was significantly (P < 0.05) higher in +T4/-ALN group than in the other groups, which were not statistically different from each other. T4 treatment (+T4/-ALN) significantly decreased the amount of cancellous bone volume (-45%) and increased osteoid surface (+254%), osteoblast surface (+111%), and osteoclast surface (+176%) relative to control values. Alendronate increased the bone volume above control values in both T4-treated (+T4/+ALN) and untreated (-T4/+ALN) rats, and prevented the T4-induced increase in bone turnover in +T4/+ALN rats. It is concluded that (1) excess thyroid hormone induces cancellous bone loss associated with high bone turnover in the rat, and (2) this bone loss can be prevented by alendronate through the inhibition of osteoclastic activity.


Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins.
Defensins are peptides that protect the host against microorganisms. Here we show that the theta-defensin retrocyclin 2 (RC2) inhibited influenza virus infection by blocking membrane fusion mediated by the viral hemagglutinin. RC2 was effective even after hemagglutinin attained a fusogenic conformation or had induced membrane hemifusion. RC2, a multivalent lectin, prevented hemagglutinin-mediated fusion by erecting a network of crosslinked and immobilized surface glycoproteins. RC2 also inhibited fusion mediated by Sindbis virus and baculovirus. Human beta-defensin 3 and mannan-binding lectin also blocked viral fusion by creating a protective barricade of immobilized surface proteins. This general mechanism might explain the broad-spectrum antiviral activity of many multivalent lectins of the innate immune system.


Cytosolic enzymes from rat tissues that activate the cooked meat mutagen metabolite N-Hydroxyamino-1-methyl-6- phenylimidazo[4,5-b]pyridine (N-OH-PhIP).
Heterocyclic amines are formed during the cooking of foods rich in protein and can be metabolically converted into cytotoxic and mutagenic compounds. These "cooked-food mutagens" constitute a potential health hazard because DNA damage arising from dietary exposure to heterocyclic amines can modify cell genomes and thereby affect future organ function. To determine enzymes responsible for heterocyclic amine processing in mammalian tissues, we performed studies to measure genotoxic activation of the N-hydroxy form of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) --a common dietary mutagen. O-Acetyltransferase, sulfotransferase, kinase, and amino-acyl synthetase activities were assayed using substrate-specific reactions and cytosolic enzymes from newborn and adult rat heart, liver, spleen, kidney, brain, lung, and skeletal muscle. The resultant enzyme-specific DNA adduct formation was quantified via (32)P-postlabeling techniques. In biochemical assays with rat tissue cytosolic proteins, O-acetyltransferases were the enzymes most responsible for N-hydroxy-PhIP (N-OH-PhIP) activation. Compared to O-acetyltransferase activation, there was significantly less kinase activity and even lesser amounts of sulfotransferase activity. Proyl-tRNA synthetase activation of N-OH-PhIP was not detected. Comparing newborn rat tissues, the highest level of O-acetyltransferase mutagen activation was observed for neonatal heart tissue with activities ranked in the order of heart > kidney > lung > liver > skeletal muscle > brain > spleen. Enzymes from cultured neonatal myocytes displayed high O-acetyltransferase activities, similar to that observed for whole newborn heart. This tissue specificity suggests that neonatal cardiac myocytes might be at greater risk for damage from dietary heterocyclic amine mutagens than some other cell types. However, cytosolic enzymes from adult rat tissues exhibited a different O-acetyltransferase activation profile, such that liver > muscle > spleen > kidney > lung > brain > heart. These results demonstrated that enzymes involved in catalyzing PhIP-DNA adduct formation varied substantially in activity between tissues and in some tissues, changed significantly during development and aging. The results further suggest that O-acetyltransferases are the primary activators of N-OH-PhIP in rat tissues.


Old Key Opens the Lock in Carborane: The in Situ NHC-Palladium Catalytic System for Selective Arylation of B(3,6)-H Bonds of o-Carboranes via B-H Activation.
An efficient in situ Pd-NHC catalytic system for regioselective arylation of B(3,6)-H bonds of o-carborane has been developed for the first time. A series of symmetric and unsymmetric 3,6-diaryl-o-carboranes anchored with active groups have been synthesized with moderate to good yields under mild conditions. This work offers an efficient protocol for selective activation of B(3,6)-H bonds and has important value in design coupling reactions for selective functionalization of o-carboranes.


The functional role of tyrosine-200 in human testis angiotensin-converting enzyme.
The active site of angiotensin-converting enzyme (ACE) has been shown by chemical modification to contain a critical tyrosine residue, identified as Tyr-200 in human testis ACE (hTACE). We have expressed a mutant hTACE containing a Tyr-200 to Phe mutation. The mutant exhibits a marked decrease in kcat: 15-fold and 7-fold for the hydrolysis of furanacryloyl-Phe-Gly-Gly and angiotensin I, respectively, whereas its Km increases by only 1.6- and 2.2-fold, respectively. We conclude that Tyr-200 is not required for substrate binding. Instead, the effect on kcat together with a 100-fold decrease in affinity for the ACE inhibitor lisinopril indicates that Tyr-200 may participate in catalysis by stabilizing the transition state complex. Thus, Tyr-200 in hTACE has a role analogous to that of Tyr-198 in carboxypeptidase A.


The effects of trypanosomosis on sperm morphology in Zebu x Friesian crossbred bulls.
Detailed studies of sperm morphological abnormalities were carried out on 12 Zebu x Friesian crossbred bulls used in a study of the effects of trypanosomosis. Four bulls were infected with T. vivax, another four with T. congolense, while four served as controls. The infected bulls developed chronic trypanosomosis. All the bulls initially had very low sperm morphological abnormalities that were within acceptable limits for fertile animals. After infection there was a rapid and progressive increase in all sperm abnormalities. Spermatozoa of infected bulls were highly deformed with multiple morphological defects. Mean percentage pre-infection baseline values prior to infection for acrosomal, sperm-head, detached heads, proximal cytoplasmic droplets, distal cytoplasmic droplets, sperm-tail, midpiece and total sperm morphological defects ranged between 0.1 +/- 0.1 for acrosomal and 8.3 +/- 3.2 for total morphological abnormalities in the semen of the bulls. All the infected bulls developed sperm morphological abnormalities of more than a mean of 40.0% from the 4th week after infection until the end of the investigation and were considered unfit for breeding. At 7 weeks post-infection (PI) until the end of the study (12 weeks PI), the controls had a mean of less than 5% sperm morphological defects, while the infected bulls had 100%. Mean percentage values of sperm morphological defects throughout the duration of the investigation for control bulls were low and within the normal range for fertile bulls. These values differed significantly (p<0.001) from the elevated values of the infected bulls. The results show that trypanosomosis due to T. vivax or T. congolense infection can render Zebu x Friesian crossbred bulls unfit for breeding within a very short time. The resultant infertility could be of economic importance in trypanosomosis-endemic sub-Saharan Africa where Zebu x Friesian crossbred bulls are kept.


Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts.
Midkine (MK) is a heparin-binding growth factor that promotes the growth, migration, and survival of various cells. Its overexpression has been observed in many human malignancies, making it an attractive therapeutic target. We established a human midkine blockade system involving RNA interference. The synthetic small interfering RNA (siRNA) targeting human midkine almost completely inhibited the secretion of midkine by a human prostate cancer cell line, PC-3, and consequently suppressed the proliferation and anchorage-independent growth of the transfected cells. The midkine siRNA, together with atelocollagen, significantly suppressed the growth of PC-3 tumors, which had been subcutaneously xenografted. These inhibitory effects of midkine siRNA were augmented by combinational treatment with a chemotherapeutic, paclitaxel (PTX), both in vitro and in vivo. The dose of PTX (12 mg/kg) used for the combinational treatment did not cause leukopenia or liver damage, which are often reported as serious adverse effects of PTX. The effect of the combination on tumor growth was comparable with that of PTX alone at higher doses that have exhibited severe adverse effects. Midkine siRNA suppressed mainly cell proliferation and slightly angiogenesis, whereas PTX enhanced apoptosis and slightly suppressed angiogenesis. The combination treatment was particularly effective for suppression of angiogenesis; consequently, it had striking effects on all aspects (proliferation, apoptosis, and angiogenesis). We established a novel and safe cancer therapy strategy involving midkine siRNA combined with PTX, with less adverse effects.


Sources and spatiotemporal variations of nitrogen and phosphorus in Liaodong Bay, China.
Excessive discharge of N and P pollutants results in deterioration of marine environment quality and reduction of sustainability and safety of marine ecology. Spatiotemporal variations characteristics and sources of N and P pollutants were determined based on the long-term monitoring data in Liaodong Bay. Results indicated that an evident spatiotemporal variation was investigated for nutrients. The highest concentrations of NH3-N, NO2-N, NO3-N and PO4-P were in spring (25.32 μg/L), summer (20.67 μg/L) and autumn (222.07 μg/L, 11.08 μg/L), respectively. The hot-spots of pollutants were mainly concentrated in estuarine and aquaculture areas. The hot spot of PO4-P gradually extended to the middle of Liaodong Bay in autumn. In addition, pollution sources in each marine functional zone were different, the main pollution source was aquaculture wastewater, river input, domestic sewage. This study provided reasonable suggestions for effectively reducing N and P pollution in Liaodong Bay, and elsewhere.


Metastasis dynamics for non-small-cell lung cancer: effect of patient and tumor-related factors.
We studied event dynamics (probability of an event occurring over a specific time interval) in patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC) according to patient and tumor characteristics. By using a database of 1506 patients who underwent initial surgery for NSCLC, event dynamics, based on a time-specific hazard rate, were evaluated. The event of interest was the development of distant metastases, with or without a local recurrence. The effect of sex, tumor size, nodal involvement, histology, lymphovascular space invasion, pleural invasion, age, and race were studied. The hazard rate for developing distant metastases was not constant over time but was characterized by specific peaks, the first being approximately 9 months after surgery and the second at 18 to 20 months for men and 24 to 26 months for women. For women, the hazard rate peaked considerably in the first year. For men, the hazard rate peaks were smaller but lasted for a longer duration. Pathologic factors associated with a higher risk of recurrence (eg, size, lymph node involvement, pleural invasion) all increased the sex-specific hazard rates. The probability of developing distant metastases after surgery for NSCLC peaks at specific and consistent time intervals after surgery, with specific differences between men and women. A factor-specific modulation of peak heights that ranged from no impact (eg, race) to relevant effects for primary tumor size, nodal involvement, and pleural invasion, possibly related to sex, was also observed. The bimodal distant metastases dynamics may be an intrinsic feature of metastatic progression in NSCLC.


Coherence of animal health, welfare and carcass quality in pork production chains.
Aim of the study was to measure the potential impact of animal health and welfare on the carcass quality. 99 pigs under equal housing and feeding conditions were involved in the study. Effects of the immune system on carcass composition, meat quality and performance data of slaughter pigs became measureable by quantification of acute phase proteins (APP), haptoglobin (Hp) and pig major acute phase protein (Pig-MAP). The results were not significantly affected by gender or breed. The calculated correlations between chosen animal health indicators and carcass quality parameters prove an influence of health and welfare on performance, carcass composition and meat quality traits. The acute phase proteins could also be valuable as a predictive indicator for risk assessment in meat inspection, as increased Hp concentrations in slaughter blood indicate a 16 times higher risk for organ abnormalities and Pig-MAP concentrations above 0.7mg/ml a 10 times higher risk.


Preconception Health Risks Among U.S. Women: Disparities at the Intersection of Disability and Race or Ethnicity.
Prior research has found that some preconception health risks are more prevalent among women in historically minoritized racial and ethnic groups. Preconception health risks are also increased among women with disabilities. Risks could be even greater among women who both have a disability and belong to a minoritized racial or ethnic group. The purpose of this study was to assess preconception health at the intersection of disability and race or ethnicity. We analyzed data from the 2016 Behavioral Risk Factor Surveillance System to estimate the prevalence of health behaviors, health status indicators, and preventive healthcare receipt among nonpregnant women 18-44 years of age. We used modified Poisson regression to compare non-Hispanic White women with disabilities and women with and without disabilities in three other race/ethnicity groups (non-Hispanic Black, Hispanic, other race) to a reference group of non-Hispanic White women without disabilities. Disability status was defined based on affirmative response to at least one of six questions about difficulty with seeing, hearing, mobility, cognition, personal care, or independent living tasks. Multivariate analyses adjusted for other sociodemographic characteristics such as age and marital status. In every racial and ethnic group, women with disabilities had a significantly higher prevalence of most preconception health risks than their counterparts without disabilities. The disparity in obesity for Black women with disabilities was additive, with the adjusted prevalence ratio (PR, 1.77; 95% confidence interval [CI], 1.57-2.00) equal to the sum of the prevalence ratios for disability alone (PR, 1.29; 95% CI, 1.19-1.41) and Black race alone (PR, 1.47; 95% CI, 1.36-1.58). Women at the intersection of disability and minoritized race or ethnicity may be at especially high risk of adverse outcomes. Targeted efforts are needed to improve the health of women of reproductive age in these doubly marginalized populations.


Thermodynamic parameters of phenylglycine interaction with UO22+, La3+ and Zr4.
Phenylglycine interactions with (UO22+, La3+ and Zr4+) transition metal ions were studied at different ionic strengths and different temperature degrees applying Bjerrum's method. The work determine and discuss both the thermodynamic stabilities and the degree of interactions [Formula: see text]. Also the work calculate and discuss the thermodynamic parameters of interactions of phenylglycine with (UO22+, La3+ and Zr4+). The variables that govern the interaction between phenylglycine and the metal ions under investigation were related to the nature of the amino acid reactive species as well as to the nature of M+ such as the valence and radius of the ion. It was observed that reactions between the M+ and L- were the most likely to occur. It was determined that the pH values affect the degree of complex formation [Formula: see text] as well as the production of various reactive spices. When the range of degree of interaction was more than 0.5 and less than 1.15, forming 1:1 stoichiometric complex. Additionally, it was shown that the stability of the complexes produced between phenylglycine and MZ+ increased in the subsequent order, which was in good accord with the Irving-Williams order.


Characterisation of the complete mitochondrial genome of Helice wuana (Grapsoidea: Varunidae) and comparison with other Brachyuran crabs.
The mitochondrial genome (mitogenome) provides important information for phylogenetic analysis and understanding evolutionary origins. Herein, we sequenced, annotated, and characterised the mitogenome of the crab Helice wuana to better understand its molecular evolution and phylogeny. The 16,359bp mitogenome includes 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes and one control region. The genome composition is highly A+T biased 68.42%, and exhibits a negative AT-skew (-0.036) and GC-skew (-0.269) among Brachyura crabs. Gene rearrangements were detected, as was tandem duplication followed by random loss, which explains the translocation of mitochondrial genes. Phylogenetic analysis showed that H. wuana and H. tientsinensis clustered on one branch with high nodal support values. These results confirm that the placement of H. wuana within the Varunidae family of Thoracotrematan crabs. This study will provided a better understanding for gene rearrangements and crab evolution in the further.


The image quality of deep-learning image reconstruction of chest CT images on a mediastinal window setting.
To assess the image quality of deep-learning image reconstruction (DLIR) of chest computed tomography (CT) images on a mediastinal window setting in comparison to an adaptive statistical iterative reconstruction (ASiR-V). Thirty-six patients were evaluated retrospectively. All patients underwent contrast-enhanced chest CT and thin-section images were reconstructed using filtered back projection (FBP); ASiR-V (60% and 100% blending setting); and DLIR (low, medium, and high settings). Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were evaluated objectively. Two independent radiologists evaluated ASiR-V 60% and DLIR subjectively, in comparison with FBP, on a five-point scale in terms of noise, streak artefact, lymph nodes, small vessels, and overall image quality on a mediastinal window setting (width 400 HU, level 60 HU). In addition, image texture of ASiR-Vs (60% and 100%) and DLIR-high was analysed subjectively. Compared with ASiR-V 60%, DLIR-med and DLIR-high showed significantly less noise, higher SNR, and higher CNR (p<0.0001). DLIR-high and ASiR-V 100% were not significantly different regarding noise (p=0.2918) and CNR (p=0.0642). At a higher DLIR setting, noise was lower and SNR and CNR were higher (p<0.0001). DLIR-high showed the best subjective scores for noise, streak artefact, and overall image quality (p<0.0001). Compared with ASiR-V 60%, DLIR-med and DLIR-high scored worse in the assessment of small vessels (p<0.0001). The image texture of DLIR-high was significantly finer than that of ASIR-Vs (p<0.0001). DLIR-high improved the objective parameters and subjective image quality by reducing noise and streak artefacts and providing finer image texture.


LH-induced desensitization of the adenylyl cyclase system in ovarian follicles.
Studies on the gonadotrophin-responsive adenylyl cyclase (AC) system of rabbit and porcine ovarian follicles reveal that hCG or LH-induced desensitization of the AC system can be divided into two phases: an initial, LH-specific phase and a second phase which is not specific for LH. The first phase occurs within the first hour after LH-hCG-receptor interaction, is agonist specific, and is not mediated by protein synthetic events or by cAMP. In view of our previous demonstration of the critical dependence of the LH-induced desensitizing process in cell-free membrane preparations of porcine follicles upon Mg2+ and ATP, we investigated the role of a phosphorylation reaction in the first phase of the AC desensitizing process. Porcine follicular membranes rich in LH-sensitive AC activity were found to contain the molecular requirements necessary for a phosphorylation reaction: namely, cAMP-dependent and cAMP-independent protein kinases as well as phosphoprotein phosphatases. The following lines of indirect evidence indicated that reversal or resensitization of the desenzitized AC system to LH was mediated by a dephosphorylation reaction. Activators of endogenous phosphoprotein phosphatases--Mn2+ and dithiothreitol--promoted a specific resensitization of the follicular AC system to LH. Likewise, a partially purified phosphoprotein phosphatase also resensitized the desensitized, LH unresponsive AC to LH, and boiling of the phosphatase prevented its effect. LH-induced desensitization of the AC system, on the other hand, did not appear to be mediated by a cAMP-dependent protein kinase, as evidenced both by the inability of beef heart protein to promote desensitization of AC and by the inability of an inhibitor of cAMP-dependent protein kinase to prevent LH-induced densensitization. The second phase of desensitization, which occurs after the first hour following hCG-LH-receptor interaction, is characterized by a loss of responsiveness to FSH as well as to LH and can be promoted by dibutryl cAMP (in the absence of LH). These results provide new evidence on the characteristics and molecular mechanism of LH-induced densensitization of the follicular AC system. These results indicate that the level of phosphorylation of membrane-associated components may, in part, regulate the activity of the AC system during this first phase of homologous desensitization.


Five Decades of HBV Infection in Italy: A Continuous Challenge.
In Italy, Hepatitis B virus (HBV) infection has been characterized by several changes over the last five decades. In 2019, the incidence of acute HBV among subjects targeted by the vaccination campaign was 0 cases in the age group 0-14 years and 0.1/100,000 in the age group 15-24. Nowadays, the burden of different stages of HBV-related chronic liver diseases is minimal. Intravenous drug use is no longer a risk factor (O.R. 0.7; 95% C.I. 0.5-1.02) for acquiring acute HBV; the proportion of cases reporting this exposure fell from 29.8% to 3.3% over the last two decades. The key public health intervention has been the compulsory vaccination campaign started in 1991 for infants 3 months old and 1-2 years old (the latter group for the first 12 years of the campaign). Moreover, non-immunogenic factors and the availability of effective oral antiviral drugs have played and continue to play a prominent role. The potential availability of new oral antiviral drugs with the inherent ability to eliminate the genomic HBV reservoirs may represent a further crucial step in the elimination of the virus in people that are already infected.


Comparison of conservative and surgical treatment in Gartland Type IIB fractures in pediatric patients.
In this study, our aim was to compare conservative treatment and surgical treatment radiologically and clinically in the treatment of pediatric Gartland type IIB SCHF, which is a controversial issue in the literature. This retrospective study included 86 patients with a Gartland type IIB humerus fracture. Forty-three patients were treated conservatively, and 43 patients were surgically treated. Radiological results were evaluated according to the Baumann angle and anterior humerus line. The Mayo Elbow Performance Score (MEPS) and Flynn's criteria were used to assess the functional evolution. The mean MEPS was 94 for the conservative treatment group and 93 for the surgical treatment group. According to Flynn's criteria, 31 (72.09%) excellent results were obtained in patients who were treated conservatively, and 26 (60.46%) excellent results were obtained in the surgical treatment group. The conservative and surgical treatment of Gartland type IIB SCHF is not superior to each other if anatomic reduction is achieved. Complications of each treatment can be prevented by following strict treatment principles.


Persistent SARS-CoV-2 PCR Positivity Despite Anti-viral Treatment in Immunodeficient Patients.
COVID-19 infection in immunodeficient individuals can result in chronically poor health, persistent or relapsing SARS-CoV-2 PCR positivity, and long-term infectious potential. While clinical trials have demonstrated promising outcomes using anti-SARS-CoV-2 medicines in immunocompetent hosts, their ability to achieve sustained viral clearance in immunodeficient patients remains unknown. We therefore aimed to study long-term virological outcomes in patients treated at our centre. We followed up immunocompromised inpatients treated with casirivimab-imdevimab (Ronapreve) between September and December 2021, and immunocompromised patients who received sotrovimab, molnupiravir, nirmatrelvir/ritonavir (Paxlovid), or no treatment from December 2021 to March 2022. Nasopharyngeal swab and sputum samples were obtained either in hospital or in the community until sustained viral clearance, defined as 3 consecutive negative PCR samples, was achieved. Positive samples were sequenced and analysed for mutations of interest. We observed sustained viral clearance in 71 of 103 patients, none of whom died. Of the 32/103 patients where sustained clearance was not confirmed, 6 died (between 2 and 34 days from treatment). Notably, we observed 25 cases of sputum positivity despite negative nasopharyngeal swab samples, as well as recurrence of SARS-CoV-2 positivity following a negative sample in 12 cases. Patients were then divided into those who cleared within 28 days and those with PCR positivity beyond 28 days. We noted lower B cell counts in the group with persistent PCR positivity (mean (SD) 0.06 (0.10) ×109/L vs 0.22 (0.28) ×109/L, p = 0.015) as well as lower IgA (median (IQR) 0.00 (0.00-0.15) g/L vs 0.40 (0.00-0.95) g/L, p = 0.001) and IgM (median (IQR) 0.05 (0.00-0.28) g/L vs 0.35 (0.10-1.10) g/L, p = 0.005). No differences were seen in CD4+ or CD8+ T cell counts. Antiviral treatment did not impact risk of persistent PCR positivity. Persistent SARS-CoV-2 PCR positivity is common among immunodeficient individuals, especially those with antibody deficiencies, regardless of anti-viral treatment. Peripheral B cell count and serum IgA and IgM levels are predictors of viral persistence.


The NMDA receptor and cocaine: evidence that MK-801 can induce behavioral sensitization effects.
Antagonism of the NMDA receptor with MK-801 is considered to be an effective pharmacologic manipulation to prevent the development of sensitization effects to drugs such as cocaine. The present study investigated this issue by comparing the behavioral response of separate groups of rats to three treatment cycles of either saline, 0.1 mg/kg MK-801, 10 mg/kg cocaine, or combined MK-801-cocaine (0.1/10 mg/kg). The treatments were spaced 1 week apart and were preceded by two nondrug baseline tests. In the first test cycle, the four groups had equivalent activity levels in the two nondrug tests. In the first drug test only the MK-801-cocaine group exhibited hyperactivity. By the third drug test, the MK-801-cocaine group exhibited an enhanced hyperactivity and the MK-801 group became hyperactive. Thus, behavioral drug sensitization developed but only with groups treated with MK-801. Antagonism of the NMDA receptor under some circumstances can be a highly effective treatment for the induction of behavioral sensitization effects.


Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout.
Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.


The Role of Carbon Monoxide in the Reactions of Arterial Branches of the Uterine Artery of Rats to Low-Intensity Irradiation with a Helium-Neon Laser.
Biomicroscopy was used to study order I-IV branches of the uterine artery in sexually mature female Wistar rats after a single 5- or 10-min direct exposure of the right broad ligament of the uterus to a helium-neon laser beam in the red band of the spectrum (λ=632.8 nm, output power 2 mW, intensity 20 mW/cm2). Under the influence of laser exposure, there was a significant increase in the diameter of small uterine branches and a weaker increase in large vessels with a well-developed muscular membrane. Preliminary administration of zinc IX protoporphyrin hemoxygenase blocker (30 mmol/kg) reduced reactivity of the vascular bed to laser irradiation, mainly of order I-II branches. It was concluded that carbon monoxide can act as an intermediary between the laser exposure and uterine vessels.


Outbreak of B.cepacia bacteremia following use of contaminated drug vials in a tertiary care centre.
We report an outbreak of Burkholderia cepacia bacteremia related to contaminated drug vials. All patients having fever post coronary angiography were analysed from February 12, 2019 to March 18, 2019. A thorough inspection of the cath lab was done by the infection control team. Surveillance cultures were taken from various places including swabs from the all the drug vials used for the patients. During the above period, a total of 898 cases had been taken up for angiographic procedures in all the four cath labs, out of which 72 were for neurological issues. Among these patients only 60 patients reported fever. No fever was reported among those who underwent angiograms for neurological issues. Of the 60 patients who had fever, 38 patients satisfied the case definition. Blood cultures were sent for 7(18.4%) patients and 17(44.7%) had been started on antibiotics. After identification of 2 cases with the positive culture and following the news that a drug manufacturing company had recalled a particular batch of drug (diltiazem), the source of the outbreak was thought to be contaminated diltiazem vials. Retrospectively it was noted that the 38 patients had received the diltiazem from three different batches. Subsequently the same organism was isolated from the drug vials also. Both the isolates were phenotypically the same. There were no patients with fever post procedure reported the week after the batch of diltiazem was recalled. The outbreak was thus linked to the contaminated diltiazem vials. Physicians should thus be aware of such outbreaks that can cause bacteremias.


[Electrophoretic study of the proteins of the hemolymph, intestine, excrement (and ova) of active and dispausal Dermacentor marginatus Sulz (Ixodidae) females].
The polyacrylamide-gel electrophoresis was used to separate the negative charged proteins from adult females of the tick Dermacentor marginatus Sulz. There were separated up to 25 protein bands from haemolymph and up to 19 bands from midgut extracts of the engorged females. The number of protein bands in excreta and eggs was 15 and 18 respectively. Haemoproteins from haemolymph, midgut and eggs were different in their electrophoretic mobility. Active and diapausing ticks showed essential differences in protein spectra and content of haemolymph (the enrichment of them was characteristic of diapausing ticks). The presence or absence of reproductive diapause affects the digestive functions and has no influence on the excretory functions of the midgut.


Kinetic therapy in multiple trauma patients with severe thoracic trauma: a treatment option to reduce ventilator time and improve outcome.
Continuous lateral rotational therapy (CLRT) has been described as a promising approach for prophylaxis and treatment of respiratory complications in critically ill patients over two decades ago. However, meta-analyses failed to demonstrate any significant benefit on outcome by CLRT, possibly due to the heterogeneity and low overall quality of available studies. Observational trial over a 3-year period on outcome in trauma patients (Injury Severity Score, ISS ≥16) with severe thoracic injury (Abbreviated Injury Scale, AISThorax ≥3) initially treated with CLRT as standard of care. Epidemiological data, injury severity, and pattern and physiological parameters were recorded. Outcome indicators were time on mechanical ventilation, length of stay, rates of pneumonia, sepsis and acute respiratory distress syndrome, hospital mortality, and rates of re-intubation. Additionally, data are compared with the results from the TraumaRegister® of the German Trauma Society. Over the 3-year period 76 patients with ISS ≥16/AISThorax ≥3 received CLRT, equaling 24 % of all patients with ISS ≥16 between 18 and 80 years. Mean ISS was 35.3 (standard deviations, SD 12.2) [71.1 % male, 97.4 % blunt trauma, mean age 43.9 years (SD 18.7)]. Mean time on CLRT was 3.3 days (SD 2.2), time on mechanical ventilation 7.8 days (SD 7.1), and 9.2 % had to be re-intubated due to respiratory complications. CLRT-related complications occurred in 8.9 %. Overall 25 % of the patients developed pneumonia (VAP = 13.2 %). Despite a significantly higher ISS we observed shorter times on mechanical ventilation and intensive care unit in our collective in comparison to data published from the nationwide TraumaRegister®. CLRT remains a therapeutic option to reduce pulmonary complications after severe chest trauma in our center. However, a RCT is needed to study the effects of other treatment options such as early extubation and non-invasive ventilation or prone/supine positioning.


Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery.
The present study aims to develop self-microemulsifying drug delivery systems (SMEDDS) in sustained-release pellets of puerarin to enhance the oral bioavailability of puerarin. The performances of puerarin-SMEDDS including oils, emulsifiers, and co-emulsifiers were evaluated. Pseudo-ternary phase diagrams shows that the optimized formulation consisted of castor oil as the oil phase, Cremophor EL as the emulsifier, and 1,2-propanediol as the co-emulsifier. SMEDDS sustained-release pellets were prepared via extrusion-spheronization. The particle size distributions of the formulations were determined using transmission electron microscopy and scanning electronic microscopy. The mean particle size was 50 ± 8 nm. The pharmacokinetics and bioavailability of the puerarin-SMEDDS sustained-release pellets and puerarin tablets were evaluated and compared in beagle dogs. The absolute bioavailability of the puerarin-SMEDDS sustained-release pellets was enhanced by approximately 2.6-fold compared with that of the puerarin tablet. The relative bioavailability (F(rel)) of the SMEDDS pellets was 259.7% compared with the tablet group. The results demonstrated that the puerarin-SMEDDS sustained-release pellets had a sustained-release effect, and could remarkably improve the oral bioavailability of puerarin.


One third of the variability in HDL-cholesterol level in a large dyslipidaemic population is predicted by age, sex and triglyceridaemia: The Paris La Pitié Study.
The objective of this study was to identify key determinants of high-density lipoprotein-cholesterol (HDL-C) level, including subclinical inflammation and insulin resistance, and to determine the prevalence of a low HDL-C phenotype in dyslipidaemic patients at high cardiovascular risk. In a cross-sectional study, we assessed the prevalence of low HDL-C phenotypes in 14 667 dyslipidaemic patients attending our specialised lipid clinic and evaluated the potential relationships between HDL-C level and 16 clinical and biological parameters. In univariate analysis, women exhibited higher plasma concentrations of HDL-C as compared with men. Levels of triglycerides, fasting blood glucose, uric acid, waist circumference, body mass index, high sensitivity C-reactive protein (hs-CRP), insulin resistance (as HOMA-IR index) and smoking were all negatively correlated with HDL-C, whereas age was positively correlated with HDL-C levels. Moderate drinkers (10-30 g/day) displayed higher HDL-C concentrations as compared with abstinent subjects; in contrast, consumption of more than 30 g alcohol/day was associated with a further non-significant elevation of HDL-C levels as compared to moderate drinkers. Multivariate analysis identified eight independent correlates of HDL-C. Age, sex and TG accounted for 37% of variability in HDL-C; modifiable factors including waist circumference, alcohol consumption and smoking, in addition to HOMA-IR and hs-CRP, accounted for an additional 5% of the variability in HDL-C. Using a cut-off of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women, 33% and 28% of men and women displayed low levels of HDL-C. Eight independent determinants of HDL-C account for 41% of variability in HDL-C in our dyslipidaemic population. Three of them, i.e. age, sex and degree of triglyceridaemia accounted for more than one third of such variability. The high prevalence of low HDL-C phenotypes in dyslipidaemic patients at elevated cardiovascular risk emphasises the need for both lifestyle and pharmacological strategies of intervention to raise HDL-C.


Leiorreuma exaltatum and Trapelia coarctata, New to Korean Lichen Flora.
The present account briefly describes two crustose lichen species new to South Korea. Detailed taxonomic descriptions of Leiorreuma exaltatum and Trapelia coarctata, supported by distribution, ecology and illustrations, are provided. Both species were collected from warm-temperate, humid forests of Jeju Island.


Case report: post-salmonellosis abscess positive for Salmonella Oranienburg.
Salmonella gastroenteritis is a self-limited infection in immunocompetent adults. Salmonella Oranienburg is a serovar that has recently caused outbreaks of gastroenteritis traced to contact with a pet turtle. Extraintestinal focal infections (EFIs) with invasive Salmonella have been reported uncommonly, examples of which include mycotic aneurysm and spinal osteomyelitis. The patient is an otherwise healthy 39-year-old male with sleep apnea presenting with pain and swelling in the left anterior chest wall several months after an episode of Salmonella gastroenteritis and bacteremia which was treated successfully with intravenous (IV) antibiotics. He was found to have a costochondral joint abscess with operative cultures positive for S. Oranienburg, a serovar reported to have been associated with pet turtles and onions in recent CDC and FDA news releases. Of note, the joint abscess began development 2-3 months after his episode of Salmonella bacteremia. At the time of surgical treatment, nearly 6 months had passed since the initial episode of gastroenteritis and bacteremia. Delayed development of a sternocostal joint abscess after Salmonella bacteremia in an otherwise healthy adult male is an unusual presentation. The patient had two different exposures: a fast food chicken lunch and a pet turtle at home. Extraintestinal focal infections with invasive Salmonella are very uncommonly reported in healthy adult patients treated in developed countries. To our knowledge, we report this sequala for the first time.


Surgery for Mycobacterium avium complex lung disease in the clarithromycin era.
Since the introduction of clarithromycin, it has been assumed that pulmonary Mycobacterium avium complex (MAC) disease can be treated with medication alone. This study examines whether surgery can still play an important role in the management of MAC lung disease in the current era. Between April 1993 and January 2001, 21 patients (11 men and 10 women) underwent a pulmonary resection for MAC infection. The median age of the patients was 56 years (range: 27-67 years). None of the patients were immunocompromised. Regimens employing clarithromycin were initiated preoperatively in all patients. The indications for surgery were failure of drug therapy in 19 patients and discontinuation of chemotherapy because of drug toxicity in two patients. The pulmonary resections (19 right lung, 2 left lung) performed included lobectomy in 16 patients, pneumonectomy in three, bilobectomy in one, and lobectomy plus segmentectomy in one. All of the patients survived the surgery. Six major postoperative complications occurred in six patients (28.6%) and these included two bronchopleural fistulas after right pneumonectomy, two space problems, one prolonged air leak, and one case of interstitial pneumonia. All postoperative complications were manageable, and four of these were treated surgically. All patients had sputum-negative status after their operation. Relapse occurred in two patients (9.5%) at six months and two years postoperative, respectively. The first patient, who originally had a right upper lobectomy, underwent a left upper lobectomy during the follow-up period, attaining sputum conversion. The second patient underwent a right pneumonectomy and then died of respiratory failure four years postoperatively. This one late death was the only fatality. Although it is associated with relatively high morbidity, surgery provides a high sputum conversion rate for patients whose MAC disease responds poorly to drug therapy. Even in the present clarithromycin era, pulmonary resection remains the treatment of choice when MAC lung disease has not been successfully eradicated by drug treatment alone.


Opioid-mediated inhibition from the subnucleus caudalis of spinal trigeminal nucleus to the neurons in the subnucleus oralis.
The influence of enkephalin-containing neurons in the subnucleus caudalis of the spinal trigeminal nucleus (STN caudalis) on the subnucleus oralis of the STN (STN oralis) was examined using chloral hydrate-anesthetized rats. In the STN oralis, conditioning stimuli applied to the STN caudalis 10-50 ms preceding the test stimulus inhibited spikes produced by tooth pulp stimulation in type B interneuron, which was activated by orthodromic stimulation but not by thalamic stimulation, without affecting those of the relay neuron. When the type B interneurons were further classified into type B1 and type B2 neurons, which were characterized by the occurrence of the STN caudalis-induced inhibition with long and short latencies, respectively, microiontophoretically applied naloxone reduced the STN caudalis-induced inhibition of th orthodromic spikes of type B1 interneurons with little effects on type B2 interneuron. Furthermore, naloxone-reversible inhibition of tooth pulp-induced spikes of the type B1 interneurons were also observed during iontophoretic application of enkephalin. These results suggest that the type B1 interneurons in the STN oralis are inhibited by opioid peptides-containing neurons in the STN caudalis.


Subgenomic HCV RNA replication and its localization in the nucleus of the infected cells.
Cell culture systems have been established, where a hepatitis C virus (HCV) subgenomic replicon was efficiently replicated and maintained for a long period. It is known that HCV contains proteins which interact with host cell proteins. To see whether a HCV RNA replicon can interact in the same way with host cell proteins, HCV RNA replicon was transfected in Huh7 cells. In most infected cells, HCV replicon is present in the cytoplasm; however, in a minority of HCV-infected cells, both the cytoplasm and the nucleus or the nucleus on its own is positive for NS3. The presence of NS3 in the nuclei of Huh7 cells indicates that the protein may play a role other than in virus replication, such as in persistence of HCV infection.


Basis for hormonal management of advanced prostate cancer.
In the early 1940s, when it was established that most prostatic cancers were androgen dependent and could be controlled by androgen withdrawal, little was known about the mechanism of androgen action. Measurements of hormones, both in the circulation and in the tissue, were not available, nor were measurements of androgen receptors known at that time. Since that time, a large body of information has been published regarding the mechanism of androgen-mediated action. With the understanding of androgen-mediated action has come the opportunity to develop drugs targeted to block specific steps in the sequence of androgen action, beginning in the hypothalamus-pituitary area and extending down to the intracellular processes of enzymatic reduction, receptor binding, and nuclear translocation of the hormone receptor complexes. The major focus in prostate cancer therapy currently is the role of the adrenal androgens. It was established in the 1970s that, after castration, there was a 75% reduction in the dihydrotestosterone (DHT) present in prostate tissue. This observation contrasted with the finding that there was a greater than 90% reduction in circulating testosterone levels in the plasma after castration. Based on this important observation regarding tissue DHT concentrations after castration, attempts were made in the 1980s to block androgen totally using simultaneous gonadal and adrenal suppression. Dramatic results were reported after this type of therapy in the early uncontrolled studies. A luteinizing hormone-releasing hormone agonist plus flutamide was used for total androgen blockade. Other techniques for such blockade were available using megestrol acetate in combination with 17-beta-estradiol. One of the key issues has been whether the 25% residual DHT after castration provides a sufficient stimulus to growth of residual prostate tumor cells. The best evidence for the importance of the role of adrenal androgens came from clinical studies in which objective clinical responses were found in patients treated with various inhibitors of androgen action after relapse and castration. If "objectively stable" is included as a category after treatment, then approximately 33% of patients who have relapses after castration can be shown to have an additional response, albeit short, to adrenal androgen withdrawal. Thus, the control of the relatively small amounts of DHT remaining after castration became a major focus for therapy in metastatic prostate cancer.


Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat.
Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. The model system utilized human liver microsomes and isoform-selective index substrates. Ritonavir and cobicistat both were strong inhibitors of CYP3A4, with IC50 values of 0.014 and 0.032 μm, respectively. A component of inhibition was time-dependent (mechanism-based). Neither drug meaningfully inhibited CYP1A2 (IC50 > 150 μm). CYP2B6, CYP2C9, CYP2C19 and CYP2D6 were inhibited by both drugs, but with IC50 values exceeding 6 μm. Consistent with previous reports, both ritonavir and cobicistat were highly potent inhibitors of CYP3A. Both drugs were weaker inhibitors of other human CYPs, with IC50 values at least two orders of magnitude higher. There was no evidence of a meaningful difference in selectivity between the two drugs.


Sodium fluxes through nonselective cation channels in the plasma membrane of protoplasts from Arabidopsis roots.
The aim of the present work was to characterize Na(+) currents through nonselective cation channels (NSCCs) in protoplasts derived from root cells of Arabidopsis. The procedure of the protoplast isolation was modified to increase the stability of Arabidopsis root protoplasts in low external Ca(2+) by digesting tissue in elevated Ca(2+). Experiments in whole-cell and outside-out modes were carried out. We found that Na(+) currents in Arabidopsis root protoplasts were mediated by cation channels that were insensitive to externally applied tetraethylammonium(+) and verapamil, had no time-dependent activation (permanently opened or completely activated within 1-2 ms), were voltage independent, and were weakly selective for monovalent cations. The selectivity sequence was as follows: K(+) (1.49) > NH(4)(+) (1.24) > Rb(+) (1.15) approximately equal to Cs(+) (1.10) approximately equal to Na(+) (1.00) > Li(+) (0.73) > tetraethylammonium(+) (0.47). Arabidopsis root NSCCs were blocked by H(+) (pK approximately equal to 6.0), Ca(2+) (K(1/2) approximately equal to 0.1 mM), Ba(2+), Zn(2+), La(3+), Gd(3+), quinine, and the His modifier diethylpyrocarbonate. They were insensitive to most organic blockers (nifedipine, verapamil, flufenamate, and amiloride) and to the SH-group modifier p-chloromercuriphenyl sulfonic acid. Voltage-insensitive, Ca(2+)-sensitive single channels were also resolved. Properties of Arabidopsis root NSCCs are discussed and compared with characteristics of similar conductances studied previously in plants and animals. It is suggested that NSCCs present a distinct group of plant ion channels, mediating toxic Na(+) influx to the cell and probably having other important roles in physiological processes of plants.


Quantitative measurement of ketone bodies in urine using reflectometry.
Recently, automated urine test strip readers became available that can report quantitative data. We explored the possibility of measuring all ketone bodies (acetone, acetoacetate, 3-hydroxybutyrate) in urine with these test strips. Monitoring urinary ketone concentrations could offer the advantages of measuring higher values (due to the low renal thresholds) and being less sensitive to fluctuations. We evaluated URISYS 2400 (Roche) quantitative reflectance data for the ketone reflectance field and compared it with biochemical data from urine samples. Using an easy sample pre-treatment with 3-hydroxybutyrate dehydrogenase, we were able to assay 3-hydroxybutyrate as well, which normally does not react on urine test strips. Within- and between-run reproducibility of the reflectance signal for high- and low-concentration urine pools was 11.0-3.6% and 11.0-5.8% for aceto-acetate, 8.2-9.2% and 10.4-16.1% for acetone, and 5.1-3.0% and 5.6-3.5% for 3-hydroxybutyrate, respectively. The lower limit of detection for acetoacetate was 0.13 mmol/L (CV=3.6%). Fair agreement was obtained between test strip data for ketones andcolorimetrically determined acetoacetate values (r=0.90). In urine test strip analysis, quantitative ketone reflectance data allow a simple and fast analysis, offering affordable screening for the detection of ketone body production in diabetes, especially in emergency settings.


Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression.
Primary or acquired resistance to current treatment protocols remains a major concern in clinical oncology and may be caused by defects in apoptosis programs. Since recent data suggest that TRAIL can bypass apoptosis resistance caused by Bcl-2, we further investigated the role of Bcl-2 in TRAIL-induced apoptosis. Here we report that overexpression of Bcl-2 conferred protection against TRAIL in neuroblastoma, glioblastoma or breast carcinoma cell lines. Bcl-2 overexpression reduced TRAIL-induced cleavage of caspase-8 and Bid indicating that caspase-8 was activated upstream and also downstream of mitochondria in a feedback amplification loop. Importantly, Bcl-2 blocked cleavage of caspases-9, -7 and -3 into active subunits and cleavage of the caspase substrates DFF45 or PARP. Also, Bcl-2 blocked cleavage of XIAP and overexpression of XIAP conferred resistance against TRAIL indicating that apoptosis was also amplified through a feedforward loop between caspases and XIAP. In contrast, in SKW lymphoblastoid cells, TRAIL-induced activation of caspase-8 directly translated into full activation of caspases, cleavage of XIAP, DFF45 or PARP and apoptosis independent of Bcl-2 overexpression, although Bcl-2 similarly inhibited loss of mitochondrial membrane potential and the release of cytochrome c, AIF and Smac from mitochondria in all cell types. By demonstrating a cell type dependent regulation of the TRAIL signaling pathway at different level, e.g. by Bcl-2 and by XIAP, these findings may have important clinical implication. Thus, strategies targeting the molecular basis of resistance towards TRAIL may be necessary in some tumors for cancer therapy with TRAIL.


Implementation and evaluation of data compression of MR images.
A full-frame bit-allocation technique of data compression has been implemented using the existing computer facilities of an MR imager. Images reconstructed from compressed data files have been compared with the original image and changes in noise and pixel value measured to evaluate any image degradation introduced by the compression process. A 256 x 256 x 8 bit brain image can be compressed in 20 seconds with a compression ratio of greater than 4:1 without significant loss of information.


Survival after resection for carcinoma of the oesophagus.
During the period 1978-1984, 525 patients referred with cancer of the oesophagus or gastro-oesophageal junction were assessed for operation and cure. After investigation, 276 patients were selected and operated upon, as a rule, 4 weeks after radiotherapy (40 Gy/4 weeks). In 224 patients (81 per cent) the oesophagus and cardia were resected and reconstructed with stomach (69 per cent), colon (21 per cent), free ileal graft (7 per cent) or Roux-en-Y-oesophagojejunostomy (3 per cent). The postresectional hospital mortality was 14 per cent in all patients and decreased to 5 per cent in 1983. Mortality was higher when the colon was used for reconstruction than when the stomach was used. By postresection staging, 82 patients were found to have stages I and II tumours and 142 patients stage III tumours. Estimated 3-year survival after resection for all male patients was 28 per cent and for all female patients was 42 per cent. Estimated 3-year survival for all patients treated for adenocarcinoma was 31 per cent. Survival was better for stages I and II patients with adenocarcinoma (52 per cent) than for stage III patients (18 per cent) (P less than 0.01). Estimated 3-year survival for all patients treated for squamous cell carcinoma was 33 per cent. Estimated 3-year survival was better for stages I and II patients with squamous cell carcinoma (48 per cent) than for stage III patients (25 per cent) (P less than 0.001). It can be concluded from this study that resection of oesophagus and cardia after radiotherapy offers hope for cure in a subgroup of patients with non-advanced oesophageal cancer. The operation can be performed with acceptable mortality by experienced surgeons, especially when the stomach is used for reconstruction.


Presence of the delta-MSH sequence in a proopiomelanocortin cDNA cloned from the pituitary of the galeoid shark, Heterodontus portusjacksoni.
Since a fourth MSH sequence, delta-MSH, has been detected in the proopiomelanocortin (POMC) gene of a dogfish and a stingray, members of superorder Squalea (class Chondrichthyes), it is possible that this novel MSH sequence might be a feature common to the POMC genes of all modern sharks and rays. As an initial step towards addressing this question, a full-length POMC cDNA was cloned and sequenced from the pituitary of the Port Jackson shark, Heterodontus portusjacksoni. The Port Jackson shark represents one of the oldest lineages in superorder Galea, and this superorder together with superorder Squalea form infraclass Neoselachii (the extant sharks and rays). The Port Jackson shark POMC cDNA has an open reading frame that is 1032 nucleotides in length and encodes the deduced amino acids sequences for beta-endorphin, ACTH/alpha-MSH, beta-MSH, gamma-MSH, and delta-MSH. Port Jackson shark delta-MSH has 83% primary sequence identity with dogfish and stingray delta-MSH, and it appears that the delta-MSH sequence may have been the result of an internal domain duplication and reinsertion of the beta-MSH sequence. The presence of the delta-MSH sequence in the POMC genes of representatives of both superorders of infraclass Neoselachii would indicate that the delta-MSH sequence must have been present in the ancestral euselachian shark that gave rise to the neoselachian radiation.


Cytokine Expression in Patients Hospitalized for Severe Odontogenic Infection in Brazil.
Severe odontogenic infections remain an important public health concern and a significant economic burden to public health care facilities. Despite this, several aspects of the disease, such as its immune response profile, remain poorly understood. The aim of this study was to search for an association between mRNA levels of the cytokines interferon-γ, interleukin (IL)-1β, tumor necrosis factor-α, IL-17A, IL-10, and transforming growth factor-β and the chemokines IL-8, CCL2/MCP-1, and CCL5 and odontogenic infection. The case group was composed of 12 patients hospitalized in consequence of severe odontogenic infection, and our control group included 12 individuals with healthy periapical tissues. Clinical samples were taken from the case (drainage site) and control (periapical interstitial fluid) groups with the aid of paper points. Total RNA was extracted, complementary DNA was synthesized, and mRNA levels were determined by quantitative polymerase chain reaction. Data analysis was performed by using SPSS, and the Wilcoxon signed rank test was used to determine statistical significance (P < .05). Data generated showed a significantly increased expression of proinflammatory cytokines (interferon-γ, IL-1β, tumor necrosis factor-α, and IL-17A), IL-8, and CCL2/MCP-1 in odontogenic infection patients. The mRNA levels of IL-10, transforming growth factor-β, and CCL5 were similar in both study groups. In general, individuals presenting with odontogenic infections exhibited extraordinary proinflammatory cytokine profiles paralleled with unaltered expression of regulatory mediators.


Effect of mild temperature shift on poly(ADP-ribose) and γH2AX levels in cultured cells.
Poly (ADP-ribose) (PAR) is rapidly synthesized by PAR polymerases (PARPs) upon activation by DNA single- and double-strand breaks. In this study, we examined the quantitative amount of PAR in HeLa cells cultured within the physiological temperatures below 41 °C for verification of the effect of shifting-up or -down the temperature from 37.0 °C on the DNA breaks, whether the temperature-shift caused breaks that could be monitored by the level of PAR. While PAR level did not change significantly when HeLa cells were cultured at 33.5 °C or 37.0 °C, it was significantly increased 2- and 3-fold when cells were cultured for 12 h and 24 h, respectively, at 40.5 °C as compared to 37.0 °C. Similar to the results with HeLa cells, PAR level was increased 2-fold in CHO-K1 cells cultured at 40.5 °C for 24 h as compared to 37.0 °C. As the cellular levels of PAR polymerase1 (PARP1) and PAR glycohydrolase (PARG), a major degradation enzyme for PAR, did not seem to change significantly, this increase could be caused by activation of PARP1 by DNA strand breaks. In fact, γH2AX, claimed to be a marker of DNA double-strand breaks, was found in cell extracts of HeLa cells and CHO-K1 cells at elevated temperature vs. 37.0 °C, and these γH2AX signals were intensified in the presence of 3-aminobenzamide, a PARP inhibitor. The γH2AX immunohistochemistry results in HeLa cells were consistent with Western blot analyses. In HeLa cells, proliferation was significantly suppressed at 40.5 °C in 72 h-continuous cultures and decreased viabilities were also observed after 24-72 h at 40.5 °C. Flow cytometric analyses showed that the HeLa cells were arrested at G2/M after temperature shift-up to 40.5 °C. These physiological changes were potentiated in the presence of 3-aminobenzamide. Decrease in growth rates, increased cytotoxicity and G2/M arrest, were associated with the temperature-shift to 40.5 °C and are indirect evidence of DNA breaks. In addition to γH2AX, PAR could be a sensitive marker for DNA single- and double-strand breaks. These two molecular markers provide evidence of physiological changes occurring within cells.


Identification of sources of environmental lead in South Africa from surface soil geochemical maps.
The bioavailability of lead in soil is of considerable importance to human and animal health. Although selective extraction has been explored as a more appropriate technique than total heavy metal analysis in environmental pollution assessments, such studies remain scarce globally and are almost non-existent in developing countries. Results for a large-scale study of extractable lead levels in undisturbed soil samples in South Africa identify several geographic areas of concern. Lead levels are considerably elevated relative to background levels in the Johannesburg urban and industrial area. Areas of active lead mining also exhibit higher surface soil values. Interestingly, areas of active and intensive coal mining activity display relatively low soil Pb values, possibly attributable to the relatively low heavy metal content of South African coal. In all instances, distribution of cadmium, a carcinogenic element, correlates with that of lead. The results demonstrate the usefulness of the quick and easy Mehlich-3 single extractant technique, an established technique in micronutrient studies, to simultaneously provide valuable environmental data for toxic metals such as Pb and Cd.


Trace determination of organophosphorus pesticides in environmental samples by temperature-controlled ionic liquid dispersive liquid-phase microextraction.
This paper described a new approach for the determination of organophosphorus pesticides by temperature-controlled ionic liquid dispersive liquid-phase microextraction prior to high-performance liquid chromatography with ultraviolet detection. Methylparathion and phoxim, two of the typical organophosphorus pesticides, were used as the model analytes for the investigation of the development and application of the new microextraction method. 1-Hexyl-3-methylimidazolium hexafluorophosphate [C6MIM][PF6] was used as the extraction solvent and the factors affecting the extraction efficiency such as the volume of [C6MIM][PF6], pH of working solutions, extraction time, centrifuging time, dissoluble temperature and salt effect were optimized. Under the optimal extraction conditions, methylparathion and phoxim exhibited good linear relationship in the concentration range of 1-100 ng mL(-1). The detection limits were 0.17 ng mL(-1) and 0.29 ng mL(-1), respectively. Precisions of proposed method (RSDs, n=6) were 2.5% and 2.7%, respectively. This proposed method was successfully applied in the analysis of four real environmental water samples and good spiked recoveries over the range of 88.2-103.6% were obtained. These results indicated that temperature-controlled ionic liquid dispersive liquid-phase microextraction had excellent application prospect in environmental field.


Performance of current ultrasound-based malignancy risk stratification systems for thyroid nodules in patients with follicular neoplasms.
To investigate the ability of the currently used ultrasound-based malignancy risk stratification systems for thyroid neoplasms (ATA, AACE/ACE/AME, K-TIRADS, EU-TIRADS, ACR-TIRADS and C-TIRADS) in distinguishing follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA). Additionally, we evaluated the ability of these systems in correctly determining the indication for biopsy. Three hundred twenty-nine follicular neoplasms with definitive postoperative histopathology were included. The nodules were categorized according to each of six stratification systems, based on ultrasound findings. We dichotomized nodules into the positive predictive group of FTC (high and intermediate risk) and negative group of FTC based on the classification results. Missed biopsy was defined as neoplasms that were diagnosed as FTCs but for which biopsy was not indicated based on lesion classification. Unnecessary biopsy was defined as neoplasms that were diagnosed as FTAs but for whom biopsy was considered indicated based on classification. The diagnostic performance and missed and unnecessary biopsy rates were evaluated for each stratification system. The area under the curve of each system for distinguishing follicular neoplasms was < 0.700 (range, 0.511-0.611). The missed biopsy rates were 9.0-22.4%. The missed biopsy rates for lesions ≤ 4 cm and lesions sized 2-4 cm were 16.2-35.1% and 0-20.0%, respectively. Unnecessary biopsy rates were 65.3-93.1%. In ≤ 4 cm group, the unnecessary biopsy rates were 62.2-89.7%. The malignancy risk stratification systems can select appropriate nodules for biopsy in follicular neoplasms, while they have limitations in distinguishing follicular neoplasms and reducing unnecessary biopsy. Specific stratification systems and recommendations should be established for follicular neoplasms. • Current ultrasound-based malignancy risk stratification systems of thyroid nodules had low efficiency in the characterization of follicular neoplasms. • The adopted stratification systems showed acceptable performance for selecting FTC for biopsy but unsatisfactory performance for reducing unnecessary biopsy.


Arterial blood gases during cardiac arrest: markers of blood flow in a canine model.
Measures of CO2 have been shown to correlate with coronary perfusion pressure and cardiac output during cardiac arrest. We evaluated arterial pH (pHa) relative to blood flow during cardiac arrest in a canine electromechanical dissociation (EMD) model of cardiac arrest using different resuscitation techniques. Following 15 min of cardiac arrest, 24 mongrel dogs received epinephrine with continued CPR or closed-chest cardiopulmonary bypass. Central arterial blood gases, end-tidal carbon dioxide (PetCO2), coronary perfusion pressure and cardiac output were measured. During CPR, prior to epinephrine or bypass, there was no correlation of pHa, PACO2 and PetCO2, with cardiac output or coronary perfusion pressure. Immediately after instituting the resuscitation techniques, both pHa and PaCO2 showed a significant correlation with cardiac output (pHa; R = -0.78, P less than 0.001 and PaCO2; R = 0.87, P less than 0.001) and with coronary perfusion pressure (pHa; R = -0.75, P less than 0.001 and PaCO2; R = 0.75, P less than 0.001). Eventual survivors (n = 15) had an early significant decrease in pHa, base excess and a significant increase in PaCO2 which was not present in non-survivors (n = 9). Neither pHa nor PaCO2 correlate with blood flow under low flow conditions of CPR. However, with effective circulatory assistance, pHa and PaCO2 reflect systemic blood flow and reperfusion washout.


Chronic transscaphoid, transcapitate perilunate fracture dislocation of the wrist: Fenton's syndrome.
The authors report about chronic Fenton's syndrome. This rare injury of the wrist is characterized by scapho-capitate fracture accompanied by 180° rotation of the head of capitate and associated perilunate dislocation. Two patients suffering from chronic Fenton's syndrome were treated with pyrocarbon capitate resurfacing prosthesis. Patients were evaluated according to the wrist range of motion, Mayo modified wrist and DASH scores. In conclusion, prosthetic surgery may achieve satisfactory results for this rare and diagnostically challenging syndrome.


A qualitative study using hybrid simulation to explore the impacts of human factors e-learning on behaviour change.
There is an international drive to increase human factors training in undergraduate medical curricula through various educational platforms. E-learning can be effective at teaching technical skills but there is limited research exploring the benefits of e-learning in human factors training. This study aimed to utilise hybrid simulation to investigate the impact of a human factors focused e-learning package for intravenous cannulation on safety behaviours. Video-reflexive ethnography (VRE) techniques and interviews were used to explore human factor-related behaviour change in hybrid simulation scenarios, before and after e-learning modular training. Ten final-year medical students were recruited for the study. Content analysis of VRE data from hybrid simulation scenarios identified which behaviours had changed; thematic analysis of semi-structured interviews uncovered why. Results demonstrate improvement in safety behaviours in the domains of physical-, cognitive- and macro-ergonomics, suggesting safer cannulation practice following training. Online videos with interactive activities were reported as the major pedagogical driver for change. The impact of the e-learning was identified across four themes: environment, person, policy-related tasks, and preparedness for practise. Reported intention to change practise and altered behaviour in the workplace supports the conclusion that this training prepares students for practise by facilitating them to incorporate human factors principles in their clinical work. E-learning is a valuable and effective method for supporting medical student learning about human factors. Hybrid simulation and VRE combine well together to evaluate behaviour change following educational interventions.


Keratin and polyamide-coated inorganic matrices as supports for glucoamylase immobilization.
Previously solubilized feather keratin and polyamide were used for coating sand, glass beads and silica gel. These new seven supports were employed for comparative studies on pure glucoamylase / EC 184.108.40.206 / immobilization. The immobilization yield of glucoamylase on keratin and polyamide coated supports was comparable with conventional matrices used earlier. The highest activity per 1 g of support was shown by the enzyme bound to polyamide-coated CPG, and the bests operational stability by the enzyme immobilized on polyamide-coated CPG with keratin subsequently deposited on it.


Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain.
ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators.


Unstable angina pectoris: a randomized study of patients treated medically and surgically.
Fifty patients with the clinical syndrome of unstable angina pectoris were evaluated. Twenty-seven were randomized into medical or surgical treatment groups and subsequently followed up. The results of the study reveal that: (1) there is approximately a 16 percent incidence rate of significant left main coronary artery disease in patients with this entity at our institution; (2) 10 percent of patients do not have angiographically significant coronary artery disease; (3) pain relief is better in the surgically treated patients, but the 1 1/2 year survival rate is not significantly different between the groups; (4) 50 percent of the medically treated patients again had the syndrome of unstable angina pectoris in the initial few months of the follow-up period; (5) the operative and late postoperative mortality rate in patients presenting with unstable angina pectoris and left main coronary artery disease in this small group of patients was 43 percent; and (6) four of six patients with this syndrome whose condition was deemed inoperable and who were not randomized died within the subsequent few months.


Decrease in calbindin content significantly alters LTP but not NMDA receptor and calcium channel properties.
The contribution of the cytosolic calcium binding protein calbindin D(28K) (CaBP) to the synaptic plasticity was investigated in hippocampal CA1 area of wild-type and antisense transgenic CaBP-deficient mice. We showed that long-term potentiation (LTP) induced by tetanic stimulation in CaBP-deficient mice was impaired. The fundamental biophysical properties of NMDA receptors and their number were not modified in CaBP-deficient mice. We also demonstrated that the physiological properties of calcium channels were identical between genotypes. An insufficient Ca(2+) entry through NMDA receptors or calcium channels, or a decrease in NMDA receptor density are unlikely to explain this impairment of LTP. Interestingly, we showed that the loss of LTP was not prevented by glycine but was restored in the presence of a low concentration of the NMDA receptor antagonist D-APV (5 microM) and of the calcium chelator BAPTA-AM (5 microM). Moreover, we observed a loss of LTP in the wild-type mice when the postsynaptic tetanic-induced [Ca(2+)](i) rise is excessively increased. Conversely, a weaker tetanus stimulation allowed LTP induction and maintenance in CaBP-deficient mice. These results suggest that a higher cytosol [Ca(2+)](i), due to the decrease of CaBP expression may impair LTP induction and maintenance mechanisms without affecting the mechanisms of calcium entry. Thus, CaBP plays a critical role in long term synaptic plasticity by limiting the elevation of calcium rise in the cytosol to some appropriate spatio-temporal pattern.


Alpha-hydroxylation of lignoceroyl-CoA by a cyanide-sensitive oxygenase in rat brain microsomes.
The enzymatic mechanism of alpha-hydroxylation of lignoceroyl-CoA, an intermediate in the synthesis of hydroxyceramide, was studied. In the presence of NADPH, sphingosine and microsomes from 20-day-old rat brain, 14C from [1-14C]lignoceroyl-CoA was incorporated into hydroxyceramide. Activity was linear with time (up to 40 min) and with protein (up to 0.8 mg). The apparent Km for lignoceroyl-CoA was about 10 microM. NADPH was a more efficient electron donor than NADH. Oxygen was required for activity, which increased linearly up to 20% O2. In 5 and 10% oxygen, the reaction was inhibited by 0.1 mM cyanide and by electron transfer chain inhibitors, cytochrome c, ferricyanide, menadione, and p-chloromercuriphenyl sulphonate; CO and SKF-525A had no effect. Moreover none of the inhibitors affected the formation of hydroxyceramide. Lignoceroyl-CoA alpha-hydroxylase appears to be an oxygenase requiring NADPH and oxygen, which involves cyanide-sensitive enzyme.


Optimized T1-weighted contrast for single-slab 3D turbo spin-echo imaging with long echo trains: application to whole-brain imaging.
T(1)-weighted contrast is conventionally obtained using multislice two-dimensional (2D) spin-echo (SE) imaging. Achieving isotropic, high spatial resolution is problematic with conventional methods due to a long acquisition time, imperfect slice profiles, or high-energy deposition. Single-slab 3D SE imaging was recently developed employing long echo trains with variable low flip angles to address these problems. However, long echo trains may yield suboptimal T(1)-weighted contrast, since T(2) weighting of the signals tends to develop along the echo train. Image blurring may also occur if high spatial frequency signals are acquired with low signal intensity. The purpose of this work was to develop an optimized T(1)-weighted version of single-slab 3D SE imaging with long echo trains. Refocusing flip angles were calculated based on a tissue-specific prescribed signal evolution. Spatially nonselective excitation was used, followed by half-Fourier acquisition in the in-plane phase encoding (PE) direction. Restore radio frequency (RF) pulses were applied at the end of the echo train to optimize T(1)-weighted contrast. Imaging parameters were optimized by using Bloch equation simulation, and imaging studies of healthy subjects were performed to investigate the feasibility of whole-brain imaging with isotropic, high spatial resolution. The proposed technique permitted highly-efficient T(1)-weighted 3D SE imaging of the brain.


Oxpentifylline in dementia: a controlled study.
The effect of oxpentifylline on mental state of patients suffering from primary degenerative dementia (PDD) and multi-infarct dementia (MID) was investigated in a double-blind study. After an initial 2-weeks washout period, the patients were randomly selected to receive either 400 mg oxpentifylline thrice daily or matched placebo tablets for 12 weeks. Eighteen male and 18 female patients aged 60-88 years were included but 5 patients dropped out during the first 2 weeks of the trial due to poor motivation. Two patients for non compliance and one for protocol violation were further excluded from final analysis. The age and sex distribution of the patients receiving placebo were comparable to those of treated patients. The mean pre-entry severity of dementia, as assessed by Folstein's mini mental state (FMMS) and Sandoz Clinical Assessment Geriatric Scale (SCAGS), was greater in the latter group (p less than 0.05). Although both groups showed slight improvement at the end of 12 weeks' treatment, no significant drug-related progress was observed. However, the MID patients (n = 4) who received oxpentifylline showed greater improvement (p less than 0.05) than the MID patients (n = 7) who were treated with placebo. No such benefit was observed in oxpentifylline-treated PDD patients. It is, therefore, suggested, that oxpentifylline (a haemorrheological agent), is probably beneficial only in MID patients, but further long-term studies involving a larger number of patients are required.


Diversity-oriented synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones by a sequence of palladium-catalyzed glycosyl thiol arylation and deprotection-lactonization reactions.
An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence of palladium-catalyzed glycosyl thiol arylation followed by deprotection-lactonization reactions has been reported. This diversity-oriented strategy enabled access to unknown complex cyclic scaffolds with polyhydroxylated appendages of biological interest.


Potential economic benefits of eliminating canine rabies.
Although canine rabies has been eliminated from industrialized countries, infected dogs remain the primary source of human and livestock exposures in Asia, Africa and much of South America. Human deaths are the most important direct economic impact of canine rabies, followed by livestock losses and the cost of PEP, while expenses associated with dog vaccination and control are major indirect impacts. The global burden of rabies disproportionately affects Asia, which experiences more than half of human rabies deaths and approximately 65% of livestock losses, and performs more than 90% of postexposure prophylaxis (PEP). Africa is second to Asia in terms of human deaths and livestock losses, but administers the least number of PEPs of the three regions. Recent experience in Latin America shows that efforts to reduce human deaths from rabies through expanded dog vaccination and improved access to PEP result in significant monetary savings. The elimination of canine rabies would lead to major economic benefits in developing countries that are often the least capable of dealing with the disease. This article forms part of a symposium in Antiviral Research on the elimination of canine rabies.