Human tumor cell heterogeneity and metastasis.
Heterogeneity within malignant neoplasms, although described for many years by pathologists, has only recently been extensively studied in the laboratory. It is now accepted that most tumors are composed of subpopulations of cells that differ in many phenotypic characteristics including the ability to form a metastasis. Cells with the capacity to metastasize are the ones most likely to prove lethal to the patient since clinicians can often control the primary neoplasm with surgery or radiotherapy. In this report the process of metastasis is discussed, those aspects of tumor cell heterogeneity that are relevant to this process are reviewed, intrapatient tumor heterogeneity is explored, and future preclinical studies are evaluated that may be useful in designing treatment strategies for patients with disseminated malignancies.


Hyperbaric oxygen ameliorates neuronal injury and neurological function recovery in rats with intracerebral hemorrhage by silencing microRNA-204-5p-targeted chloride channel protein 3.
Hyperbaric oxygen (HBO) therapy is of clinical utility in patients with transient cerebral ischemia. The investigatory study was to identify the potential regulatory mechanism of HBO treatment on neuronal injury and neurological function recovery in rats with intracerebral hemorrhage (ICH). Firstly, the rat model of ICH was established by collagenase, and the experimental rats were treated with HBO at 2.5 absolute atmospheres for 60 min each time. Next, lentivirus interfering with microRNA (miR)-204-5p or chloride channel protein 3 (CLCN3) expression was injected via the tail vein. Afterward, neurological function assessment was conducted, serum S100β and NSE contents were detected by enzymer-linked immunosorbent assay, and pathological conditions of brain tissue were observed by hematoxylin-eosin staining. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining was used to detect neuronal apoptosis. The results showed that HBO alleviated neuronal injury and neurological function recovery in ICH rats and reduced serum S100β and NSE content (all P<0.05). At the same time, overexpressing miR-204-5p or depleting CLCN3 further promoted the therapeutic effect of HBO on ICH rats (all P<0.05), while silencing miR-204-5p or elevating CLCN3 did oppositely (all P<0.05). In conclusion, HBO alleviates neuronal injury and neurological function recovery in ICH rats by silencing miR-204-5p-targeted CLCN3.


Interictal intracranial electroencephalography for predicting surgical success: The importance of space and time.
Predicting postoperative seizure freedom using functional correlation networks derived from interictal intracranial electroencephalography (EEG) has shown some success. However, there are important challenges to consider: (1) electrodes physically closer to each other naturally tend to be more correlated, causing a spatial bias; (2) implantation location and number of electrodes differ between patients, making cross-subject comparisons difficult; and (3) functional correlation networks can vary over time but are currently assumed to be static. In this study, we address these three challenges using intracranial EEG data from 55 patients with intractable focal epilepsy. Patients additionally underwent preoperative magnetic resonance imaging (MRI), intraoperative computed tomography, and postoperative MRI, allowing accurate localization of electrodes and delineation of the removed tissue. We show that normalizing for spatial proximity between nearby electrodes improves prediction of postsurgery seizure outcomes. Moreover, patients with more extensive electrode coverage were more likely to have their outcome predicted correctly (area under the receiver operating characteristic curve > 0.9, P « 0.05) but not necessarily more likely to have a better outcome. Finally, our predictions are robust regardless of the time segment analyzed. Future studies should account for the spatial proximity of electrodes in functional network construction to improve prediction of postsurgical seizure outcomes. Greater coverage of both removed and spared tissue allows for predictions with higher accuracy.


One-year follow-up of the Stent Restenosis (STRESS I) Study.
We present the completed 1-year follow-up results of the original Stent Restenosis Study (STRESS I), in which 407 patients with symptomatic ischemic heart disease and new lesions of the native coronary circulation were randomly assigned to treatment with either the Palmaz-Schatz coronary stent or conventional percutaneous transluminal coronary angioplasty (PTCA). The present study compares the safety of elective stenting to balloon angioplasty (PTCA) in terms of freedom from clinical events up to 1 year after treatment. Patients were enrolled and treated from January 1991 through February 1993, and follow-up data were collected and verified until July 1995. Ninety-seven percent of all patients had complete follow-up (deceased or alive with known clinical status) beyond 8 months, and 94% beyond 11 months. Anginal status between 9 to 15 months postprocedure was available for 78% of patients. At 1 year, 154 patients (75%) assigned to stent implantation and 141 (70%) to PTCA were free of all clinical events (death, myocardial infarction, or any revascularization procedure), and 162 stent patients (79%) and 149 PTCA patients (74%) were free from death, myocardial infarction, or target lesion revascularization. Symptom-driven target lesion revascularization occurred in 12% of the stent group versus 17% of the PTCA group. None of these differences in clinical events was statistically significant. Only 2 patients in the stent group and 7 in the PTCA group had a first event after 239 days, and freedom from angina at 1 year was reported in equal frequency in both groups (84%). There appear to be no late adverse effects of stent implantation. However, these results are limited by low statistical power, narrow patient selection, and the anticoagulation regimen used in the early experience with this device.


Release mechanisms and applications of drug delivery systems for extended-release.
Drug delivery systems with extended-release profiles are ideal in improving patient compliance with enhanced efficacy. To develop devices capable of a prolonged delivery kinetics, it is crucial to understand the various underlying mechanisms contributing to extended drug release and the impact thereof on modulating the long-term performance of such systems in a practical application environment. This review article intends to provide a comprehensive summary of release mechanisms in extended-release drug delivery systems, particularly polymer-based systems; however, other material types will also be mentioned. Selected current research in the delivery of small molecule drugs and macromolecules is highlighted. Emphasis is placed on the combined impact of different release mechanisms and drug properties on the long-term release kinetics in vitro and in vivo. The development of drug delivery systems over an extended duration is promising but also challenging when considering the numerous interrelated delivery-related parameters. Achieving a well-controlled extended drug release requires advanced techniques to minimize burst release and lag phase, a better understanding of the dynamic interrelationship between drug properties and release profiles over time, and a thorough elucidation of the impact of multiple in vivo conditions to methodically evaluate the eventual clinical efficacy.


Experimental fascial autografting for the supraspinatus tendon defect: remodeling process of the grafted fascia and the insertion into bone.
To elucidate the postoperative histologic changes of fascial autografting, tendinous defects (1.5 x 1.5 cm) were created close to the supraspinatus insertion and were covered by fascial autografts in 21 rabbits. Shoulders harvested on the fourth day and 1, 2, 3, 4, 6, and 8 weeks after surgery were examined histologically and immunohistochemically. At the fascia-bone junction, chondrocytes started to appear at 2 weeks after surgery and increased rapidly thereafter. Although a tidemark was not seen, remodeling of direct insertion with fibrocartilage was almost complete by 8 weeks. The distribution of collagen types II and III represented a pattern similar to that of a normal supraspinatus tendon insertion. In the grafted fascia, the cellular density showed a marked increase over time (r2 = 0.74, P <.0001). Our study revealed that both the tendinous tissue and its insertion were reformed after this procedure. Fascial autografting might be useful for repairing a supraspinatus tendon defect.


Specificity of the Escherichia coli proline transport system.
The presence of both the carbonyl portion of the carboxyl group at position 2 of the pyrrolidine ring and a secondary amine was essential for uptake of a compound by the proline permease of Escherichia coli. The permease possessed a high affinity for azetidine-2-carboxylic acid and for compounds with ring structures smaller than the pyrrolidine ring. Pipecolic acid, the higher homologue of proline, and its derivatives were not transported. Cis- and trans-3,4-methano-prolines, also six-membered ring structures, behaved anomolously in that they possessed a high affinity for the permease. The difference between the methano-prolines and other six-membered ring structures probably resides in the fact that the former exist in the "boat" configuration whereas the latter possess the "chair" configuration. In general, substituted prolines in the cis configuration displayed a higher affinity for the permease than did corresponding trans isomers, though the affinity for substituted prolines was influenced by the position, size, and polar or nonpolar nature of the substituent group. At O C many analogues with affinity for proline permease exchanged with intracellular proline, but some analogues, notably trans-3-methyl- and trans-4-methyl-L-prolines, though possessing high affinity for the permease, showed an almost complete inability to exchange with intracellular proline.


Charge neutralization process of mobile species at any distance from the electrode/solution interface. 1. Theory and simulation of concentration and concentration gradients developed during potentiostatic conditions.
The theoretical framework of a general model for the simulation of concentration profiles of electroactive and nonelectroactive species, driven by an electrochemical process under potentiostatic conditions, is presented. Based on this analysis, finite differences simulations are performed to calculate the actual profiles under different experimental conditions. Furthermore, the effect of experimental parameters (diffusion coefficients of the ions of the redox couple or the supporting electrolyte, charge of the different species, etc.) on the concentration profiles is also examined. The results obtained when low and high concentrations of supporting electrolyte are compared aid understanding of the effect of the electrolyte on the measurements. The presented model also underlines the role of supporting electrolyte species when nonspecific techniques are employed to measure the concentration changes produced by electroactive species. On the other hand, if a highly specific technique were used to detect changes in the concentration or concentration gradient of a given species, then it would be possible to estimate the respective profiles of the other species. The simulations suggest that techniques measuring concentration gradients are more sensitive to determining concentration changes than those involving a measurable linearly related to concentration.


Human Enhancement and the Story of Job.
This article explores some implications of the concept of transformative change for the debate about human enhancement. A transformative change is understood to be one that significantly alters the value an individual places on his or her experiences or achievements. The clearest examples of transformative change come from science fiction, but the concept can be illuminatingly applied to the enhancement debate. We argue that it helps to expose a threat from too much enhancement to many of the things that make human lives valuable. Among the things threated by enhancement are our relationships with other human beings. The potential to lose these relationships provides a compelling reason for almost all humans to reject too much enhancement.


[Selective use of glucocorticoids during the perioperative period of transsphenoidal surgery for pituitary tumors].
There is consensus in promoting the selective use of glucocorticoids (GC) in the peri-operative period of transsphenoidal surgery (TE) for pituitary adenomas (PA). To evaluate the safety of a selective glucocorticoid administration protocol and the usefulness of immediate postoperative cortisol levels as a predictor of final eucortisolism. Clinical and biochemical data from 40 patients aged 27 to 78 years (65% males) were prospectively collected. Exclusion criteria were previous use of GC, apoplexy and Cushing disease. Patients with pre-operative short synthetic ACTH test (SST) > 18 µg/dl or basal cortisol > 15 µg/dl did not receive GC. A morning serum cortisol (SC) threshold of 10 µg/dl in postoperative days one to three was used to decide a discharge without GC. Hypotension, dizziness or nausea, requirement of increased dose of corticosteroids, hospitalizations and emergency service visits were investigated, as well as surgical and endocrinological complications. Corticotropic status was evaluated three months after surgery. Macroadenomas were present in 87% of patients. Median hospital stay was 4 days and follow up lasted 9 months. No differences were found in gender, age or tumor size between patients who received or not GC (35 and 65% respectively). Eighty five percent of patients were discharged without GC and all of them had normal corticotropic function three months after surgery. A SC ≥ 15 µg/dl had 100% specificity to predict eucortisolism. Selective glucocorticoid administration is safe. A normal corticotropic function before surgery and in the immediate postoperative period are useful to identify patients who do not need GC.


Glaucoma and Dry Eye Disease: Opportunity to Assess and Treat.
Dry eye disease (DED) has been found to occur at a higher prevalence in individuals with glaucoma than in individuals without glaucoma. The relationship between glaucoma and DED may be, in part, a result of glaucoma therapy. Greater number of antiglaucoma medications used and greater number of antiglaucoma eyedrops instilled per day have been associated with ocular surface disease in patients with glaucoma. Use of antiglaucoma medication has also been associated with higher levels of ocular surface inflammatory markers and ocular surface alterations. There is evidence to suggest that antiglaucoma medications with preservatives and, to some extent, antiglaucoma medication formulations without preservatives may contribute to ocular surface signs and symptoms. Trabeculectomy for glaucoma has also been associated with ocular surface signs related to DED; however, there may be benefits of trabeculectomy and other procedures for glaucoma due to reduced use of antiglaucoma medications. Patients with glaucoma with ocular surface disease have been found to have greater ocular surface symptoms, poorer vision-related quality of life, and poorer antiglaucoma medication adherence compared with patients with glaucoma without ocular surface disease. Because of the potential negative impact of DED on patients with glaucoma, patients with glaucoma may benefit from evaluation for DED. Management of DED in patients with glaucoma may include modifications to antiglaucoma medications and use of treatments for DED.


Maturation of Eugenia pyriformis seeds under different hydric and thermal conditions.
This study aims to analyze the maturation and dispersal of Eugenia pyriformis Cambess. seeds produced in different years, and the influence of variation in thermal and hydric environment on seed physical and physiological characteristics at dispersal. Fruits at different developmental stages were harvested in the city of São Paulo between 2003 and 2010, as well as in the cities of Campinas and Lavras, in 2009 and 2010 and analyzed for size and color. The seeds were extracted from the fruits and their dry mass, water content, germination and vigor were assessed. Results showed that seed maturation is unsynchronized to the maturation of the fruit, taking 45 days on average (430 growing degree-days), longer in rainy times or lower temperatures. Seeds with higher physiological quality were produced in rainy years and when the temperature range was larger. We concluded therefore that hydric and thermal environmental variations during development influence the maturation of Eugenia pyriformis seeds and are able to determine the formation cycle and the final seed quality.


One needle transcrural celiac plexus block. Single shot or continuous technique, or both.
The purpose of the study was to establish a one needle transcrural technique for the celiac plexus block in the lateral position. Contrary to the conventional prone bilateral approach, the lateral position with a cushion under the flank is better tolerated and makes bony landmarks more accessible. Unilateral needle placement reduces the morbidity of the technique and should also enable one to apply single administration or continuous blocks, or both. Primary anatomic studies on 20 corpses were performed. The needles were inserted anteromedially, on the left side, 4-6 cm lateral from the spinous process of L1 vertebral body, to reach the celiac plexus area at the level of the celiac axis, and 30 mL of methylene blue was injected. Autopsy revealed the needle tips placed preaortic or paraaortic and methylene blue covered the celiac plexus area bilaterally with a predominance on the left side. With the same technique, an epidural catheter was inserted via the needle and injected methylene blue covered the area of the plexus as well. This technique was further employed in the pain clinic, on 35 consecutive patients with pancreatic or gastric carcinoma, for diagnostic celiac plexus block and subsequent neurolysis for pain relief (70 celiac plexus blocks). The technique was employed in the first 10 cases with the aid of computed tomography and subsequently using only fluoroscopy. The effects were comparable to the other techniques of blocking the celiac plexus. Clinical results proved that the unilateral, transcrural technique in a lateral position is simple, safe, and gives a reliable celiac plexus block or neurolysis effects under fluoroscopy, or both, comparable to the results where computed tomography was used. The possibility of continuous block makes this technique useful in clinical practice.


Estrogen-induced augmentation of endothelium-dependent nitric oxide-mediated vasodilation in isolated rat cerebral small arteries.
We examined chronic effects of 17beta-estradiol (E(2)beta) on the responses of isolated rat anterior cerebral small arteries to vasoactive substances with special reference to endothelial function. Female Sprague-Dawley rats were separated into four groups: (1) sham-operated group (Sham), (2) sham-operated plus E(2)beta treated group (Sham+E), (3) ovariectomized group (OVX), (4) ovariectomized plus E(2)beta treated group (OVX+E). 5-Hydroxytryptamine (5-HT) (10(-10)-10(-3) M) and U46619 (10(-15)-10(-8) M) induced concentration-dependent contractions in the cerebral small arteries. The 5-HT- and U46619-induced contractions were not affected by pretreatment with 3 x 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME). No significant difference in high potassium (80 mM)- and the agonists-mediated contractions was observed among the four groups. Administration of acetylcholine (ACh) (10(-9)-10(-3) M) and sodium nitroprusside (SNP) (10(-8)-10(-3) M) caused dose-related relaxations in the cerebral small arteries precontracted by 10(-8) M U46619. Chronic treatment with E(2)beta caused a significant potentiation of the ACh-induced relaxations in the Sham+E and OVX+E groups. The dose-response curve for ACh in the OVX group was quite similar to that obtained with the Sham group. The ACh-induced relaxation was reduced significantly by pretreatment with 3 x 10(-5) M L-NAME, and an additional treatment with 10(-3) M L-arginine reversed significantly the L-NAME-induced inhibition. The removal of endothelial cells produced a significant reduction of the ACh-induced relaxation. Indomethacin (10(-5) M) did not alter the ACh-induced relaxation. The findings suggest that E(2)beta potentiates ACh-induced endothelium-dependent relaxation in rat anterior cerebral arteries and that the potentiation may be, in part, mediated by increasing production and release of endogenous NO from the endothelial cells.


Two cyanobacterial response regulators with diguanylate cyclase activity, Rre2 and Rre8, participate in biofilm formation.
Phototrophic bacteria face diurnal variations of environmental conditions such as light and osmolarity that affect their carbon metabolism and ability to generate organic compounds. The model cyanobacterium, Synechocystis sp. PCC 6803 forms a biofilm when it encounters extreme conditions like high salt stress, but the molecular mechanisms involved in perception of environmental changes that lead to biofilm formation are unknown. Here, we studied two two-component regulatory systems (TCSs) that contain diguanylate cyclases (DGCs), which produce the second messenger c-di-GMP, as potential components of the biofilm-inducing signaling pathway in Synechocystis. Analysis of single mutants provided evidence for involvement of the response regulators, Rre2 and Rre8 in biofilm formation. A bacterial two-hybrid assay showed that Rre2 and Rre8 each formed a TCS with a specific histidine kinase, Hik12 and Hik14, respectively. The in vitro assay showed that Rre2 had DGC activity regardless of its de/phosphorylation status, whereas Rre8 required phosphorylation for DGC activity. Hik14-Rre8 likely functioned as an inducible sensing system in response to environmental change. Biofilm assays with Synechocystis mutants suggested that pairs of hik12-rre2 and hik14-rre8 responded to high salinity-induced biofilm formation. Inactivation of hik12-rre2 and hik14-rre8 did not affect the performance of the light reactions of photosynthesis. These data suggest that Hik12-Rre2 and Hik14-Rre8 participate in biofilm formation in Synechocystis by regulating c-di-GMP production via the DGC activity of Rre2 and Rre8.


DNA branch nuclease activity of vaccinia A22 resolvase.
DNA replication, recombination, and repair can result in formation of diverse branched DNA structures. Many large DNA viruses are known to encode DNA branch nucleases, but several of the expected activities have not previously been found among poxvirus enzymes. Vaccinia encodes an enzyme, A22 resolvase, which is known to be active on four-stranded DNA junctions (Holliday junctions) or Holliday junction-like structures containing three of the four strands. Here we report that A22 resolvase in fact has a much wider substrate specificity than previously appreciated. A22 resolvase cleaves Y-junctions, single-stranded DNA flaps, transitions from double strands to unpaired single strands ("splayed duplexes"), and DNA bulges in vitro. We also report site-directed mutagenesis studies of candidate active site residues. The results identify the likely active site and support a model in which a single active site is responsible for cleavage on Holliday junctions and splayed duplexes. Lastly, we describe possible roles for the A22 resolvase DNA-branch nuclease activity in DNA replication and repair.


Robotic mitral valve plasty for mitral regurgitation after blunt chest trauma in Barlow's disease.
We successfully treated a case of mitral regurgitation due to chest trauma in Barlow's disease. A 71-year-old man was admitted with severe mitral regurgitation after blunt compression of the chest by a heavy object 5 months earlier. Preoperative examination revealed wide chordae tendineae rupture and myxomatous changes to the bileaflets. Neo-chordae reconstruction of the anterior mitral leaflet using loop technique, triangular resection of the posterior mitral leaflet, and ring annuloplasty was performed via surgical robot. Robotic mitral valve plasty for severe mitral regurgitation due to chest trauma in Barlow's disease was achieved safely with good clinical and excellent cosmetic results.


Preparation and evaluation of 111In-labeled leukocytes as an abscess imaging agent in dogs.
Leukocytes labeled with 111In chelated with 8-hydroxyquinoline were evaluated as an abscess imaging agent in dogs. The labeling technique is simple and offers 75-95% efficiency. The half-clearance time of the labeled leukocytes is 6-10 hours, and the target-to-blood activity ratios are higher than those of other compounds now in use. The authors suggest that 111In-labeled leukocytes replace 67Ga citrate as a routine abscess imaging agent.


Higher R2* in the Red Nucleus Is Associated With Lead Exposure in an Asymptomatic Welder Cohort.
Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation in workers with chronic welding fume exposure, with a focus on iron-rich subcortical regions of the cerebellum and basal ganglia. Occupational exposure, whole blood metal, and brain MRI data were obtained from 29 controls and 42 welders. R2* (1/T2*) and R1 (T1 relaxation rate) values were used to estimate brain iron and manganese content, respectively. Blood metals and brain R2* (in the red nucleus [RN], dentate nucleus, caudate, putamen, globus pallidus, and substantia nigra) were compared between groups. Associations between brain R2* values and exposure metrics were tested within each group, and analyses were adjusted for potential confounders. Welders had significantly higher levels of whole blood lead, manganese, iron, and copper. Welders also had higher R2* RN (p = .002), but not R1. A 2nd-order polynomial modeled the association between R2* RN and a long-term welding exposure metric. In welders, but not controls, R2* RN was associated positively with whole blood lead (r = 0.54, p = .003), and negatively with whole blood manganese (r = -0.43, p = .02). Higher blood Pb and lower blood Mn independently accounted for variance in high RN R2*. Together, these data suggest that higher RN R2* values may mark lead exposure in welders. Because lead is a known neurotoxicant, additional studies are warranted to confirm this finding, and ascertain its scientific and public/occupational health implications.


Ocular trauma.
This article guides the primary care physician in determining whether an injury to the eye requires immediate care, immediate referral, or routine treatment. Prevention of ocular trauma through government regulation and the wearing of protective eye gear is emphasized.


Traumatic Rupture of an Intermediate Tendon in a Patient with Patellar Duplication.
Patellar duplication is a rare asymptomatic condition. The diagnosis is often made following a traumatic event associated with an injury to the knee extensor mechanism. The treatment is often surgical and consists in removal of the smaller part of the patella with tendon reinsertion. The presence and rupture of an intermediate tendon between the two parts of the patella have not been reported in the modern literature. We present a traumatic rupture of an intermediate tendon in a patient with horizontal patellar duplication. The surgical management consisted of tenorrhaphy protected with a figure-of-eight tension band wire approximating the two parts of the patella. The patient recovered full knee range of motion and quadriceps strength at the last 8-month follow-up.


The role of ERCP in the diagnosis and treatment of idiopathic recurrent pancreatitis in children and adolescents.
ERCP was performed in 51 patients, aged 1 to 18 years, as part of diagnostic evaluation for recurrent pancreatitis without obvious cause or as therapeutic intervention. ERCP was successful in 50 patients (98%). Thirty-four patients (68%) had anatomic findings indicating a possible cause of recurrent pancreatitis. Three patients (6%) had findings suggestive of sphincter of Oddi dysfunction. Eighteen of the 37 patients (49%) with ductal abnormalities underwent endoscopic therapy, with a favorable outcome in 15 (83%). Eleven patients were treated surgically, and 8 of these patients (73%) improved symptomatically. Eight patients received no treatment, and 6 of them (67%) had recurrent bouts of clinical pancreatitis. One mild case of pancreatitis (1.9%) occurred after ERCP, and 3 mild cases followed endoscopic therapy. In conclusion, ERCP is a relatively safe technique that produces opacification of the desired ductal system with a high degree of accuracy and provides useful information in the evaluation of children with idiopathic recurrent pancreatitis. These data suggest that endoscopic pancreatic therapy may result in symptomatic improvement, eliminating the need for surgery in selected children. Furthermore, the study demonstrates that manipulation of the pancreatic duct is comparatively safe and less hazardous than formerly believed.


Observations of summer sun protection among children in New Zealand: 1998-2000.
To examine sun protection among New Zealand children (ten years and under) at beaches and playgrounds. In the summers of 1998, 1999 and 2000, observations were made of 753 children at selected beaches and playgrounds in Dunedin and Hawkes Bay to determine the extent of sun protection. Parents/carers were also interviewed about sun protection. Across most body sites, levels of protection were high. Clothing and SPF15+ sunscreen were used most often, while the use of shade was relatively low. About four in every ten parents/caregivers were aware of the UV index or burn-time. Level of sun protection among children at beaches was best predicted by parent/carer's own level of protection, the child's perceived susceptibility to burning, and being a preschooler. Observed levels of sun protection among the children were high and most likely reflected an increased awareness among parents and carers of the social acceptability of protective behaviours. Nevertheless, opportunities to seek shade were limited, and the provision of shade at beaches and playgrounds represents an important next step in a community wide approach to sun protection.


Production of toxin by Clostridium botulinum type A strains cured by plasmids.
Twelve strains of Clostridium botulinum type A and seven strains of Clostridium sporogenes were screened for plasmids by agarose gel electrophoresis of cleared lysates of cells from 5 ml of mid-log-phase culture. Nine type A strains had one or more plasmids of 4.3, 6.8, or 36 megadaltons (MDa); several strains showed a large plasmid of 61 MDa, but it was not consistently recovered. Four C. sporogenes strains had one or more plasmids of 4.3, 5.6 or 36 MDa. Isolates obtained from cultures of plasmid-containing C. botulinum type A strains grown in ionic detergent broth and from spontaneously arising variants were screened both for toxin production and for plasmid content. Toxigenicity of C. botulinum could not be correlated with the presence of any one plasmid.


A radiation hybrid map of the proximal long arm of human chromosome 11 containing the multiple endocrine neoplasia type 1 (MEN-1) and bcl-1 disease loci.
We describe a high-resolution radiation hybrid map of the proximal long arm of human chromosome 11 containing the bcl-1 and multiple endocrine neoplasia type 1 (MEN-1) disease gene loci. We used X-ray irradiation and cell fusion to generate a panel of 102 hamster-human somatic cell hybrids containing fragments of human chromosome 11. Sixteen human loci in the 11q12-13 region were mapped by statistical analysis of the cosegregation of markers in these radiation hybrids. The most likely order for these loci is C1NH-OSBP-(CD5/CD20)-PGA-FTH1-COX8-PYGM -SEA-KRN1-(MTC/P11EH/HSTF1/INT2)-GST3- PPP1A. Our localization of the human protooncogene SEA between PYGM and INT2, two markers that flank MEN-1, suggests SEA as a potential candidate for the MEN-1 locus. We map two mitogenic fibroblast growth factor genes, HSTF1 and INT2, close to bcl-1, a mapping that is consistent with previously published data. Our map places the human leukocyte antigen genes CD5 and CD20 far from the bcl-1 locus, indicating that CD5 and CD20 expression is unlikely to be altered by bcl-1 rearrangements. PPP1A, which has been postulated as a MEN-1 candidate tumor suppressor gene, and GST3, a gene transcriptionally active in many human cancers, both map distal to the bcl-1 translocation cluster and the region containing MEN-1, and therefore are unlikely to be directly involved in bcl-1 or MEN-1.


Hemodynamic effects of BTB-cyclic AMP in anesthetized dogs.
The hemodynamic effects of 8-benzylthio-N6-n butyl adenosine 3',5' cyclic monophosphate (BTB-cAMP) were studied in anesthetized dogs. BTB-cAMP was given intravenously in doses of 1, 3 and 9 mg/kg, respectively. BTB-cAMP induced dose-dependent increases in heart rate, max LV dp/dt, cardiac output and stroke volume, and decreases in mean blood pressure and total peripheral resistance. BTB-cAMP had less of an effect on heart rate and blood pressure than dibutyryl cAMP (DB-cAMP), but showed a greater effect in augmenting cardiac contractility, with earlier manifestations of maximum action. Although the duration of its action is shorter, BTB-cAMP has possible therapeutic applications in cardiovascular diseases such as cardiogenic shock and congestive heart failure. It may also be a better agent than DB-cAMP for the treatment of patients with congestive heart failure because of a less potent hypotensive effect.


Function-unknown glycoside hydrolase family 31 proteins, mRNAs of which were expressed in rice ripening and germinating stages, are alpha-glucosidase and alpha-xylosidase.
In rice (Oryza sativa L., var Nipponbare) seeds, there were three mRNAs encoding for function-unknown hydrolase family 31 homologous proteins (ONGX-H1, ONGX-H3 and ONGX-H4): ONGX-H1 mRNA was expressed in ripening stage and mRNAs of ONGX-H3 and ONGX-H4 were found in both the ripening and germinating stages [Nakai et al., (2007) Biochimie 89, 49-62]. This article describes that the recombinant proteins of ONGX-H1 (rONGXG-H1), ONGX-H3 (rONGXG-H3) and ONG-H4 (rONGXG-H4) were overproduced in Pichia pastoris as fusion protein with the alpha-factor signal peptide of Saccharomyces cerevisiae. Purified rONGXG-H1 and rONGXG-H3 efficiently hydrolysed malto-oligosaccharides, kojibiose, nigerose and soluble starch, indicating that ONGX-H1 and ONGX-H3 are alpha-glucosidases. Their substrate specificities were similar to that of ONG2, a main alpha-glucosidase in the dry and germinating seeds. The rONGXG-H1 and rONGX-H3 demonstrated the lower ability to adsorb to and degradation of starch granules than ONG2 did, suggesting that three alpha-glucosidases, different in action to starch granules, were expressed in ripening stage. Additionally, purified rONGXG-H4 showed the high activity towards alpha-xylosides, in particular, xyloglucan oligosaccharides. The enzyme hardly hydrolysed alpha-glucosidic linkage, so that ONGX-H4 was an alpha-xylosidase. Alpha-xylosidase encoded in rice genome was found for the first time.


Shear melting of a colloidal glass.
We use confocal microscopy to explore shear melting of colloidal glasses, which occurs at strains of approximately 0.08, coinciding with a strongly non-Gaussian step size distribution. For larger strains, the particle mean square displacement increases linearly with strain and the step size distribution becomes Gaussian. The effective diffusion coefficient varies approximately linearly with shear rate, consistent with a modified Stokes-Einstein relationship in which thermal energy is replaced by shear energy and the length scale is set by the size of cooperatively moving regions consisting of approximately 3 particles.


Pyoderma vegetans associated with severe psoriatic arthritis: good response to etanercept.
Pyoderma vegetans (PV) is an inflammatory dermatosis, characterized clinically by large exudative vegetating plaques, and histopathologically by epidermal pseudoepitheliomatous hyperplasia and dense inflammatory infiltrates. Although PV is a very rare condition, it is a chronic disorder that may accompany any systemic process that compromises immunity. Treatment is very difficult, and correction of predisposing causes may be useful. We present a 49-year-old woman affected by severe psoriatic arthritis since she was 19, with giant verrucous plaques on her lower limbs that had worsened progressively during the last 15 years. After ruling out other vegetating cutaneous disorders, PV was diagnosed in association with psoriasis. Despite numerous previous systemic and topical therapeutic attempts no response was observed. Etanercept was introduced, which resulted in a marked improvement within 3 weeks. Herein, we report a diagnostic and therapeutic challenge of the first case of PV associated with psoriasis that presented a good response to etanercept.


Anatomical variations in the human sinuatrial nodal artery.
To analyze the anatomical variations of sinuatrial nodal branch(es) of the coronary artery mainly regarding their number; a recent report from Japan claims the presence of 2 branches in up to 50% of cases, an occurrence that would permit adequate flow compensation in case of occlusion or section of 1 of these branches. The sinuatrial nodal branch(es) of 50 human hearts fixed in formol solution were dissected with the aid of a Normo Health 3.0 degree visor magnifying lens, measured, and classified as to the origin, route, and number of branches. In 94% (n = 47) of cases, a single sinuatrial nodal branch was found. classified: (A) two right side types, R1 (in 46% of cases, n = 23), situated medial to the right auricle and R2 (in 4% of cases, n = 2), situated on the posterior surface of the right atrium; (B) three left side types, L1 (in 24% of cases, n = 12), situated medial to the left auricle, L2 (in 16% of cases, n = 8), situated posterior to the left auricle, and L3 (in 4% of cases, n = 2), situated on the posterior surface of the left atrium. Except for R2, each type was subdivided into 'a' or 'b' types, according to whether the sinuatrial nodal branch(es) occurred in a clockwise or counterclockwise orientation around the base of the superior cava vena. In 4% of cases (n = 2), 2 sinuatrial nodal branch(es) were observed with 1 branch originating from each of the coronary arteries. In 1 case (2%), 3 sinuatrial nodal branch(es) were found, 2 from the right coronary artery and the third probably from the bronchial branch of the thoracic aorta. In 30% of the cases, the sinuatrial nodal branch(es) formed a ring around the base of the superior cava vena. In all cases, the sinuatrial nodal branch(es) supplied collateral branches to the atrium and/or the auricle of the same side as its origin and/or to the opposite side. The low frequency of 2 sinuatrial nodal branch(es) in Brazilian individuals, compared to the higher frequency found among the Japanese, is probably due to a variation associated with ethnic group origin.


High chloroquine treatment failure rates and predominance of mutant genotypes associated with chloroquine and antifolate resistance among falciparum malaria patients from the island of Car Nicobar, India.
An in vivo chloroquine efficacy study was undertaken on the island of Car Nicobar because a temporal rise in the Plasmodium falciparum parasite population containing mutations in the chloroquine resistance transporter (PfCRT) protein has been reported there. A WHO protocol with a 28 day follow-up schedule was used for chloroquine efficacy studies. Finger-prick blood from P. falciparum malaria patients was used for sequencing the genes encoding PfCRT (exon 2), dihydrofolate reductase (PfDHFR) and dihydropteroate synthetase (PfDHPS). The majority of patients showed chloroquine treatment failure (60.42%, n=48). A higher early treatment failure (ETF) rate was recorded among non-responders (23 of 29, 79.31%). Each patient, irrespective of their chloroquine response, was infected with P. falciparum that contained mutated PfCRT (predominantly genotype C72V73I74E75T76) associated with high chloroquine resistance and none with the wild-type pfcrt gene. Therefore, mutated PfCRT was also present in the P. falciparum isolates of all the chloroquine responders. The majority of individuals from both groups also contained parasites with a high number of two-locus PfDHFR-PfDHPS mutations, associated with a high level of antifolate resistance. There is a predominance of chloroquine- and antifolate-resistant P. falciparum malaria in Car Nicobar, requiring an alternative antimalarial drug treatment policy, such as implementation of artesunate combination therapy (ACT), for this island.


UVB irradiation induces lipid peroxidation and reduces antioxidant enzyme activities in human keratinocytes in vitro.
Exposure of human keratinocytes to UVB irradiation resulted in formation of conjugated double bonds and thiobarbituric acid reactive material. The activities of superoxide dismutase and catalase, enzymes which protect cells against oxidative damage, were concomitantly reduced. The present study suggests that in keratinocytes, exposure to UVB irradiation leads to a chain of events resulting in lipid peroxidation reactions accompanied by an impairment of the cellular defence system against reactive oxygen species. These phenomena may act synergistically in UVB-induced cutaneous pathological processes, such as carcinogenesis.


Non-invasive assessments for liver fibrosis: The crystal ball we long for.
Non-invasive assessment of liver fibrosis has been one of the most rapidly advancing fields in hepatology in the last decade. Progressive liver fibrosis results in cirrhosis, hepatocellular carcinoma (HCC), and various liver-related complications in essentially all chronic liver diseases. Assessment of liver fibrosis allows clinicians to determine the prognosis, need of treatment, disease progression, and response to treatment in patients with chronic liver disease. Liver biopsy has been the gold standard in last few decades and most adopted diagnostic tool in clinical trials. Nonetheless, it is impractical to apply the test in a large number of patients or to do it serially. Hence, various non-invasive assessments have been developed and adopted in some international management guidelines. Liver stiffness measurement (LSM) with transient elastography is one of the most widely validated non-invasive assessments for liver fibrosis. It is an accurate and reproducible method to predict advanced fibrosis in chronic hepatitis B. Using transient elastography, it is possible to perform repeated liver fibrosis assessments on a large number of asymptomatic patients. The key challenge of his tool is the confounding effect of alanine aminotransferase (ALT) level, such that decrease in LSM may only reflect ALT normalization, hence not accurate enough to indicate regression of liver fibrosis. This may be partially handled by combining LSM with a serum-based formula, which is independent of ALT such as the Forns index and enhanced liver fibrosis test. An LSM-based HCC risk score is useful to prioritize patients for HCC surveillance.


Functional and genetic analysis of choroid plexus development in zebrafish.
The choroid plexus, an epithelial-based structure localized in the brain ventricle, is the major component of the blood-cerebrospinal fluid barrier. The choroid plexus produces the cerebrospinal fluid and regulates the components of the cerebrospinal fluid. Abnormal choroid plexus function is associated with neurodegenerative diseases, tumor formation in the choroid plexus epithelium, and hydrocephaly. In this study, we used zebrafish (Danio rerio) as a model system to understand the genetic components of choroid plexus development. We generated an enhancer trap line, Et(cp:EGFP) (sj2), that expresses enhanced green fluorescent protein (EGFP) in the choroid plexus epithelium. Using immunohistochemistry and fluorescent tracers, we demonstrated that the zebrafish choroid plexus possesses brain barrier properties such as tight junctions and transporter activity. Thus, we have established zebrafish as a functionally relevant model to study choroid plexus development. Using an unbiased approach, we performed a forward genetic dissection of the choroid plexus to identify genes essential for its formation and function. Using Et(cp:EGFP) (sj2), we isolated 10 recessive mutant lines with choroid plexus abnormalities, which were grouped into five classes based on GFP intensity, epithelial localization, and overall choroid plexus morphology. We also mapped the mutation for two mutant lines to chromosomes 4 and 21, respectively. The mutants generated in this study can be used to elucidate specific genes and signaling pathways essential for choroid plexus development, function, and/or maintenance and will provide important insights into how these genetic mutations contribute to disease.


Ocular Fundus Photography as a Tool to Study Stroke and Dementia.
Although cerebral small vessel disease has been linked to stroke and dementia, due to limitations of current neuroimaging technology, direct in vivo visualization of changes in the cerebral small vessels (e.g., cerebral arteriolar narrowing, tortuous microvessels, blood-brain barrier damage, capillary microaneurysms) is difficult to achieve. As the retina and the brain share similar embryological origin, anatomical features, and physiologic properties with the cerebral small vessels, the retinal vessels offer a unique and easily accessible "window" to study the correlates and consequences of cerebral small vessel diseases in vivo. The retinal microvasculature can be visualized, quantified and monitored noninvasively using ocular fundus photography. Recent clinic- and population-based studies have demonstrated a close link between retinal vascular changes seen on fundus photography and stroke and dementia, suggesting that ocular fundus photography may provide insights to the contribution of microvascular disease to stroke and dementia. In this review, we summarize current knowledge on retinal vascular changes, such as retinopathy and changes in retinal vascular measures with stroke and dementia as well as subclinical makers of cerebral small vessel disease, and discuss the possible clinical implications of these findings in neurology. Studying pathologic changes of retinal blood vessels may be useful for understanding the etiology of various cerebrovascular conditions; hence, ocular fundus photography can be potentially translated into clinical practice.


Asian Americans respond less favorably to excitement (vs. calm)-focused physicians compared to European Americans.
Despite being considered a "model minority," Asian Americans report worse health care encounters than do European Americans. This may be due to affective mismatches between Asian American patients and their European American physicians. We predicted that because Asian Americans value excitement (vs. calm) less than European Americans, they will respond less favorably to excitement-focused (vs. calm) physicians. In Study 1, 198 European American, Chinese American, and Hong Kong Chinese community adults read a medical scenario and indicated their preference for an excitement-focused versus calm-focused physician. In Study 2, 81 European American and Asian American community college students listened to recommendations made by an excitement-focused or calm-focused physician in a video, and later attempted to recall the recommendations. In Study 3, 101 European American and Asian American middle-aged and older adults had multiple online encounters with an excitement-focused or calm-focused physician and then evaluated their physicians' trustworthiness, competence, and knowledge. As predicted, Hong Kong Chinese preferred excitement-focused physicians less than European Americans, with Chinese Americans falling in the middle (Study 1). Similarly, Asian Americans remembered health information delivered by an excitement-focused physician less well than did European Americans (Study 2). Finally, Asian Americans evaluated an excitement-focused physician less positively than did European Americans (Study 3). These findings suggest that while physicians who promote and emphasize excitement states may be effective with European Americans, they may be less so with Asian Americans and other ethnic minorities who value different affective states. (PsycINFO Database Record


Allergic contact dermatitis of the mouse ear.
Allergic contact dermatitis to picryl chloride on the mouse ear was registered by measuring the increasing wet weight during the inflammatory reaction. This quantitative technique permitted the use of small experimental groups of regular laboratory mice. Full sensitization to picryl chloride is achieved as early as 3 days after a single painting with the hapten. The allergic reaction peaks at 24 h after challenge. Sensitization and challenge are not inhibited, whether by antihistamine, histamine liberator, or antiserotonin. The hypersensitivity state lasts at least 4 months.


Know when to say "when" in endodontics: smoke on the water.
Ultimately, this article is a challenge to assess preoperatively both the patient and tooth and ask several important questions before a handpiece is ever picked up: (1) Can this tooth be restored? (2) Should this tooth be restored? (3) Does the patient want to save the tooth, and will the patient have the needed follow-up treatment? (4) If this tooth cannot be restored as it is now, can it be made restorable through periodontal procedures? (5) If the tooth is restorable and the patient was my mother, am I the doctor to bring about the best long-term prognosis for the tooth endodontically? (6) Can this patient tolerate the contemplated treatment physically, mentally, emotionally, and financially? The long-term goal for the patient should be the maintenance of the tooth in asymptomatic function. In 30 years, like the Deep Purple rendition of Highway Star and Smoke on the Water, which had appeal to me in Seattle, someone will hopefully look at a given root canal and say that the treatment was originally performed well, for the right reasons, and stood the test of time.


Vitamin d receptor polymorphisms predispose to primary biliary cirrhosis and severity of the disease in polish population.
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver condition characterized by the immune-mediated damage of the intrahepatic bile ducts. Polymorphisms of vitamin D receptor (VDR) are considered to contribute to its pathogenesis however their incidence varies in different populations and their potential association with the course of the disease has not been studied. In this paper we investigated the incidence and correlation of three VDR polymorphisms (BsmI, ApaI or TaqI) with various clinical, biochemical, and serological factors in a homogenous group of 143 Caucasian patients with PBC. Control group comprises 306 DNA samples from umbilical cord blood of healthy newborn children. When compared to controls, we observed a significant dominance of the b allele in the BsmI (OR = 1.69 [1.27-2.24]; P = 0.0003) and t allele in the TaqI (OR = 0.62 [0.47-0.82], P = 0.0001) in patients with PBC. Moreover the BsmI and TaqI polymorphisms were associated with the presence of advanced fibrosis/liver cirrhosis at the diagnosis of PBC. Pairwise linkage disequilibrium (LD) calculations proved that the analyzed SNPs are within an LD block (100% of LDs were D'>0.9). Our study showed, for the first time, that the analyzed polymorphisms of VRD may exert an effect on a natural history of PBC.


Is there any correlation between liver graft regeneration and recipient's pretransplant skeletal muscle mass?-a study in extended left lobe graft living-donor liver transplantation.
The end-stage liver disease causes a metabolic dysfunction whose most prominent clinical feature is the loss of skeletal muscle mass (SMM). In living-donor liver transplantation (LDLT), liver graft regeneration (GR) represents a crucial process to normalize the portal hypertension and to meet the metabolic demand of the recipient. Limited data are available on the correlation between pre-LDLT low SMM and GR. Retrospective study on a cohort of 106 LDLT patients receiving an extended left liver lobe graft. The skeletal muscle index (SMI) at L3 level was used for muscle mass measurement, and the recommended cut-off values of the Japanese Society of Hepatology guidelines were used as criteria for defining low muscularity. GR was evaluated as rate of volume increase at 1 month post-LT [graft regeneration rate (GRR)]. The median GRR at 1 month post-LT was 91% (IQR, 65-128%) and a significant correlation with graft volume-to-recipient standard liver volume ratio (GV/SLV) (rho -0.467, P<0.001), graft-to-recipient weight ratio (GRWR) (rho -0.414, P<0.001), donor age (rho -0.306, P=0.001), 1 month post-LT cholinesterase serum levels (rho 0.397, P=0.002) and pre-LT low muscularity [absent vs. present GRR 97.5% (73.1-130%) vs. 83.5% (45.2-110.9%), P=0.041] was noted. Moreover in male recipients, but not in women, it was shown a direct correlation with pre-LT SMI (rho 0.352, P=0.020) and inverse correlation with 1 month post-LT SMI variation (rho -0.301, P=0.049). A low GRR was identified as an independent prognostic factor for recipient overall survival (HR 6.045, P<0.001). Additionally to the hemodynamic factors of portal circulation and the quality of the graft, the metabolic status of the recipients has a significant role in the GR process. A pre-LT low SMM is associated with impaired GRR and this negative impact is more evident in male recipients.


Frequency of operative trauma to anal sphincters: evaluation with endoanal ultrasound.
Sphincter trauma after anorectal surgery is usually asymptomatic. Frequency of trauma cannot be established with the clinical examination only. The frequency of operative sphincter defects and their correlation with disorders of continence was evaluated with the endoanal ultrasound. This study includes 123 subjects who had undergone anorectal surgery in the past and were examined with endoanal ultrasound for various indications such as continence disorders, recurrent fistula, idiopathic perineal pain, or simple postoperative follow-up. No subjects had isolated external anal sphincter defects. Nineteen of 123 patients (15%) had minor or major continence disorders, 55 patients (45%) had no sphincter defects, 42 (34%) had only internal anal sphincter (IAS) defects, and 26 (21%) had simultaneously external and internal anal sphincter (EAS) defects. The incidence of IAS and EAS trauma after Milligan-Morgan hemorrhoidectomy was 1/18 (5.5%) and 0/18 respectively; after fistula repair, 24/42 (57%) and 12/42 (29%); and after anal dilatation, 13/17 (76%) and 4/17 (24%). Sixteen of 26 patients (62%) with EAS trauma and 51/68 patients (75%) with IAS trauma did not report any disorders of continence. In patients with two or more operations, the frequency of IAS trauma was 74%, 30% for EAS trauma, and 26% for continence disorders.


Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma.
A Phase II trial was conducted in patients with advanced malignant melanoma with intravenous Paclitaxel and Dacarbazine (DTIC). The initial starting dose for Paclitaxel was 135 mg/m2 followed by DTIC 800 mg/m2. Due to the lack of myelosuppression and other toxicities, the starting dose for Paclitaxel was escalated to 250 mg/m2 and the dose for DTIC escalated to 1000 mg/m2. Twenty-five patients were enrolled in this study. Among the 25 patients assessable for response, three patients had a partial response with a response rate of 12% (CI 3-31%) and one patient had stable disease. Three additional patients showed evidence of anti-tumor activity with minor responses. For patients who had no prior chemotherapy or biochemotherapy, the response rate was 20%. Toxicity was generally tolerable and included mainly neurotoxicity from Paclitaxel. At the doses and schedule used, the combination of Paclitaxel and DTIC did not appear to increase the response rate compared to each agent used singly.


Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease.
Numerous studies show a direct relation between circulating autoantibodies, characteristic of systemic autoimmune disorders, and primary hypertension in humans. Whether these autoantibodies mechanistically contribute to the development of hypertension remains unclear. Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by aberrant immunoglobulin production, notably pathogenic autoantibodies, and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Because plasma cells produce the majority of serum immunoglobulins and are the primary source of autoantibodies in SLE, we hypothesized that plasma cell depletion using the proteasome inhibitor bortezomib would lower autoantibody production and attenuate hypertension. Thirty-week-old female SLE (NZBWF1) and control (NZW [New Zealand White]) mice were injected IV with vehicle (0.9% saline) or bortezomib (0.75 mg/kg) twice weekly for 4 weeks. Bortezomib treatment significantly lowered the percentage of bone marrow plasma cells in SLE mice. Total plasma IgG and anti-dsDNA IgG levels were higher in SLE mice compared with control mice but were lowered by bortezomib treatment. Mean arterial pressure (mm Hg) measured in conscious mice by carotid artery catheter was higher in SLE mice than in control mice, but mean arterial pressure was significantly lower in bortezomib-treated SLE mice. Bortezomib also attenuated renal injury, as assessed by albuminuria and glomerulosclerosis, and reduced glomerular immunoglobulin deposition and B and T lymphocytes infiltration into the kidneys. Taken together, these data show that the production of autoantibodies by plasma cells mechanistically contributes to autoimmune-associated hypertension and suggests a potential role for patients with primary hypertension who have increased circulating immunoglobulins.


Parallel Detection of Refractive Index Changes in a Porous Silicon Microarray Based on Digital Images.
A new technique for the refractive index change with high-sensitivity measurements was proposed by the digital image of porous silicon (PSi) microarray utilization in this paper. Under the irradiation of a He-Ne laser, the surface images of the PSi array cells with the microcavity structure were obtained by the digital imaging equipment, whereas the refractive index change of each array cells was detected by calculating the average gray value of the image and the refractive index change measurement sensitivity was 10-4. This technique could be utilized in the label-free and parallel detection of refraction index changes induced by a biological reaction in the microarray or the chip.


Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors.
GABAA receptors are important for inhibition in the CNS where neurosteroids and protein kinases are potent endogenous modulators. Acting individually, these can either enhance or depress receptor function, dependent upon the type of neurosteroid or kinase and the receptor subunit combination. However, in vivo, these modulators probably act in concert to fine-tune GABAA receptor activity and thus inhibition, although how this is achieved remains unclear. Therefore, we investigated the relationship between these modulators at synaptic-type α1β3γ2L and extrasynaptic-type α4β3δ GABAA receptors using electrophysiology. For α1β3γ2L, potentiation of GABA responses by tetrahydro-deoxycorticosterone was reduced after inhibiting protein kinase C, and enhanced following its activation, suggesting this kinase regulates neurosteroid modulation. In comparison, neurosteroid potentiation was reduced at α1β3(S408A,S409A)γ2L receptors, and unaltered by PKC inhibitors or activators, indicating that phosphorylation of β3 subunits is important for regulating neurosteroid activity. To determine whether extrasynaptic-type GABAA receptors were similarly modulated, α4β3δ and α4β3(S408A,S409A)δ receptors were investigated. Neurosteroid potentiation was reduced at both receptors by the kinase inhibitor staurosporine. By contrast, neurosteroid-mediated potentiation at α4(S443A)β3(S408A,S409A)δ receptors was unaffected by protein kinase inhibition, strongly suggesting that phosphorylation of α4 and β3 subunits is required for regulating neurosteroid activity at extrasynaptic receptors. Western blot analyses revealed that neurosteroids increased phosphorylation of β3(S408,S409) implying that a reciprocal pathway exists for neurosteroids to modulate phosphorylation of GABAA receptors. Overall, these findings provide important insight into the regulation of GABAA receptors in vivo, and into the mechanisms by which GABAergic inhibitory transmission may be simultaneously tuned by two endogenous neuromodulators.


Delayed pneumoperitoneum following traumatic haemopneumothorax. A case report.
An unusual case of delayed pneumoperitoneum following a penetrating wound of the chest is presented. The mechanism of pneumoperitoneum, the diagnostic dilemma of injury to the abdomen in penetrating wounds of the lower chest, and the alternative methods used in achieving early diagnosis of diaphragmatic penetration are discussed.


[Clinical implication of IL-10 in patients with immune and inflammatory diseases].
The immune system is regulated by soluble glycoproteins produced by a wide variety of cells. IL-10 is a soluble protein produced by helper T (Th) cells, macrophages (M phi)/monocytes (Mo), and B cells, which exhibits a wide array of both immunosuppressive and immunostimulatory properties. We examined the pathological significance of this new cytokine "IL-10", and its clinical implications. IL-10 was discovered in 1989 as an activity produced by murine type 2Th (Th2) cells which suppressed cytokine production such as interferon gamma (IFN gamma) by type 1Th (Th1) cells. Its inhibitory effects were mainly recognized in vivo in animal experiments. In humans, unlike in mice, it is difficult to separate Th1 from Th2 cells. However, as we expected, marked suppressive activities on M phi/Mo were observed in humans. We have examined the serum levels of IL-10 in several diseases. In autoimmune diseases, some of the patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) had higher titers of IL-10 in their sera than the normal controls. Conversely, some patients with common variable immunodeficiency and with inflammatory bowel diseases showed lower titers of IL-10 in their sera than the healthy controls. Most bacterial endotoxin shock patients had lower levels of serum IL-10 than cardiogenic shock patients. Collectively, the ability of IL-10 to suppress the production of inflammatory monokines and to elevate anti-inflammatory monokines, suggests a strong anti-inflammatory role in diseases such as septic endotoxin shock and inflammatory bowel diseases. Also, the IL-10 antagonist such as soluble IL-10 receptor might be a candidate for the treatment of B cell mediated autoimmune diseases such as SLE by selectively enhancing Th1 immunity.


Reversible subclinical hypothyroidism in the presence of adrenal insufficiency.
To describe 3 different scenarios of reversible hypothyroidism in young patients with adrenal insufficiency. We present 3 case reports of patients with adrenal insufficiency--one with delayed puberty, the second with type 1 diabetes and poor weight gain, and the third with hypoglycemia-related seizures and glucocorticoid deficiency--who had biochemical evidence of hypothyroidism. Our first patient (case 1) initially had a mildly elevated thyrotropin (thyroid-stimulating hormone or TSH) level and a normal free thyroxine (FT4) level that, on follow-up assessment, had progressed to persistent mild elevation of TSH and low FT4 concentration. The other 2 patients (cases 2 and 3) had low FT4 and mildly elevated TSH values at the time of diagnosis of adrenal insufficiency. In all 3 patients, the results of thyroid function tests normalized with use of physiologic doses of adrenal hormone replacement therapy, without thyroid hormone replacement. All 3 patients remained euthyroid after 4, 3, and 1 year of follow-up, respectively. These observations add insights into the complexities of the thyroadrenal interactions. These examples are important because thyroid hormone replacement in the setting of adrenal insufficiency could be unwarranted.


Anti-hyperglycemic Effect of Long-Term Bis(hinokitiolato)zinc Complex ([Zn(hkt)2]) Ingestion on Insulin Resistance and Pancreatic Islet Cells Protection in Type 2 Diabetic KK-Ay Mice.
Zinc (Zn) is a trace element with anti-diabetes mellitus (anti-DM) effects. Zn complexes exhibit stronger insulin-like activity than Zn ions. Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) was recently reported to be a potent anti-DM candidate. We examined the effects of [Zn(hkt)2] on insulin resistance and pancreatic islet cells through in vivo long-term ingestion studies. In an in vivo study, we performed 4-month long-term [Zn(hkt)2] administration experiments in KK-Ay mice as a type 2 DM animal model. Ingestion of [Zn(hkt)2] resulted in lower blood glucose levels compared with the non-treated KK-Ay mice (control group). Additionally, [Zn(hkt)2] treatment decreased plasma insulin concentration compared with that of the non-treated KK-Ay group. [Zn(hkt)2] treatment resulted in a significant suppression of islet cell enlargement and a significantly decreased number of insulin-positive cells compared with the non-treated KK-Ay control group. The [Zn(hkt)2] treatment group showed the increasing tendency in the amount of Zn levels in peripheral organs; liver, muscle, adipose, and pancreas, compared with the non-treated KK-Ay control group. However, the Zn level in the pancreas of the [Zn(hkt)2] treatment group did not show the significant increase compared with the non-treated KK-Ay control group. This accumulation of Zn in pancreas suggested that [Zn(hkt)2] mainly effects on the peripheral tissue, and [Zn(hkt)2] has the less effect on the pancreas directly. Thus, we concluded that [Zn(hkt)2] exerted the main effect on peripheral organs by ameliorating insulin resistance.


Aggregation-resistant VHs selected by in vitro evolution tend to have disulfide-bonded loops and acidic isoelectric points.
When panned with a transient heat denaturation approach against target enzymes, a human V(H) (antibody heavy chain variable domain) phage display library yielded V(H)s with composite characteristics of binding, non-aggregation and reversible thermal unfolding. Moreover, selection was characterized by enrichment for V(H)s with (i) an even number of disulfide forming Cys residues in complementarity-determining region (CDR) 1 and CDR3 and (ii) acidic isoelectric points. This parallels naturally occurring camelid and shark single-domain antibodies (sdAbs) which are also characterized by (i) solubility and reversible unfolding, (ii) a high occurrence of disulfide forming Cys in their CDRs, particularly, in CDR1 and CDR3 and (iii) acidic V(H)s as inferred here by a pI distribution analysis, reported here, of pools of human and camelid V(H) and V(H)H (camelid heavy chain antibody V(H)) sequences. Our results, reinforced by previous observations by others, suggest that protein acidification may yet be another mechanism nature has devised to create functional sdAbs and that this concept along with the inclusion of inter-CDR disulfide linkages may be applied to human V(H) domains/libraries for non-aggregation optimization. In addition, calculation of theoretical pIs of V(H)s selected by panning may be used for rapid and precise identification of non-aggregating V(H)s.


Electrophilic Trifluoromethylselenolation of Boronic Acids.
Trifluoromethylselenylated compounds are emergent compounds with interesting physicochemical properties that still suffer from a lack of efficient synthetic methods. We recently developed an efficient one-pot strategy to generate in situ CF₃SeCl and use it in various reactions. Herein, we continue our study of the reactivity scope of this preformed reagent. Cross-coupling reactions with aromatic and heteroaromatic boronic acids have been investigated. The expected products have been obtained, using a stoichiometric amount of copper, with moderate yields.


New Advances in Infant Feeding: New Products and Novel Technologies.
Breastfeeding is the best way to provide ideal food for infants. However, there are many situations in which breastfeeding is unviable (maternal illness, hygiene problems, intravenous feeding requirement, storage). Safe, efficient, and nutritious products should be offered by the industry to mothers and healthcare professionals as an alternative. The present review aims to update the state of the art regarding the most innovative developments in infant feeding formulation and, the promising novel technologies that are being investigated to achieve a balance between the microbiological stability, organoleptic and nutritional value of baby food. The research lines included in the present systematic review are focused on both, the most innovative ingredients and emergent technologies applied increasing the offer of tailor-made nutritional profiled products with improved quality and safety. According to the reviewed research and recently published patents the current emergence of a new generation of infant products is remarkable, with specific product lines aimed at infants at different stages of development and affected by several disorders (low-weight babies, premature neonates, allergenic patients), with special emphasis on the application of novel technologies (e.g. High Hydrostatic Pressure (HHP) and microencapsulation) as potential techniques to ensure the microbiological safety of developed products, and the improvement of their nutritional value, complementary to the addition of functional ingredients, such as omega 3 and 6 fatty acids, amino acids, prebiotics and probiotics, and medicinal herb supplementation (e.g. lemon balm, royal jelly). The present research work provides a general view of recent advances in infant products processing and formulation focusing on the technological effects and quality/safety developments.


Reduced Graphene Oxide/Alumina, A Good Accelerant for Cellulose-Based Artificial Nacre with Excellent Mechanical, Barrier, and Conductive Properties.
In this article, a simple strategy was employed to fabricate bioinspired hybrid composite with carboxymethyl cellulose (CMC), graphene oxide, and reduced graphene oxide/alumina (rGO/Al) by a facile solution casting method. The tensile strength and toughness of rGO/Al-CMC-GO can reach 586.6 ± 12 MPa, 12.1 ± 0.44 MJm-3, respectively, due to the interface strengthening of alumina, which is 1.43 and 12 times higher than steel and about 4.3 and 6.7 times that of nature nacre. The artificial nacre hybrid composite is conductive due to the introduction of rGO/Al on the surface. Interestingly this structure can also be coated on the surface of cotton thread to give the thread good mechanical performance and conductivity. Additionally, the artificial nacre has better fire shielding and gas barrier properties. The oxygen permeability (OP) for 1% rGO/Al-CMC decreased from 0.0265 to 0.003 mLμm m-2 day-1 kpa-1, the water vapor permeability (WVP) decreased from 0.363 to 0.205 gmmm-2 day-1 kpa-1 when the concentration increased from 1% rGO/Al to 6% rGO/Al. It is believed this work provided a simple and feasible strategy to fabricate ultrastrong and ultratough graphene-based artificial nacre multifunctional materials.


Aortic dissection presenting as pleural effusion.
Aortic dissection is a life threatening emergency. This case illustrates the unusual way an aortic dissection can present. This patient presented with sharp, left interscapular pain, which subsided after a while and left-sided pleural effusion. Further investigations revealed that this was a case of thoracic aortic dissection with a leak into pleural space. She underwent thoracic endovascular aortic repair with stent graft insertion.


Constrictive pericarditis complicating endovascular pacemaker implantation.
A patient is described who has 6 months of progressive dyspnea and peripheral edema for 4 years following implantation of an endovascular pacemaker, which was complicated by a large hemorrhagic pericardial effusion. Evaluation was consistent with constrictive pericarditis, which is an extremely unusual complication of pacemaker implantation.


OPTIMISTIC GROWTH: COMPETITION AND AN ONTOGENETIC NICHE-SHIFT SELECT FOR RAPID GROWTH IN PUMPKINSEED SUNFISH (LEPOMIS GIBBOSUS).
Intrinsic growth rate is emerging as an important life-history trait that can be modified by natural selection. One factor determining optimal intrinsic growth rates is the pattern of resource availability. Organisms that experience chronically low resource levels tend to have slow intrinsic growth rates. However, this does not necessarily hold if resource levels change as an organism grows. We present a theoretical model showing that rapid growth is favored when resource levels for small size classes are low relative to resource levels for large size classes. We call such a growth strategy "optimistic" because rapid growth is based on an expectation that resources will improve once a minimum size is reached. We provide empirical support for this hypothesis by examining the intrinsic growth rates of pumpkinseed sunfish derived from three populations sympatric with bluegill sunfish (an important competitor with small size classes) to three populations allopatric with bluegill sunfish raised under common conditions. Rapid growth has evolved in the sympatric fish to reach the size refuge from competition as quickly as possible.


[Alectinib for an Octogenarian Patient with Poor Performance Status and ALK Fusion Gene-Positive Lung Cancer-A Case Report].
An 89-year-old female who had been clinically diagnosed with primary lung cancer underwent right upper lobectomy and lymph node dissection(ND2a-2). Postoperative pathological staging revealed a stage ⅡA(pT1bN1M0)adenocarcinoma that was negative for an EGFR mutation. Nineteen months after surgery, the patient developed a mediastinal lymph node metastasis, and radiotherapy was prescribed. Thirty-eight months later, she developed new mediastinal/hilar lymph node metastases and was prescribed pemetrexed(500 mg on day 1 of each of 3 weeks)as the first-line therapy. A complete response was evident after 10 courses. However, she developed grade 3 nausea, and pemetrexed was discontinued. During 10 months of follow-up, no new lesion appeared; therefore, follow-up was discontinued. Ninety-three months after surgery, she was referred to our hospital because an abnormal shadow was apparent on chest roentgenography. A thorough examination revealed pleural dissemination, pulmonary metastases, mediastinal/hilar lymph node metastases, an adrenal metastasis, and bone metastases. Although her performance status(PS)was poor(grade 4), as the diagnosis was ALK fusion gene-positive adenocarcinoma, alectinib(600 mg once daily)was commenced as the second-line therapy. Complete response was achieved 14 months later(ie, 108 months after surgery and 89 months after postoperative recurrence). Thus, an octogenarian patient with poor PS and ALK fusion gene-positive adenocarcinoma exhibited a complete response after treatment with alectinib.


[Attitude of physicians about facing chlamydia and gonorrhea at family planning clinics performing abortions].
Medical doctors performing pregnancy terminations in Family Planning Clinics are especially involved in Chlamydia screening and treatment. More than 90% of them are GP. Screenings are done : at patient's request; when risk factors or significant symptoms are present; always before any intrauterine invasive act. In our region, the population detected Chlamydia carrier is around 6 % and essentially feminine. The best screening campains won't succeed to an incidence decrease as long as they remain centred only on feminine population. The screen men for Chlamydia became now so easy (by PCR technique on urine sample), that it should be proposed by the GP to all "risky male".


Sumatriptan is an agonist at 5-HT receptors on myenteric neurones in the guinea-pig gastric antrum.
Sumatriptan, a 5-hydroxytryptamine(1D) (5-HT(1D))-receptor agonist used in the treatment in migraine, inhibits gastric motility via the enteric nervous system. As no studies have reported enteric neuronal 5-HT(1D) receptors, we used conventional intracellular recordings to characterize the actions of sumatriptan on 145 guinea-pig antral myenteric neurones. In 24 of 29 neurones with a 5-HT(1P) receptor-mediated depolarizing response to 5-HT, application of sumatriptan caused a dose-dependent depolarization, accompanied by increased membrane resistance and enhanced excitability. Depolarizing responses to sumatriptan occurred both in cholinergic and in nitrergic neurones. Sumatriptan did not mimic the 5-HT(3) receptor-mediated fast-depolarizing responses or 5-HT(1A) receptor-mediated inhibitory responses to 5-HT. Sumatriptan had no effect on neurones not responding to 5-HT. The depolarizing response to sumatriptan was inhibited by renzapride, but not by 5-HT(1-7) receptor antagonists. We conclude that sumatriptan behaves as an agonist at the 5-HT(1P) receptor on myenteric neurones in the guinea-pig gastric antrum. The actions of sumatriptan on gastric motility seem to be attributable to a direct action on enteric neurones.


Disability, functioning, and quality of life among treatment-seeking young autistic adults and its relation to depression, anxiety, and stress.
In this study, we consecutively recruited treatment-seeking young autistic adults without intellectual impairment aged 16-30 years who presented to a mental health service and evaluated general health (distress, quality of life, and disability), functioning (work loss days and social functioning), and mood symptoms (depression, anxiety, and stress) in those diagnosed with autism spectrum disorder (n = 96). This group was compared to young adults presenting to the same service with primary mental health disorders (depression, n = 343; bipolar, n = 132; psychosis, n = 166; and anxiety, n = 303). This study also investigated the influence of mood symptoms on general health and functioning in the autism spectrum disorder group. Young autistic adults reported significant general health and functioning impairments that were of similar degree to those presenting with primary mental health disorders. Interestingly, the autistic group also reported similarly high levels of mood symptoms to those with primary depressive and anxiety disorders. In the autistic group, depressive symptoms were strongly associated with distress, quality of life, and work loss days, while stress symptoms were strongly associated with disability. This study highlights further research, and mental health services are required specifically targeting young autistic adults to address their significant unmet needs.


Allergen Specific IgE, Number and Timing of Past Suicide Attempts, and Instability in Patients with Recurrent Mood Disorders.
Suicide and decompensation of mental illness peak in spring and, to a lesser extent, in fall. Several recent studies reported that suicide and decompensation peaks coincided with spring and fall aeroallergen peaks. Allergic symptoms occur as the result of a complex biochemical cascade initiated by IgE antibodies (sensitization) and allergens (triggers). Animal models have shown molecular/neurochemical changes in the brain, as well as relevant behavioral changes associated with this IgE-mediated biochemical cascade. These factors suggest that seasonal allergy could precipitate suicidality and mood instability. In the current study, we compared the prior suicide attempt and history of decompensation of mood disorders in allergen sensitive vs nonsensitive patients. Further, we compared the ratio of events (attempts and decompensations) during the allergy season to events occurring during the rest of the year. Patients with Major Depressive Disorder or Bipolar I or II Disorder (n=80) were studied. There were no statistical differences in any measurement performed between the allergen sensitive and nonsensitive patients. These negative results are not consistent with recent epidemiological studies supporting a predictive association between allergy and categorical measures of suicidality (ideation, attempts, and completion). Clinical samples are likely not adequate to study less than strong predictive associations with suicide and suicide risk factors.


Knowledge about cancer in West Bengal - a pilot survey.
A pilot survey was conducted based on 900 respondents of the population of West Bengal to assess their level of awareness regarding cancer with the aim of estimating associations between response variables (knowledge about cancer) and predictor variables (age, sex, level of education). The data of the pilot survey revealed that 98% of the respondents had heard of the disease 'Cancer'. Unfortunately only 35% of the respondents were aware of the 7-danger signals (i.e. the primary symptoms of cancer) as defined by the World Health Organisation (WHO). None of the respondents knew all 7-primary symptoms of cancer and the majority (about 88%) knew only one or two (mainly tumour lumps and ulcers). Only 44.67% were aware of the major risk factors (like smoking and tobacco chewing). The percentage of the respondents believing that most cancers are curable in early stages was 58%. Some of the respondents (21%) expressed the vague idea that cancer is a infectious disease which is creating a problem of isolation from the family/society with some unfortunate cancer patients. Over 11% of the respondents suggested that a cancer diagnosis should be kept secret from neighbours due to some social stigma like problems with daughters' marriage. Only 8% had experienced any cancer awareness programme conducted by any organisation, only 37% had listened to any cancer awareness programme conducted by the All India Radio, only 36% had seen any cancer awareness programme conducted by Doordarsan/ private Television channels, only 34% had read cancer awareness articles in the newspapers/magazines and only 13% had seen posters/hoardings regarding cancer awareness. The results thus revealed a huge lack regarding cancer awareness in the region. Most of the respondents (68%) expressed a wish for starting cancer awareness programmes. From the Pilot Survey it has been found that the average Knowledge Index of the respondents is 58+ 1.7 irrespective of the socio-economic and personal status. On testing of associations, there was no statistically significant association of the Knowledge Index with the domicile status (rural or urban), sex, occupation and religion of the respondents. However, statistically significant links were evident with the level of education (p=0.00001), social participation (p=0.00004) and income (p=0.00013) of the respondents.


Suppression of auxin signalling promotes rice susceptibility to Rice black streaked dwarf virus infection.
Auxin plays a fundamental role in plant growth and development, and also influences plant defence against various pathogens. Previous studies have examined the different roles of the auxin pathway during infection by biotrophic bacteria and necrotrophic fungi. We now show that the auxin signalling pathway was markedly down-regulated following infection of rice by Rice black streaked dwarf virus (RBSDV), a dsRNA virus. Repression of the auxin receptor TIR1 by a mutant overexpressing miR393 increased rice susceptibility to RBSDV. Mutants overexpressing the auxin signalling repressors OsIAA20 and OsIAA31 were also more susceptible to RBSDV. The induction of jasmonic acid (JA) pathway genes in response to RBSDV was supressed in auxin signalling mutants, suggesting that activation of the JA pathway may be part of the auxin signalling-mediated rice defence against RBSDV. More importantly, our results also revealed that OsRboh-mediated reactive oxygen species levels played important roles in this defence. The results offer novel insights into the regulatory mechanisms of auxin signalling in the rice-RBSDV interaction.


Rapid species-level identification of vaginal and oral lactobacilli using MALDI-TOF MS analysis and 16S rDNA sequencing.
Lactobacillus represents a large genus with different implications for the human host. Specific lactobacilli are considered to maintain vaginal health and to protect from urogenital infection. The presence of Lactobacillus species in carious lesions on the other hand is associated with progressive caries. Despite their clinical significance, species-level identification of lactobacilli still poses difficulties and mostly involves a combination of different phenotypic and genotypic methods. This study evaluated rapid MALDI-TOF MS analysis of vaginal and oral Lactobacillus isolates in comparison to 16S rDNA analysis. Both methods were used to analyze 77 vaginal and 21 oral Lactobacillus isolates. The concordance of both methods was at 96% with five samples discordantly identified. Fifteen different Lactobacillus species were found in the vaginal samples, primarily L. iners, L. crispatus, L. jensenii and L. gasseri. In the oral samples 11 different species were identified, mostly L. salivarius, L. gasseri, L. rhamnosus and L. paracasei. Overall, the species found belonged to six different phylogenetic groups. For several samples, MALDI-TOF MS analysis only yielded scores indicating genus-level identification. However, in most cases the species found agreed with the 16S rDNA analysis result. MALDI-TOF MS analysis proved to be a reliable and fast tool to identify lactobacilli to the species level. Even though some results were ambiguous while 16S rDNA sequencing yielded confident species identification, accuracy can be improved by extending reference databases. Thus, mass spectra analysis provides a suitable method to facilitate monitoring clinically relevant Lactobacillus species.


Cyclosporin A absorption profiles in pediatric renal transplant recipients predict the risk of acute rejection.
The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.


Physical activity and reduction of health risks: how far are the benefits independent of fat loss?
This paper considers how far the postulated health benefits of exercise are attributable to a decrease of body fat. Some of the well-accepted gains such as a reduction in the risk of ischemic heart disease are seen even when the data are controlled for body mass. However, other responses such as a reduced incidence of some types of cancer and a decrease of waking blood pressure are closely linked to body fat content and associated metabolic disturbances. The medium-term weight loss is relatively similar for an exercise programme and a dietary regimen, but exercise tends to conserve lean tissue. Exercise also has unique beneficial effects upon musculo-skeletal disorders and mood state. Perhaps most importantly, it improves the quality of life, helping to maintain physical abilities and thus independence into extreme old age. Nevertheless, the optimum recommendation for the moderately obese patient is usually to combine a progressive exercise regiment with a moderate restriction of food intake.


Tongue texture may contribute to the assessment of malignant risk of thyroid nodules.
In the present study, it was aimed to evaluate whether there is an objective tongue image indicator that could be used to evaluate malignant risk of thyroid nodules through a cross sectional study. From December 2018 to December 2020, the TFDA-1 digital tongue-face diagnostic instrument was used to collect the tongue images. TDAS 2.0 software was used for tongue image analysis. A standardized database was constructed by combining patient physical examination results and tongue image analysis results. The relationship between tongue image index and TI-RADS classification of thyroid nodules was tested. A total of 5,900 cases were collected and 4,615 cases were included in the present study after excluding 154 cases due to incomplete information, 1,221 cases with thyroid nodules were separated into 417 cases TI-RADS 2 group, 693 cases in TI-RADS 3 group and 111 cases in TI-RADS 4 group. Without considering confounding factors, tongue image indexes zhiCon, zhiASM, zhiENT, zhiMEAN, zhiClrB, zhiClrR, zhiClrG, zhiClrI, zhiClrL and zhiClrY were significantly different among the three groups (P<0.05). Excluding the influence of age, sex, body mass index, smoking and drinking, the results of one-way variance linear trend analysis showed that the values of zhiCon, zhiENT and zhiMEAN increased with the increasing TI-RADS category, while the values of zhiASM decreased with the increase of TI-RADS category. Tongue texture index may be helpful for differentiating the benign and malignant of thyroid nodules.


Clinical and molecular sub-classification of hepatocellular carcinoma relative to alpha-fetoprotein level in an Asia-Pacific island cohort.
Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular sub-classes of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC. Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis. Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival. Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.


Adherence to chemoprophylaxis and Plasmodium falciparum anti-circumsporozoite seroconversion in a prospective cohort study of Dutch short-term travelers.
We conducted a prospective study in a cohort of short-term travelers assessing the incidence rate of anti-circumsporozoite seroconversion, adherence to chemoprophylaxis, symptoms of malaria during travel, and malaria treatment abroad. Adults were recruited from the travel clinic of the Public Health Service Amsterdam. They kept a structured daily travel diary and donated blood samples before and after travel. Blood samples were serologically tested for the presence of Plasmodium falciparum anti-circumsporozoite antibodies. Overall, the incidence rate (IR) of anti-circumsporozoite seroconversion was 0.8 per 100 person-months. Of 945 travelers, 620 (66%) visited high-endemic areas and were advised about both chemoprophylaxis and preventive measures against mosquito bites. Most subjects (520/620 = 84%) took at least 75% of recommended prophylaxis during travel. Travel to Africa, use of mefloquine, travel duration of 14-29 days in endemic areas, and concurrent use of DEET (N,N-diethyl-meta-toluamide) were associated with good adherence practices. Four travelers without fever seroconverted, becoming anti-circumsporozoite antibody-positive. All four had been adherent to chemoprophylaxis; two visited Africa, one Suriname, one India. Ten subjects with fever were tested for malaria while abroad and of these, three received treatment. All three were adherent to chemoprophylaxis and tested negative for anti-circumsporozoite antibodies. Travel to Africa, using mefloquine, travel duration of 14-29 days in endemic areas, and use of DEET were associated with good adherence to chemoprophylaxis. The combination of chemoprophylaxis and other preventive measures were sufficient to protect seroconverting travelers from clinical malaria. Travelers who were treated for malaria abroad did not seroconvert.


Sleep patterns of 7-week-old infants at familial risk for attention deficit hyperactivity disorder.
Sleep patterns of 26 seven-week-old boys at familial risk for attention deficit hyperactivity disorder (ADHD) and 18 control infants were compared by objective (actigraph) and subjective (maternal sleep diary) measures, over five consecutive 24-hr periods. Actigraph findings indicated that the groups differed on stability (SD) of quiet sleep only during the day. Reports in maternal sleep diaries indicated that they also differed on stability of waking and stability of sleep duration, again only during the day. No group differences were found in terms of average scores, whether calculated for the entire 24-hr periods, for nights, or for days. Mothers in the risk group reported that fathers were less involved in infant care than did those in the control group. These findings suggest that as early as 7 weeks of age, infants at risk for ADHD differ from controls only on stability of their sleep patterns during the day, when environmental regulatory factors are more intensive.


An Enterotoxin-Like Binary Protein from Pseudomonas protegens with Potent Nematicidal Activity.
Soil microbes are a major food source for free-living soil nematodes. It is known that certain soil bacteria have evolved systems to combat predation. We identified the nematode-antagonistic Pseudomonas protegens strain 15G2 from screening of microbes. Through protein purification we identified a binary protein, designated Pp-ANP, which is responsible for the nematicidal activity. This binary protein inhibits Caenorhabditis elegans growth and development by arresting larvae at the L1 stage and killing older-staged worms. The two subunits, Pp-ANP1a and Pp-ANP2a, are active when reconstituted from separate expression in Escherichia coli The binary toxin also shows strong nematicidal activity against three other free-living nematodes (Pristionchus pacificus, Panagrellus redivivus, and Acrobeloides sp.), but we did not find any activity against insects and fungi under test conditions, indicating specificity for nematodes. Pp-ANP1a has no significant identity to any known proteins, while Pp-ANP2a shows ∼30% identity to E. coli heat-labile enterotoxin (LT) subunit A and cholera toxin (CT) subunit A. Protein modeling indicates that Pp-ANP2a is structurally similar to CT/LT and likely acts as an ADP-ribosyltransferase. Despite the similarity, Pp-ANP shows several characteristics distinct from CT/LT toxins. Our results indicate that Pp-ANP is a new enterotoxin-like binary toxin with potent and specific activity to nematodes. The potency and specificity of Pp-ANP suggest applications in controlling parasitic nematodes and open an avenue for further research on its mechanism of action and role in bacterium-nematode interaction.IMPORTANCE This study reports the discovery of a new enterotoxin-like binary protein, Pp-ANP, from a Pseudomonas protegens strain. Pp-ANP shows strong nematicidal activity against Caenorhabditis elegans larvae and older-staged worms. It also shows strong activity on other free-living nematodes (Pristionchus pacificus, Panagrellus redivivus, and Acrobeloides sp.). The two subunits, Pp-ANP1a and Pp-ANP2a, can be expressed separately and reconstituted to form the active complex. Pp-ANP shows some distinct characteristics compared with other toxins, including Escherichia coli enterotoxin and cholera toxin. The present study indicates that Pp-ANP is a novel binary toxin and that it has potential applications in controlling parasitic nematodes and in studying toxin-host interaction.