The U sign: tenth landmark to the central region on brain surface reformatted MR imaging.
Identification of the central region is of special importance to avoid neurologic deficits in brain surgery. Brain surface reformatted images (Mercator view) map the frontoparietal brain surface in 1 view and provide a synopsis of the most important landmarks. In this view, the U-shaped subcentral gyrus appears as a distinctive anatomic structure enclosing the Sylvian end of the central sulcus. The purpose of this study was to add the subcentral gyrus as a new landmark to the central region (U sign) and to compare its frequency and applicability with common landmarks in healthy hemispheres. Mercator views of 178 hemispheres in 100 patients were generated from 3D MR imaging datasets. The hemispheres were evaluated on Mercator views for the presence or absence of each of the 9 common landmarks and the new U sign identifying the central region. The new landmark U sign was most common (96.6%), followed by the thin postcentral gyrus sign (95.5%). The least common landmark was the Ω-shaped handknob (54.5%). None of the landmarks could be identified in all hemispheres. All landmarks could be identified bilaterally in only 1.3% of patients. On the Mercator view, the new U sign is an applicable and even the most frequent landmark to identify the central region. Considering the variability of the anatomic structures of the brain, including the motor hand area, the synopsis of all 10 landmarks on this surface-reformatting projection is a helpful adjunct to standard MR imaging projections to identify the central region.


[State of the islands of Langerhans in various animal species after administration of 8-(arensulfonylamino)-quinolines].
The action of 8-(arensulfonylamino)-quinolines on the insular tissue of the pancreas was studied in frogs, pigeons, mice, golden hamsters, rats, rabbits, cats and dogs. There eas a decrease of zinc content in the Langerhans islets at the earliest stages after injection of the drug. Other histochemical components and histostrucutre of the islets changed with the more pronounced effect of the drug. Permanent diabetes with characteristic morphological picture of the pancreas developed in rabbits only. A possible action of chelating factors on human Langerhans islets is suggested on the basis of comparative pathological study.


Charged-particle emission tomography.
Conventional charged-particle imaging techniques - such as autoradiography - provide only two-dimensional (2D) black ex vivo images of thin tissue slices. In order to get volumetric information, images of multiple thin slices are stacked. This process is time consuming and prone to distortions, as registration of 2D images is required. We propose a direct three-dimensional (3D) autoradiography technique, which we call charged-particle emission tomography (CPET). This 3D imaging technique enables imaging of thick tissue sections, thus increasing laboratory throughput and eliminating distortions due to registration. CPET also has the potential to enable in vivo charged-particle imaging with a window chamber or an endoscope. Our approach to charged-particle emission tomography uses particle-processing detectors (PPDs) to estimate attributes of each detected particle. The attributes we estimate include location, direction of propagation, and/or the energy deposited in the detector. Estimated attributes are then fed into a reconstruction algorithm to reconstruct the 3D distribution of charged-particle-emitting radionuclides. Several setups to realize PPDs are designed. Reconstruction algorithms for CPET are developed. Reconstruction results from simulated data showed that a PPD enables CPET if the PPD measures more attributes than just the position from each detected particle. Experiments showed that a two-foil charged-particle detector is able to measure the position and direction of incident alpha particles. We proposed a new volumetric imaging technique for charged-particle-emitting radionuclides, which we have called charged-particle emission tomography (CPET). We also proposed a new class of charged-particle detectors, which we have called particle-processing detectors (PPDs). When a PPD is used to measure the direction and/or energy attributes along with the position attributes, CPET is feasible.


A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children.
The purpose of the Correction of Myopia Evaluation Trial (COMET) was to evaluate the effect of progressive addition lenses (PALs) compared with single vision lenses (SVLs) on the progression of juvenile-onset myopia. COMET enrolled 469 children (ages 6-11 years) with myopia between -1.25 and -4.50 D spherical equivalent. The children were recruited at four colleges of optometry in the United States and were ethnically diverse. They were randomly assigned to receive either PALs with a +2.00 addition (n = 235) or SVLs (n = 234), the conventional spectacle treatment for myopia, and were followed for 3 years. The primary outcome measure was progression of myopia, as determined by autorefraction after cycloplegia with 2 drops of 1% tropicamide at each annual visit. The secondary outcome measure was change in axial length of the eyes, as assessed by A-scan ultrasonography. Child-based analyses (i.e., the mean of the two eyes) were used. Results were adjusted for important covariates, by using multiple linear regression. Of the 469 children (mean age at baseline, 9.3 +/- 1.3 years), 462 (98.5%) completed the 3-year visit. Mean (+/-SE) 3-year increases in myopia (spherical equivalent) were -1.28 +/- 0.06 D in the PAL group and -1.48 +/- 0.06 D in the SVL group. The 3-year difference in progression of 0.20 +/- 0.08 D between the two groups was statistically significant (P = 0.004). The treatment effect was observed primarily in the first year. The number of prescription changes differed significantly by treatment group only in the first year. At 6 months, 17% of the PAL group versus 30% of the SVL group needed a prescription change (P = 0.0007), and, at 1 year, 43% of the PAL group versus 59% of the SVL group required a prescription change (P = 0.002). Interaction analyses identified a significantly larger treatment effect of PALs in children with lower versus higher baseline accommodative response at near (P = 0.03) and with lower versus higher baseline myopia (P = 0.04). Mean (+/- SE) increases in the axial length of eyes of children in the PAL and SVL groups, respectively, were: 0.64 +/- 0.02 mm and 0.75 +/- 0.02 mm, with a statistically significant 3-year mean difference of 0.11 +/- 0.03 mm (P = 0.0002). Mean changes in axial length correlated with those in refractive error (r = 0.86 for PAL and 0.89 for SVL). Use of PALs compared with SVLs slowed the progression of myopia in COMET children by a small, statistically significant amount only during the first year. The size of the treatment effect remained similar and significant for the next 2 years. The results provide some support for the COMET rationale-that is, a role for defocus in progression of myopia. The small magnitude of the effect does not warrant a change in clinical practice.


Inflammatory Fibroid Polyp of the Small Intestine: A Case Report and Systematic Literature Review.
Starting from a case presentation, this review aims to present literature data on inflammatory fibroid polyps (IFPs) of the small intestine. Case report and systematic review. A comprehensive systematic review of English literature using PubMed was conducted, based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The used key words were: "inflammatory fibroid polyp" or "Vanek", including only cases with IFPs localized of the small intestine, published from 1976 to 2019. We present a case of a 38-year old patient with intestinal IFP presenting with acute abdomen due to intussusception diagnosed with ultrasound (US) based on a target sign and visible solid tumor in the small intestine leading to prompt surgical treatment. A diagnosis of IFP was made based on the pathohistological findings. Moreover, a systematic review of small intestine IFPs was conducted which is, to our knowledge, the first comprehensive systematic literature review on this topic. The analysis included 53 case reports or case series concerning 77 cases of small bowel IFPs. The patients were aged from 4 to 75 years (average 45.2), with a female predominance (59.7%). The most common localization was the ileum in 77.9% cases, followed by the jejunum (13%) and the duodenum (6.5%). The most common clinical presentation was abdominal pain due to intussusception (63.6%). Regarding diagnostic methods, computed tomography (CT) was frequently used as primary diagnostic method (26%) followed by exploratory laparotomy (16.9%), endoscopy (7.8%) and US (6.5%). Combination of US and CT contributed to the diagnosis in 9.1% of cases. The majority of cases were treated surgically (92.21%), while only a minority benefited of minimally invasive techniques such as endoscopy. Small bowel IFPs, ones of the least common benign tumors, are characterized by variable clinical signs and symptoms and can potentially lead to serious consequences for the patient.


[Anemia as a risk factor for CKD and CVD].
Chronic kidney disease (CKD) is now recognized as a risk factor of both end-stage renal disease (ESRD) and independently cardiovascular disease (CVD). Therefore, a specific renoprotective intervention is strongly recommended, including blood pressure control as well as anemia improvement with erythropoietin stimulating agents (ESAs). Treatment of renal anemia with ESAs has been proved to improve quality of life (QOL) and finally reduce patient mortality. Recently, Silverberg, et al. created a novel clinical entity of Cardio-Renal Anemia (CRA) syndrome, in which anemia plays a key role for worsening both CKD and cardiac performance in a vicious circle. An appropriate and vigorous treatment of anemia has now been accepted to terminate or weaken the circle. Recently, two large-scaled randomized controlled trials were reported, being the CREATE (cardiovascular risk reduction by early anemia treatment with epoetin beta) study and the CHOIR (correction of hemoglobin and outcomes in renal insufficiency) study. They demonstrated that early initiation of ESA treatment and targeting at higher hemoglobin level (near normal level) failed to show the lowering effects for cardiovascular events as compared to a group in which Hb targeting was lower (sub-normal level) in pre-dialysis CKD patients. While there has been many argues in these reports especially about baseline patients characteristics, being a quite high incidence of severe cardiovascular co-morbidity. Thus, further evidences should be accumulated to resolve a proper target level of Hb in ESA treatment.


CLIC4 is enriched at cell-cell junctions and colocalizes with AKAP350 at the centrosome and midbody of cultured mammalian cells.
CLIC4 is a member of the chloride intracellular channel (CLIC) protein family whose principal cellular functions are poorly understood. Recently, we demonstrated that several CLIC proteins, including CLIC4, interact with AKAP350. AKAP350 is concentrated at the Golgi apparatus, centrosome, and midbody and acts as a scaffolding protein for several protein kinases and phosphatases. In this report, we show that endogenous CLIC4 and AKAP350 colocalize at the centrosome and midbody of cultured cells by immunofluorescence microscopy. Unlike AKAP350, CLIC4 is not enriched in the Golgi apparatus but is enriched in mitochondria, actin-based structures at the cell cortex, and the nuclear matrix, indicating that CLIC4-AKAP350 interactions are regulated at specific subcellular sites in vivo. In addition to the centrosome and midbody, CLIC4 colocalizes with AKAP350 and the tight junction protein ZO-1 in the apical region of polarized epithelial cells, suggesting that CLIC4 may play a role in maintaining apical-basolateral membrane polarity during mitosis and cytokinesis. Biochemical studies show that CLIC4 behaves mainly as a soluble cytosolic protein and can associate with proteins of the microtubule cytoskeleton. The localization of CLIC4 to the cortical actin cytoskeleton and its association with AKAP350 at the centrosome and midbody suggests that CLIC4 may be important for regulating cytoskeletal organization during the cell cycle. These findings lead to the conclusion that CLIC4 and possibly other CLIC proteins have alternate cellular functions that are distinct from their proposed roles as chloride channels.


Studies on the origin-specific DNA-binding domain of simian virus 40 large T antigen.
The origin-specific DNA-binding domain of simian virus 40 large T antigen was analyzed, and its C-terminal boundary was found to be at or before amino acid 259. This does not include the zinc finger structural motif located at amino acids 302 to 320 (J. M. Berg, Science 232:485-486, 1986). Interestingly, N-terminal fragments of 266 and 272 amino acids and larger displayed dramatically reduced origin-binding activity. In addition, the specific DNA-binding properties of truncated proteins purified from both bacterial and mammalian sources were compared. Truncated T antigens from mammalian cells bound specific DNA fragments more efficiently than did their bacterial counterparts. These results implicate posttranslational modification with a role in regulating the DNA-binding activity of large T antigen.


A known-plaintext heuristic attack on the Fourier plane encryption algorithm.
The Fourier plane encryption algorithm is subjected to a known-plaintext attack. The simulated annealing heuristic algorithm is used to estimate the key, using a known plaintext-ciphertext pair, which decrypts the ciphertext with arbitrarily low error. The strength of the algorithm is tested by using this estimated key to decrypt a different ciphertext which was also encrypted using the same original key. We assume that the plaintext is amplitude-encoded real-valued image, and analyze only the mathematical algorithm rather than a real optical system that can be more secure. The Fourier plane encryption algorithm is found to be susceptible to a known-plaintext heuristic attack.


Vibrational coupling between helices influences the amide I infrared absorption of proteins: application to bacteriorhodopsin and rhodopsin.
The amide I spectrum of multimers of helical protein segments was simulated using transition dipole coupling (TDC) for long-range interactions between individual amide oscillators and DFT data from dipeptides (la Cour Jansen et al. J. Chem. Phys.2006, 125, 44312) for nearest neighbor interactions. Vibrational coupling between amide groups on different helices shift the helix absorption to higher wavenumbers. This effect is small for helix dimers (1 cm(-1)) at 10 Å distance and only moderately affected by changes in the relative orientation between the helices. However, the effect becomes considerable when several helices are bundled in membrane proteins. Particular examples are the 7-helix membrane proteins bacteriorhodopsin (BR) and rhodopsin, where the upshift is 4.3 and 5.3 cm(-1), respectively, due to interhelical coupling within a BR monomer. A further upshift of 4.0 cm(-1) occurs when BR monomers associate to trimers. We propose that interhelical vibrational coupling explains the experimentally observed unusually high wavenumber of the amide I band of BR.


Overexpression of VvWRKY2 in tobacco enhances broad resistance to necrotrophic fungal pathogens.
WRKY genes encode proteins belonging to a large family of transcription factors that are involved in various developmental and physiological processes and in plant responses to pathogen infections. In the present work, a full-length cDNA from a Vitis vinifera L. cv. Cabernet Sauvignon grape berry library was isolated and characterized. The cDNA, designated VvWRKY2, encodes a polypeptide of 536 amino acids that shows the structural features of group I of WRKY protein family. VvWRKY2 is expressed in the different organs of healthy grapevine plants. In leaves, VvWRKY2 is induced by wounding and after infection with Plasmopara viticola. Constitutive expression of VvWRKY2 in tobacco reduced the susceptibility of transgenic tobacco to three types of fungal pathogens infecting different parts of the plant: Botrytis cinerea (leaves), Pythium spp. (roots) and Alternaria tenuis (seeds). The results indicate that VvWRKY2 may be involved in the resistance of grapevine against the pathogens.


Developing tTA transgenic rats for inducible and reversible gene expression.
To develop transgenic lines for conditional expression of desired genes in rats, we generated several lines of the transgenic rats carrying the tetracycline-controlled transactivator (tTA) gene. Using a vigorous, ubiquitous promoter to drive the tTA transgene, we obtained widespread expression of tTA in various tissues. Expression of tTA was sufficient to strongly activate its reporter gene, but was below the toxicity threshold. We examined the dynamics of Doxycycline (Dox)-regulated gene expression in transgenic rats. In the two transmittable lines, tTA-mediated activation of the reporter gene was fully subject to regulation by Dox. Dox dose-dependently suppressed tTA-activated gene expression. The washout time for the effects of Dox was dose-dependent. We tested a complex regime of Dox administration to determine the optimal effectiveness and washout duration. Dox was administered at a high dose (500 microg/ml in drinking water) for two days to reach the effective concentration, and then was given at a low dose (20 microg/ml) to maintain effectiveness. This regimen of Dox administration can achieve a quick switch between ON and OFF statuses of tTA-activated gene expression. In addition, administration of Dox to pregnant rats fully suppressed postnatal tTA-activated gene expression in their offspring. Sufficient levels of Dox are present in mother's milk to produce maximal efficacy in nursing neonates. Administration of Dox to pregnant or nursing rats can provide a continual suppression of tTA-dependent gene expression during embryonic and postnatal development. The tTA transgenic rat allows for inducible and reversible gene expression in the rat; this important tool will be valuable in the development of genetic rat models of human diseases.


Detection of pathogenic Campylobacter species in blood culture systems.
Because differences in recognition of Campylobacter fetus and Campylobacter jejuni in systemic infections may be due partially to differences in the ability to cultivate these organisms, we studied their growth characteristics in two widely used blood culture systems. In the Roche Septi-Chek system (Hoffman-La Roche, Inc., Nutley, N.J.), over a broad range of inocula all strains were detected in broth within 2 days and on paddles within 3 days. In the BACTEC 6B aerobic bottles (Johnston Laboratories, Inc., Towson, Md.), C. jejuni and C. fetus took a median of 5 and 3 days, respectively, to reach the growth index threshold. However, in the BACTEC 7D anaerobic bottles, C. fetus required a median of 2 days to reach the growth index threshold, whereas for C. jejuni the median was greater than 10 days. The poor performance of C. jejuni in both BACTEC systems may have been due to unfavorable incubation atmospheres and may partially explain why C. jejuni bacteremia is so infrequently detected. Overall, the Roche Septi-Chek system was excellent for detecting Campylobacter strains in blood cultures.


Further result on guaranteed H∞ performance state estimation of delayed static neural networks.
This brief considers the guaranteed H∞ performance state estimation problem of delayed static neural networks. An Arcak-type state estimator, which is more general than the widely adopted Luenberger-type one, is chosen to tackle this issue. A delay-dependent criterion is derived under which the estimation error system is globally asymptotically stable with a prescribed H∞ performance. It is shown that the design of suitable gain matrices and the optimal performance index are accomplished by solving a convex optimization problem subject to two linear matrix inequalities. Compared with some previous results, much better performance is achieved by our approach, which is greatly benefited from introducing an additional gain matrix in the domain of activation function. An example is finally given to demonstrate the advantage of the developed result.


Does Tension Headache Have a Central or Peripheral Origin? Current State of Affairs.
The aim of this narrative review is to analyze the evidence about a peripheral or central origin of a tension headache attack in order to provide a further clarification for an appropriate approach. Tension headache is a complex and multifactorial pathology, in which both peripheral and central factors could play an important role in the initiation of an attack. Although the exact origin of a tension headache attack has not been conclusively established, correlations have been identified between certain structural parameters of the craniomandibular region and craniocervical muscle activity. Future research should focus on improving our understanding of the pathology with the ultimate goal of improving diagnosis. The pathogenesis of tension-type headache involves both central and peripheral mechanisms, being the perpetuation over time of the headache attacks what would favor the evolution of an episodic tension-type headache to a chronic tension-type headache. The unresolved question is what factors would be involved in the initial activation in a tension headache attack. The evidence that favors a peripheral origin of the tension headache attacks, that is, the initial events occur outside the brain barrier, which suggests the action of vascular and musculoskeletal factors at the beginning of a tension headache attack, factors that would favor the sensitization of the peripheral nervous system as a result of sustained sensory input.


MR-based hippocampal volumetry in the diagnosis of Alzheimer's disease.
We evaluated a new magnetic resonance (MR)-based technique for performing volumetric measurements of temporal lobe structures. The technique was designed to assist in making the clinical diagnosis of dementia of the Alzheimer type (DAT). We chose specific anatomic regions of interest because of their known involvement in memory function and in the neuropathology of DAT and used a regression model to assess the effects of age on the volumes of the anterior temporal lobe (ATL) and the hippocampal formation (HF). These measurements were normalized by total intracranial volume (TIV). The volumetric measurements of both the normalized ATL and HF were significantly smaller (p less than 0.001) in DAT patients (N = 20) than in controls (N = 22), but the HF volumes provided much better separation between the two groups. Eighty-five percent of the DAT patients fell below the range of the HF/TIV measurement for the control subjects. This separation held up over the entire age range studied. Normalized volumes of both the HF and ATL decreased with age significantly for both the DAT patients and the controls. These results support the contention that MR-based HF volumetric measurements are accurate in differentiating DAT patients from cognitively normal elderly individuals. This technique may be a useful adjunct in making the clinical diagnosis of DAT.


[Effect of the availability of a medicalized mobile ICU (MMICU) on the hospital admissions after an out-of-hospital cardiorespiratory arrest (OH-CRA)].
Patients admitted in an ICU after OH-CRA before and after the implementation of a MMICU were evaluated. During a period of 11 years, divided into a pre-MMICU period (1988-1993) and a post-MMICU period (1994-1998), 39 patients were admitted in the pre period and 64 patients in the post period. The basal characteristics, the etiologies of OH-CRA and of death in ICU they were similar. The incidence of severe anoxic encephalopathy (SAE) it doubled in the post period. There were not significant differences both to the discharge from ICU and to the hospital discharge. We conclude that after implementing a MMICU more patients are admitted in ICU resuscitated after OH-CRA. The survival does not vary, but the incidence of SAE increases.


Charcot foot.
Successful management of the Charcot foot is one of the most challenging undertakings faced by physicians. However, many times such patients undergo prolonged and attentive care only to develop further deformity, and in many cases succumb to amputation. Research in the past few years has yielded a new understanding of the Charcot process that should serve as the basis for improved therapeutic measures. The authors discuss these more recent developments and how this knowledge may be applied to better serve the patient. In addition, surgical reconstruction of the diabetic Charcot foot is introduced and discussed.


Pharmacogenetic testing after a simple DNA isolation method on buccal swab samples.
To evaluate whether the quality and quantity of DNA isolated from noninvasively obtained buccal swab (BS) samples, using the previously described isolation method for dried blood spot (DBS) samples was satisfactory. From 25 healthy volunteers, DBS samples were obtained by the capillary finger prick method and BS samples were obtained by rubbing a sterile, dry cotton swab against the inside of their cheek. Thereafter, DNA was isolated. In addition, the quantity of the obtained DNA was measured and melting curve analyses for both sampling methods were performed to establish the quality of the obtained DNA from both the DBS and BS samples. The derivative melting curves of the DNA samples obtained from the capillary blood and BS were comparable and highly reproducible. The mean DNA concentrations measured were 16.0 ng/microl (12.6-19.4 ng/microl) and 70.2 ng/microl (57.3-83.1 ng/microl), respectively, for the DBS and BS samples (p < 0.001). The DBS DNA isolation method appeared to be extremely useful to discriminate between genotypes. This expands the possibilities of this quick and easy DNA isolation procedure. In particular, the noninvasive BS sampling method appeared to be a good alternative to invasive sampling methods.


Lymphoepithelial cyst of the pancreas: case report and review of the literature.
Lymphoepithelial cyst of the pancreas (LCP) is a rare, benign cyst mimicking pseudocyst or cystic neoplasm. Literature describing LCP is limited to case or brief series reports, and the natural history of this condition is largely unknown. A literature review was carried out in order to elucidate the clinical, pathological and biochemical features of LCP. The aim of this study was to define diagnostic criteria and treatment. A Medline and Pubmed search was conducted by using the key-words "lymphoepithelial cyst" and "pancreas". The articles found were accurately examined and all details regarding clinical and pathological features were included in a data-base. Furthermore, a case recently observed in our unit was added to the review. Ninety-two cases of LCP were found in the worldwide literature, including the case that we observed. LCP occurs more frequently in males (M:F=5.5:1), its preferred site is the tail of the pancreas, and its size ranges between 2 and 10centimetres. Histologically, it is a true cyst delineated by a keratinizing squamous epithelium surrounded by lymphoid tissue. LCP is asymptomatic in the majority of cases and preoperative diagnosis is complicated by a lack of specific radiological features of the disease. An accurate preoperative diagnosis can only be made by obtaining cytological specimens and placing them in the hands of a pathologist who is familiar with the cytological appearances of the disease. LCP is a rare lesion worldwide, without any prevalence in different countries or in different ethnic groups. Understanding the features of LCP, making an accurate diagnosis and differentiating it from cystic neoplasm preoperatively is vital, as when it is diagnosed certainly, a conservative treatment is justified. Otherwise, radical surgery in the form of pancreatic resection is required to exclude the diagnosis of pancreatic cystic neoplasm.


An endogenous small interfering RNA pathway in Drosophila.
Drosophila endogenous small RNAs are categorized according to their mechanisms of biogenesis and the Argonaute protein to which they bind. MicroRNAs are a class of ubiquitously expressed RNAs of approximately 22 nucleotides in length, which arise from structured precursors through the action of Drosha-Pasha and Dicer-1-Loquacious complexes. These join Argonaute-1 to regulate gene expression. A second endogenous small RNA class, the Piwi-interacting RNAs, bind Piwi proteins and suppress transposons. Piwi-interacting RNAs are restricted to the gonad, and at least a subset of these arises by Piwi-catalysed cleavage of single-stranded RNAs. Here we show that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious rather than the canonical Dicer-2 partner, R2D2 (ref. 14). Endogenous small interfering RNAs arise both from convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join Argonaute-2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. These observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.


Prognostic Role of Late Gadolinium Enhancement in Patients With Hypertrophic Cardiomyopathy and Low-to-Intermediate Sudden Cardiac Death Risk Score.
Sudden cardiac death (SCD) is the most life-threating complication of hypertrophic cardiomyopathy. Guidelines of the European Society of Cardiology (ESC) suggest the implantation of an implantable cardioverter defibrillator in primary prevention according to a 5-year risk SCD score ≥6%. The aim of the study is to evaluate the prognostic role of late gadolinium enhancement (LGE) in patients with a 5-year risk SCD score <6%. In this multicenter study, we performed cardiac magnetic resonance in 354 consecutive hypertrophic cardiomyopathy patients (257 males, range of age 54 ± 17) with a risk SCD score <6% (302 with <4% and 52 with ≥4 and <6% risk). Hard cardiac events, including SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator interventions, sustained ventricular tachycardia, occurred in 22 patients. LGE was detected in a high proportion (92%) of patients with hard cardiac events (p = 0.002). At receiver-operating characteristic curve analysis, LGE extent ≥10% was the best threshold to predict major arrhythmic events (area under the curve: 0.74). Kaplan-Meier curves showed that patients with LGE ≥10% had a worse prognosis than those with lower extent (p < 0.0001). LGE extent was the best independent predictor of hard cardiac events (hazard ratio 1.05; 95% confidence interval [CI] 1.03 to 107; p < 0.0001). The estimates 5-year risk of hard cardiac event was 2.5% (95% CI 0.8 to 4.2) in patients with LGE extent <10% and 23.4% (95% CI 10.2 to 36.5) for those with LGE extent ≥10%. In conclusion, this study demonstrates as the extent of LGE ≥10% is able to recognize additional patients at increased risk for malignant arrhythmic episodes in a population with low-to-intermediate ESC SCD risk score.


Adenomas are precursor lesions for malignant growth in nonpolyposis hereditary carcinoma of the colon and rectum.
The relationship of adenoma to carcinoma of the colon and rectum in individuals of families with nonpolyposis hereditary carcinoma of the colon and rectum syndrome is uncertain. In five families with hereditary carcinoma of the colon and rectum, the medical records of 39 patients who had 50 instances of carcinoma of the colon and rectum develop were studied. Six instances of disease were found in adenomas: Dukes' A in two; Dukes' B in three, and Dukes' C in one. The malignant polyp was the only neoplastic lesion in the colon in five of these instances. In only 12 of the patients (31 per cent) were adenomas (seven patients) or secondary disease (five patients) ever found. These data suggest that while uncommon adenomas are precursor lesions for malignant neoplasms in patients with carcinoma of the colon and hereditary carcinoma of the colon and rectum syndrome.


Identifying contact-mediated, localized toxic effects of MWCNT aggregates on epithelial monolayers: a single-cell monitoring toxicity assay.
Aggregates of multiwalled carbon nanotubes (MWCNT) impair the barrier properties of human airway cell monolayers. To resolve the mechanism of the barrier alteration, monolayers of Calu-3 human airway epithelial cells were exposed to aggregated MWCNT. At the cell-population level, trans-epithelial electrical resistance (TEER) was used as an indicator of barrier competence, caspase activity was assessed with standard biochemical assays, and cell viability was investigated by biochemical techniques and high-throughput screening (HTS) technique based on automated epifluorescence microscopy. At cell level, the response to MWCNT was investigated with confocal microscopy, by evaluating cell death (calcein/propidium iodide (PI)), proliferation (Ki-67), and apoptosis (caspase activity). At the cell-population level, exposure to aggregated MWCNT caused a decrease in TEER, which was not associated with a decrease in cell viability or onset of apoptosis even after an 8-d exposure. In contrast, confocal imaging demonstrated contact with MWCNT aggregates triggered cell death after 24 h of exposure. In the presence of a natural surfactant, both TEER decrease and contact-mediated toxicity were mitigated. With confocal imaging, increased proliferation and apoptosis were detected in Calu-3 cells next to the aggregates. Contact-mediated cytotoxicity was recorded in two additional cell lines (BEAS-2B and A549) derived from human airways. Similar results were confirmed by adopting two additional MWCNT preparations with different physico-chemical features. This indicates MWCNT caused localized damage to airway epithelial monolayers in vitro and altered the apoptotic and proliferative rate of epithelial cells in close proximity to the aggregates. These findings provide evidence on the pathway by which MWCNT aggregates impair airway barrier function, and support the use of imaging techniques as a possible regulatory-decision supporting tool to identify effects of aggregated nanomaterials not readily detected at cell population level.


Utilizing multiple methods to classify malnutrition among elderly patients admitted to the medical and surgical intensive care units (ICU).
The nutritional status of elderly patients requiring ICU admission is largely unknown. This study evaluated the prevalence of malnutrition in elderly patients (>65 years) admitted to the surgical and medical ICUs, agreement between assessment techniques and associations between malnutrition and adverse outcomes. For this prospective cohort, nutritional status was classified concurrently using the Mini Nutrition Assessment (MNA), Subjective Global Assessment (SGA), Nutrition Risk Score 2002 (NRS 2002) and MNA-short form (MNA-SF). Demographic and relevant medical information were collected from the medical record prior to the nutrition interview and/or following hospital discharge. Descriptive statistics, inter-rater agreement and regression analyses were conducted. The average patient was 74.2 (±6.8) years of age with a mean APACHE II score of 11.9 (±3.6). Malnutrition was prevalent in 23-34% of patients (n = 260) with excellent agreement between raters. Compared to MNA, NRS 2002 had the highest sensitivity, while SGA and MNA-SF had higher specificity. Malnutrition at ICU admission was associated with longer hospital LOS, a lower propensity for being discharged home and a greater need for hospice care or death at discharge (all p values <0.05). These relationships were diminished when controlling for severity of illness. Future work in this elderly population needs to explore the role of disease acuity, inflammation and body composition in the nutrition assessment process and in the examination of outcomes.


Seroprevalence of SARS-CoV-2 antibodies among homeless people living rough, in shelters and squats: A large population-based study in France.
Overcrowded housing, as well as inadequate sanitary conditions, contribute to making homeless people particularly vulnerable to the SARS-CoV-2 infection. We aimed to assess the seroprevalence of the SARS-CoV-2 infection among people experiencing homelessness on a large city-wide scale in Marseille, France, taking into account different types of accommodation. A consortium of outreach teams in 48 different locations including streets, slums, squats, emergency or transitional shelters and drop-in centres participated in the inclusion process. All participants consented to have a validated rapid antibody assay for immunoglobulins M (IgM) and G (IgG) and to answer a questionnaire on medical health conditions, comorbidities, and previous COVID-19 symptoms. Information on their housing conditions since the COVID-19 crisis was also collected from the participants. From June 01 to August 05, 2020, 1,156 homeless participants were enrolled in the study and tested. The overall seroprevalence of SARS-CoV-2 IgG/IgM antibodies was 5.6% (95%CI 2.3-7.0), ranging from 2.2% in people living on the streets to 8.1% in people living in emergency shelters (P = 0.009). Around one third of the seropositive participants reported COVID-19 symptoms. Compared to the general population in Marseille (3.6%), the homeless population living in the same urban area experienced a significantly increased risk of SARS-CoV-2 infection (|z| = 3.65 > 1.96). These findings highlight the need for regular screening among the homeless to prevent clustering in overcrowded or inadequate accommodations. It is also necessary to provide essential resources to keep homeless people healthy, the vast majority of whom have cumulative risk factors for SARS-CoV-2 infection.


Melatonin ameliorates sodium valproate-induced hepatotoxicity in rats.
Valproic acid (VPA) is a anticonvulsant and mood-stabilizing agent used to treat epilepsy in patients of all ages. However, it can cause hepatotoxicity with increased oxidative stress. Melatonin (MEL) is known as antioxidant and antiinflammatory agent. Therefore, the present study designed to investigate the probable protective role of melatonin against VPA-induced liver toxicity. For that purpose, 28 Wistar rats were randomly selected and divided into four groups, namely the Group C (vehicle), VPA (500 mg/kg/day VPA), MEL + VPA (10 mg/kg/day melatonin + 500 mg/kg/day VPA) and MEL (10 mg/kg/day melatonin). The agents were given by oral gavage for 14 days. Blood and liver tissue samples from all the rats were harvested on the 15th day of experiment. Biochemical analyses were conducted on the blood samples. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), alpha glutathione S-transferases (α-GST), nuclear factor-κB (NF-κB), myeloperoxidase (MPO) and changes in gene expression were examined in the liver tissues. Also, liver histopathological analyses were conducted. VPA administration significantly increased the levels of α-GST, MDA, NF-κB and of IL-1β, TNF-α gene expression in the liver compared to Group C. Moreover, vacuolization, hydropic degeneration, inflammatory cell infiltration, and sinusoidal congestion were commonly detected in the VPA-treated group along with the highest apoptotic index (TUNEL staining) values. Melatonin administration was revealed to exhibit powerful protective properties at cellular, inflammatory and oxidative level activities against VPA-induced liver toxicity. Therefore, melatonin administration may be used as an adjuvant therapy against to VPA-induced liver toxicity.


Circum Black Sea phylogeography of Barbus freshwater fishes: divergence in the Pontic glacial refugium.
We used DNA sequence variation at the mitochondrial cytochrome b gene (1141 bp) to assess the phylogeography of Barbus fishes in the Black Sea region. Our aim was to test whether the recent ( approximately 22 000-7500 years ago) freshwater phase of the Black Sea was a conduit for gene flow among freshwater fishes that today are found in streams entering the saltwater Black Sea. Deep phylogeographical breaks suggestive of allopatric divergence were observed between four regional groups of populations. Coalescent simulation used to distinguish between this and an alternative scenario that the phylogeographical structure was due to random lineage sorting showed that the contemporary populations were unlikely (P < 0.001) to have been founded by a single ancestral population. Divergences between the lineages (0.86-2.54%) were dated to the Middle to Late Pleistocene using distances and a molecular clock corrected for superimposed substitutions. Taken together, this evidence suggests that multiple refugial populations survived over several later glaciations in the vicinity of the Black Sea. This Pontic refugium served as the primary source for the postglacial expansion throughout Europe as far as the Atlantic basin. However, only one of the phylogeographical lineages contributed to this dispersion, whereas the others remain restricted to the Black Sea region and followed independent evolutionary trajectories.


Ambiguity-free edge-bundling for interactive graph visualization.
Graph visualization has been widely used to understand and present both global structural and local adjacency information in relational data sets (e.g., transportation networks, citation networks, or social networks). Graphs with dense edges, however, are difficult to visualize because fast layout and good clarity are not always easily achieved. When the number of edges is large, edge bundling can be used to improve the clarity, but in many cases, the edges could be still too cluttered to permit correct interpretation of the relations between nodes. In this paper, we present an ambiguity-free edge-bundling method especially for improving local detailed view of a complex graph. Our method makes more efficient use of display space and supports detail-on-demand viewing through an interactive interface. We demonstrate the effectiveness of our method with public coauthorship network data.


Sustained Release of Tacrolimus From a Topical Drug Delivery System Promotes Corneal Reinnervation.
Corneal nerve fibers provide sensation and maintain the epithelial renewal process. Insufficient corneal innervation can cause neurotrophic keratopathy. Here, topically delivered tacrolimus is evaluated for its therapeutic potential to promote corneal reinnervation in rats. A compartmentalized neuronal cell culture was used to determine the effect of locally delivered tacrolimus on sensory axon regeneration in vitro. The regenerating axons but not the cell bodies were exposed to tacrolimus (50 ng/mL), nerve growth factor (50 ng/mL), or a vehicle control. Axon area and length were measured after 48 hours. Then, a biodegradable nanofiber drug delivery system was fabricated via electrospinning of a tacrolimus-loaded polycarbonate-urethane polymer. Biocompatibility, degradation, drug biodistribution, and therapeutic effectiveness were tested in a rat model of neurotrophic keratopathy induced by stereotactic trigeminal nerve ablation. Sensory neurons whose axons were exposed to tacrolimus regenerated significantly more and longer axons compared to vehicle-treated cultures. Trigeminal nerve ablation in rats reliably induced corneal denervation. Four weeks after denervation, rats that had received tacrolimus topically showed similar limbal innervation but a significantly higher nerve fiber density in the center of the cornea compared to the non-treated control. Topically applied tacrolimus was detectable in the ipsilateral vitreal body, the plasma, and the ipsilateral trigeminal ganglion but not in their contralateral counterparts and vital organs after 4 weeks of topical release. Locally delivered tacrolimus promotes axonal regeneration in vitro and corneal reinnervation in vivo with minimal systemic drug exposure. Topically applied tacrolimus may provide a readily translatable approach to promote corneal reinnervation.


Arthroscopic Stabilization After a First-Time Dislocation: Collision Versus Contact Athletes.
There is no universally accepted definition of "contact" or "collision" sports in the literature. The few available studies evaluating contact and collision sports consider them to be synonymous. However, athletes in collision sports purposely hit or collide with each other or with inanimate objects with greater force and frequency than in contact sports, which could jeopardize functional outcomes. To compare the functional outcomes, return to sports, and recurrences in a series of contact and collision athletes with a first-time anterior shoulder dislocation treated using arthroscopic stabilization with suture anchors. Cohort study; Level of evidence, 2. A total of 56 athletes were enrolled in this study, including 22 contact athletes and 34 collision athletes. All athletes underwent arthroscopic shoulder stabilization using suture anchors. Range of motion, the Rowe score, a visual analog scale (VAS) for pain, and the Athletic Shoulder Outcome Scoring System (ASOSS) were used to assess functional outcomes. Return to sports and recurrences were also evaluated. The mean age at the time of surgery was 22.2 years, and the mean follow-up was 62.4 months (range, 36-94 months). No significant difference in shoulder motion was found between preoperative and postoperative results or between the contact and collision groups. The Rowe, VAS, and ASOSS scores showed statistical improvement in both groups after surgery (P = .001). Patients in the contact group returned to sports significantly faster than those in the collision group (5.2 vs 6.9 months, respectively; P = .01). In all, 43 athletes (76.8%) returned to near-preinjury sports activity levels (≥90% recovery) after surgery: 86.4% of patients in the contact group and 70.6% in the collision group (P = .04). The total recurrence rate was 8.9%. There were 5 recurrences (14.7%) in the collision group and no recurrences in the contact group (P < .01). Arthroscopic stabilization for anterior instability of the shoulder is a reliable procedure with respect to shoulder function, range of motion, and postoperative return to sports in contact and collision athletes. Compared with the contact group (0%), the collision group yielded a higher failure rate (14.7%). Moreover, patients in the contact group returned significantly faster (5.2 vs 6.9 months, respectively) and to and more returned to preinjury or near-preinjury activity levels (86.4% vs 70.6% of patients, respectively) than patients in the collision group.


Positional identification of RT1-B (HLA-DQ) as susceptibility locus for autoimmune arthritis.
Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.


Efficient syntheses of (-)-crinine and (-)-aspidospermidine, and the formal synthesis of (-)-minfiensine by enantioselective intramolecular dearomative cyclization.
Polycyclic alkaloids bearing all-carbon quaternary centers possess a diversity of biological activities and are challenging targets in natural product synthesis. The development of a general and asymmetric catalytic method applicable to the efficient syntheses of a series of complex polycyclic alkaloids remains highly desirable in synthetic chemistry. Herein we describe an efficient palladium-catalyzed enantioselective dearomative cyclization which is capable of synthesizing two important classes of tricyclic nitrogen-containing skeleton, chiral dihydrophenanthridinone and dihydrocarbazolone derivatives bearing all-carbon quaternary centers, in excellent yields and enantioselectivities. The P-chiral monophosphorus ligand AntPhos is crucial for the reactivity and enantioselectivity, and the choice of the N-phosphoramide protecting group is essential for the desired chemoselectivity. This method has enabled the enantioselective total syntheses of three distinctive and challenging biologically important polycyclic alkaloids, specifically a concise and gram-scale synthesis of (-)-crinine, an efficient synthesis of indole alkaloid (-)-aspidospermidine and a formal enantioselective synthesis of (-)-minfiensine.


Cell death in ovarian chambers of Drosophila melanogaster.
An ultrastructural analysis has been made of certain ovarian chambers undergoing abnormal development. The earliest morphological change in these chambers consists of the alteration of the nuclear material which is then followed by engulfment of portions of the nurse cell cytoplasm, including the nuclear fragments, into the overlying follicle cells. The continuation of this process leads to the progressive disappearance of nurse cells with the concomitant formation of huge dense vacuoles in the follicle layer. The morphological features described in the present investigation are similar to those found in other tissues and interpreted as leading to cell death. It is suggested that certain ovarian chambers undergo cell death as a result of the incapability of furthering their development. The role played by cell death in oogenesis is also discussed on the basis of the current literature.


The Influence of Polysaccharides on Lipid Metabolism: Insights from Gut Microbiota.
Polysaccharides are complex molecules of more than ten monosaccharide residues interconnected through glycosidic linkages formed via condensation reactions. Polysaccharides are widely distributed in various food resources and have gained considerable attention due to their diverse biological activities. This review presented a critical analysis of the existing research literature on anti-obesity polysaccharides and investigates the complex interplay between their lipid-lowering activity and the gut microbiota, aiming to provide a comprehensive overview of the lipid-lowering properties of polysaccharides and the underlying mechanisms of action. In this review, the study summarized the roles of polysaccharides in improving lipid metabolism via gut microbiota, including the remodeling of the intestinal barrier, reduction of inflammation, inhibition of pathogenic bacteria, reduction of trimethylamine N-oxide (TMAO) production, and regulation of the metabolism of short-chain fatty acids (SCFAs) and bile acids (BAs). These mechanisms collectively contributed to the beneficial effects of polysaccharides on lipid metabolism and overall metabolic health. Furthermore, polysaccharide-based nanocarriers combined with gut microbiota have broad prospects for developing targeted and personalized therapies for hyperlipidemia and obesity.


Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.
Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.


[Colorectal cancer. Precancerous conditions].
Colorectal precancerous stages are primarily benign lesions of the colon mucosa with a potential to malignant degeneration. They are macroscopically seen as polypoid lesions, but not only "adenomas" are to be seen as precancerous. Polypoid lesions which are not of neoplastic origin are not capable of malignant degeneration. Precancerous dysplasias are also found in the flat atrophic mucosa of chronically inflamed colon mucosa , which complicates the macroscopical judgement in the endoscopy. Problems also arise for the pathologist in the separation between inflammatory regenerative epithelatypia and high-grade dysplasia.


Entorhinal and septal inputs differentially control sensory-evoked responses in the rat dentate gyrus.
Averaged sensory-evoked potentials were recorded from the outer molecular layer of the dentate gyrus in naïve rats and in rats conditioned to respond in the presence of an auditory stimulus. Two components (negative peaks) of the potentials were functionally distinguished in terms of responsiveness to unique or conditioned auditory stimuli. Each component was independently generated by a separate input pathway to the dentate gyrus: The perforant path provided an "insignificance" or "unexpected" feature of the sensory stimulus when appropriate, and the septum controlled the development of a second component as a function of the behavioral significance of the stimulus during the acquisition of auditory discrimination behavior. A reciprocal relationship between the peak amplitudes of both components of the average evoked potentials dependent on the relative behavioral significance of the sensory stimulus was observed in all animals during extinction and reconditioning of the sensory discrimination task. The findings indicate that the entorhinal and septal projections to the dentate granule cells are activated differentially by sensory stimuli as a function of their acquired behavioral significance to the animal.


Pyrocatechol violet as a marker to characterize liposomal membrane permeability using the chelation and the first-order derivative spectrophotometry.
Pyrocatechol violet (PV), a chelating agent for cupric ions was used to characterize liposomal membrane permeability. After cupric ions were added to PV liposomes, free PV turned into its chelate (PV-Cu), and encapsulated PV kept stable since liposomal membranes prevented metal ions from permeating. After the light scattering background of liposomes and the absorbance of PV were eliminated by the first-order derivative spectrophotometric method, PV-Cu i.e. free PV in liposome suspensions could be determined without separation. The released PV from liposomes could also be determined. Because PV release is relevant to liposomal membrane permeability, PV becomes a marker to characterize the membrane permeability. This new method was simple, rapid, sensitive, and was used to measure the temperature-dependent liposomal membrane permeability in this paper. Dipalmitoylphosphatidylcholine (DPPC) and soybean lecithin liposomes showed the peaks of release at 40 degrees C and 39 degrees C, respectively.


Molecular characterization of the mde operon involved in L-methionine catabolism of Pseudomonas putida.
A 15-kb region of Pseudomonas putida chromosomal DNA containing the mde operon and an upstream regulatory gene (mdeR) has been cloned and sequenced. The mde operon contains two structural genes involved in L-methionine degradative metabolism: the already-identified mdeA, which encodes L-methionine gamma-lyase (H. Inoue, K. Inagaki, M. Sugimoto, N. Esaki, K. Soda, and H. Tanaka. J. Biochem. (Tokyo) 117:1120-1125, 1995), and mdeB, which encodes a homologous protein to the homodimeric-type E1 component of pyruvate dehydrogenase complex. A rho-independent terminator was present just downstream of mdeB, and open reading frames corresponding to other components of alpha-keto acid dehydrogenase complex were not found. When MdeB was overproduced in Escherichia coli, the cell extract showed the E1 activity with high specificity for alpha-ketobutyrate rather than pyruvate. These results suggest that MdeB plays an important role in the metabolism of alpha-ketobutyrate produced by MdeA from L-methionine. Accordingly, mdeB encodes a novel E1 component, alpha-ketobutyrate dehydrogenase E1 component, of an unknown alpha-keto acid dehydrogenase complex in P. putida. In addition, we found that the mdeR gene was located on the opposite strand and began at 127 bp from the translational start site of mdeA. The mdeR gene product has been identified as a member of the leucine-responsive regulatory protein (Lrp) family and revealed to act as an essential positive regulator allowing the expression of the mdeAB operon.


Mathematical analysis of catabolic function loss in a population of Pseudomonas putida mt-2 during non-limited growth on benzoate.
Pseudomonas putida mt-2, harbouring the TOL plasmid PWW0, was grown continuously on benzoate in a phauxostat at a non-limited rate. The gradual decrease in the population carrying the complete TOL plasmid was caused predominantly by a growth-rate advantage of spontaneous mutants carrying a partially deleted plasmid (TOL- cells). The growth-rate difference (v) was quantified both by measuring the increase in the dilution rate (from 0.68 to 0.79 h-1; v = 0.11 h-1) and by mathematical analysis of the ingrowth of TOL- cells (v = 0.12 h-1). The latter procedure also established that the segregation rate was of the order of magnitude 10(-5) h-1. Similar values for the growth-rate advantage and the segregation rate were found when both benzoate and succinate were present in non-limiting concentrations. It is suggested that the growth-rate disadvantage of the wild-type strain is caused by inhibitory effects of an intermediate in the degradation of benzoate via the plasmid-encoded meta-pathway.


[Automatic perimetry in screening programs].
This work has studied the use of automatic perimetry in glaucoma screening programs. Subjects with suspicious glaucoma were selected on the basis of tonometry and direct ophthalmoscopy. Visual fields were analyzed using the G1 program of the Octopus 500 E automatic perimeter. A prevalence of 3.49% of glaucoma was observed in persons above 40 years old. This represents a higher incidence in comparison to other studies. The inclusion only of those subjects with suspicious glaucoma for automatic perimetry has resulted in a more precise and earlier diagnosis of glaucoma without unduly prolonging the duration of the study. Undoubtedly, automatic perimetry can improve both the reliability of the diagnosis and incidence of glaucoma in screening programs. Moreover, this does not necessarily mean more prolonged or costly studies.


Addiction, physical dependence, and tolerance: precise definitions to help clinicians evaluate and treat chronic pain patients.
Pain is among the most common complaints for which people seek medical care; yet pain is also among the most undertreated patient complaints. Reasons for this include reluctance by clinicians to prescribe and support the use of opioids, often due to a fear of addiction. To address this issue, three major health professional organizations that deal with the treatment of pain and addiction, the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine, formed the Liaison Committee on Pain and Addiction (LCPA). The first mission of the LCPA was to formulate precise definitions of the terms addiction, physical dependence, and tolerance. This report explains these definitions and discusses how they apply to clinical practice.


Comparison of higher-dose intradermal hepatitis B vaccination to standard intramuscular vaccination of healthcare workers.
To compare the immunogenicity of hepatitis B vaccine administered via intradermal (ID) versus intramuscular (IM) route. Subjects chose either to specify the route of immunization or to undergo random allocation to vaccination by the ID (0.15 mL) or the IM (1.0 mL) route. Yeast-derived recombinant hepatitis B vaccine was given at 0, 30, and 180 days. Hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) were measured by microparticle enzyme immunoassay. 763 subjects were enrolled. Baseline screening identified 65 subjects (8%) who were positive for HBsAb or HBcAb. Vaccination was completed by 590 (85%) of 698 enrollees (370 ID, 220 IM). Seroconversion rates (geometric mean titers [GMT]>0 IU/mL HBsAb) for those vaccinated ID were 99% and 96% for screening at 9 months and 1 year post-vaccination, respectively; subjects vaccinated intramuscularly had similar rates of 95% and 96%. Seropositivity rates (GMT > or = 10 IU/mL HBsAb) showed a similar pattern, with 95%, 92%, and 73% at 9 months and 1 and 2 years, respectively, for those vaccinated ID, and 94%, 93%, and 81% for those having IM vaccination. GMT for HBsAb was significantly higher for individuals vaccinated IM than for those vaccinated ID (P<.0001). The GMT ratio for the IM and ID routes decreased over time, being 9.3 at 9 months, 7.8 at 1 year, and 5.9 at 2 years. An unanticipated side effect of intradermal vaccination was skin discoloration at injection sites, which persisted for at least 2 years postvaccination. Two thirds (112/166) of respondents reported that they would have selected the ID route despite the discoloration. Higher-dose ID vaccination (3 vs 1 microg per injection) uses one sixth of the dose required for standard IM vaccination. It is a cost-effective way to vaccinate populations against hepatitis B virus, but the long-term efficacy of the ID route must still be investigated.


The in vivo delivery of heterologous proteins by microencapsulated recombinant cells.
The microencapsulation of recombinant cells is a novel and potentially cost-effective method of heterologous protein delivery. A 'universal' cell line, genetically modified to secrete any desired protein, is immunologically protected from tissue rejection by enclosure in microcapsules. The microcapsule can then be implanted in different recipients to deliver recombinant proteins in vivo.


Infection with hepatitis A and TT viruses and socioeconomic status in Rio de Janeiro, Brazil.
The prevalence of antibodies directed against the enterically transmitted hepatitis A virus (HAV) was measured in 2 groups of people living in Rio de Janeiro, Brazil. Of 1,056 health care workers (HCWs), 778 (73.7%) were anti-HAV positive. A high prevalence of anti-HAV antibodies (85.7%) was also found among 274 voluntary blood donors (BDs). TT virus (TTV) is a DNA virus that has been found in the sera of patients with post-transfusion hepatitis of unknown etiology. Occurrence of virus shedding suggests that the fecal-oral route may be an important mode of TTV transmission, particularly in the developing world. The presence of TTV DNA was analyzed by PCR in the sera of 191 HCWs and 151 BDs. TTV was detected in 65.4% of HCWs and 79.5% of BDs. In both groups, a family income of < US$400 per month and a level of education of < 11 y of schooling were found to be risk factors for HAV infection. Furthermore, a low family income was associated with TTV viremia in the HCW group. However, the presence of TTV DNA was associated with neither low level of education nor anti-HAV positivity.


Valuing quality of life and improvements in glycemic control in people with type 2 diabetes.
Outcomes research is used increasingly for assessing the health economic benefits of new therapeutic programs and interventions. The measurement properties of the outcomes assessment tools are important. If overlooked, they can mislead health care administrators and caregivers regarding the importance and value of these programs and interventions. We reviewed the literature and conducted two analyses to determine the absolute, relative, and operative quality-of-life ranges for people with type 2 diabetes. Quality of life and fasting blood glucose and HbA1c concentrations were measured at baseline and at 4, 8, and 12 weeks of treatment in 569 men and women randomized to either glipizide gastrointestinal therapeutic system (GITS) or placebo in a double-blind, multicenter clinical trial. A subgroup of 290 patients completed a diabetes-specific health states questionnaire at endpoint (week 12 or early termination) rating 10 health-state descriptions on a health thermometer scale ranging from 0 (death) to 100 (full health). Health losses at the higher end of the scale had a greater negative utility than did comparable losses at lower health states, indicating patients' strong preferences for maintaining asymptomatic or mildly symptomatic conditions. Patients rated their current health state at 83.4 +/- 0.8% of full health and indicated that a loss of 27 points below this value would prevent them from living and working as they currently do. The calibration analysis applied to the quality-of-life scales suggested that the targeted range for clinical investigation and quality-of-care evaluation must be more narrowly focused. Effect sizes as seemingly small as 2% (0.25 responsiveness units) on the absolute scale can correspond to quality-of-life losses of 15-20% on the personal operative scale. Differences in glycemic control clearly affected quality of life. Those patients with the best HbA1c responses (decreasing 1.5% or more from baseline) versus those with the worst responses (increasing 1.5% or more from baseline) were separated by 0.6 responsiveness units for the overall quality-of-life summary measure. The calibration analysis suggested that this degree of better glycemic control provides a nearly 50% gain in quality of life according to personal expectations within the operative range. In conclusion, general measures of quality of life may be too crude and insensitive to capture the important gains in health outcomes due to new therapeutic interventions and programs in diabetes. Quality-of-care evaluations for diabetes are at risk of favoring inferior programs with lower costs simply because gains or losses in health outcomes go undetected.


Tamponade efficiency of perfluorohexyloctane and silicone oil solutions in a model eye chamber.
As no single tamponade agent yet fulfils all the requirements of a long term inferior tamponade, attempts have been made to mix tamponade materials. This study investigated perfluorohexyloctane (F(6)H(8)) and silicone oil solutions designed to take advantage of the high specific gravity and interfacial tension of the F(6)H(8) and the high viscosity of silicone oil. Solutions of three different densities were examined (1.01, 1.03 and 1.06 g/cm(3)) inside transparent chambers made of surface modified poly(methylmethacrylate) (PMMA). Compared to F(6)H(8), the solutions had poorer contact with hydrophilic surface of the chambers. The higher the specific gravity of the solution, the better was the contact. The solution with a specific gravity 1.01 g/cm(3) is probably of no use clinically. The model eye chamber made of surface modified PMMA is an efficient way of screening and choosing solutions with promising physical properties. Solutions of silicone oil with F(6)H(8) in other proportions or with other semifluorinated alkanes may be of interest.


CARD11 blockade suppresses murine collagen-induced arthritis via inhibiting CARD11/Bcl10 assembly and T helper type 17 response.
The scaffold protein caspase recruitment domain-containing protein 11 (CARD11) is implicated in the regulation of inflammation and autoimmunity. The present study aimed to explore the role of CARD11 in the pathogenesis of rheumatoid arthritis (RA). Mice with collagen-induced arthritis (CIA) were treated with either CARD11-targeted interfering RNA (CARD11 siRNA) or control siRNA by intraperitoneal injection every 3 days after CIA establishment. The clinical score of arthritis was recorded every other day. Synovial inflammation and cartilage erosion were evaluated by histology and microcomputed tomography (micro-CT). Serum anti-type II collagen (anti-CII) antibodies and cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The CARD11/Bcl10 formation and nuclear factor-kappa B (NF-κB) activation was assessed by immunoprecipitation and immunoblotting, and the percentage of T helper type 17 (Th17) cells was determined by flow cytometry. Systemic administration of CARD11 siRNA significantly reduced the clinical score of CIA severity. As indicated by the histology, joint inflammation and destruction were attenuated by CARD11 siRNA treatment. Micro-CT demonstrated less severe joint destruction in CARD11 siRNA-treated mice than in control mice. CARD11 siRNA treatment resulted in inhibition of CARD11/Bcl10 formation and the subsequent NF-κB activation. In addition, treatment with CARD11 siRNA resulted in a pronounced decrease in proinflammatory cytokines interleukin (IL)-1β, IL-6 and IL-17. Serum anti-CII antibody and the percentage of Th17 cells were also significantly reduced. CARD11 is involved in the pathogenesis of CIA by formation of the CARD11/Bcl10 complex and enhancement of the Th17 cell response. Targeting CARD11 provides a novel research direction in the development of therapeutic strategies for RA.


Bone conducted responses in the neonatal rat auditory cortex.
Rats are born deaf and start hearing at the end of the second postnatal week, when the ear canals open and low-intensity sounds start to evoke responses in the auditory cortex. Here, using μECoG electrode arrays and intracortical silicon probe recordings, we found that bone-conducted (BC) sounds evoked biphasic responses in the auditory cortex starting from postnatal day (P) 8. The initial phase of these responses, generated by thalamocortical input, was followed by intracortical propagation within supragranular layers. BC-evoked responses co-localized with the responses evoked by electrical stimulation of the cochlea and the deepest layers of the inferior colliculus prior to onset of low-threshold hearing (P13), as well as with the responses evoked by high-frequency (30 kHz) low-intensity (70 dB) air-conducted sounds after that. Thus, BC signals reach high-frequency processing regions of the auditory cortex well before the onset of low-threshold hearing, reflecting early integrity of the auditory system.


Comparison of pharmacist managed anticoagulation with usual medical care in a family medicine clinic.
The beneficial outcomes of oral anticoagulation therapy are dependent upon achieving and maintaining an optimal INR therapeutic range. There is growing evidence that better outcomes are achieved when anticoagulation is managed by a pharmacist with expertise in anticoagulation management rather than usual care by family physicians. This study compared a pharmacist managed anticoagulation program (PC) to usual physician care (UC) in a family medicine clinic. A retrospective cohort study was carried out in a family medicine clinic which included a clinical pharmacist. In 2006, the pharmacist assumed anticoagulation management. For a 17-month period, the PC group (n = 112) of patients on warfarin were compared to the UC patients (n = 81) for a similar period prior to 2006. The primary outcome was the percentage of time patients' INR was in the therapeutic range (TTR). Secondary outcomes were the percentage of time in therapeutic range within ± 0.3 units of the recommended range (expanded TTR) and percentage of time the INR was >5.0 or <1.5. The baseline characteristics were similar between the groups. Fifty-five percent of the PC group was male with a mean age of 67 years; 51% of the UC group was male with a mean age of 71 years. The most common indications for warfarin in both groups were atrial fibrillation, mechanical heart valves and deep vein thrombosis. The TTR was 73% for PC and 65% for UC (p < 0.0001). The expanded TTR for PC was 91% and 85% for UC (p < 0.0001). The percentage of time INR values were <1.5 was 0.7% for PC patients and 1.9% for UC patients (p < 0.0001), and >5 were 0.3% for PC patients and 0.1% for UC (p < 0.0001). The pharmacist-managed anticoagulation program within a family practice clinic compared to usual care by the physicians achieved significantly better INR control as measured by the percentage of time patients' INR values were kept in both the therapeutic and expanded range. Based on the results of this study, a collaborative family practice clinic using pharmacists and physicians may be an effective model for anticoagulation management with these results verified in future prospective randomized studies.


An efficient, tunable, and robust source of narrow-band photon pairs at the 87Rb D1 line.
We present an efficient and robust source of photons at the 87Rb D1-line (795 nm) with a narrow bandwidth of δ = 226(1) MHz. The source is based on non-degenerate, cavity-enhanced spontaneous parametric down-conversion in a monolithic optical parametric oscillator far below threshold. The setup allows for efficient coupling to single mode fibers. A heralding efficiency of ηheralded = 45(5) % is achieved, and the uncorrected number of detected photon pairs is 3.8 × 103/(s mW). For pair generation rates up to 5 × 105/s, the source emits heralded single photons with a normalized, heralded, second-order correlation function g c(2)<0.01. The source is intrinsically stable due to the monolithic configuration. Frequency drifts are on the order of δ/20 per hour without active feedback on the emission frequency. We achieved fine-tuning of the source frequency within a range of >2 GHz by applying mechanical strain.


Natural history of murine gamma-herpesvirus infection.
Murine gamma-herpesvirus 68 (MHV-68) is a natural pathogen of small rodents and insectivores (mice, voles and shrews). The primary infection is characterized by virus replication in lung epithelial cells and the establishment of a latent infection in B lymphocytes. The virus is also observed to persist in lung epithelial cells, dendritic cells and macrophages. Splenomegaly is observed two weeks after infection, in which there is a CD4+ T-cell-mediated expansion of B and T cells in the spleen. At three weeks post-infection an infectious mononucleosis-like syndrome is observed involving a major expansion of Vbeta4+CD8+ T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characterized as lymphomas of B-cell origin. The genome from MHV-68 strain g2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma-herpesviruses. The genome includes cellular homologues for a complement-regulatory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of novel genes M1 to M4. The function of these genes in the context of latent infections, evasion of immune responses and virus-mediated pathologies is discussed. Both innate and adaptive immune responses play an active role in limiting virus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the initial stages of infection. In contrast, type II IFN is not essential for the recovery from infection in the lung, but a failure of type II IFN receptor signalling results in the atrophy of lymphoid tissue associated with virus persistence. Splenic atrophy appears to be the result of immunopathology, since in the absence of CD8+ T cells no pathology occurs. CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product. CD4+ T cells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4+ T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly the memory CD8+ T cells generated are unable to inhibit virus recurrences in the lung. This could be explained in part by the observations that this virus can downregulate major histocompatibility complex class I expression and also restrict inflammatory cell responses by producing a chemokine-binding protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma-herpesvirus infection through vaccination and chemotherapy. Vaccination with gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reduction in splenomegaly and virus latency but does not block replication in the lung, nor the establishment of a latent infection. Even when lung virus infection is greatly reduced following the action of CD8+ T cells, induced via a prime-boost vaccination strategy, a latent infection is established. Potent antiviral compounds such as the nucleoside analogue 2'deoxy-5-ethyl-beta-4'-thiouridine, which disrupts virus replication in vivo, cannot inhibit the establishment of a latent infection. Clearly, devising strategies to interrupt the establishment of latent virus infections may well prove impossible with existing methods.


Decision model of segmental compared with total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer.
In choosing the appropriate surgical option for patients with colon cancer and Lynch syndrome, goals of treatment are to maximize life expectancy while preserving quality of life. This study constructs a decision model that encompasses these two related considerations. We constructed a state-transition (Markov) model based on assumptions obtained from available data sources and published literature. Two strategies were considered for the treatment of colon cancer in a patient with Lynch syndrome: segmental colectomy (SEG) and total abdominal colectomy (TAC) with ileorectal anastomosis. Quality-adjusted life years (QALYs) were calculated based on utility states for patients based on the colectomy they received. Multiple sensitivity analyses were planned to examine the impact of each assumption on model results. For young (30-year-old) patients with Lynch syndrome, mean survival was slightly better with TAC than with SEG (34.8 v 35.5 years). When QALYs were considered, the two strategies were approximately equivalent, with QALYs per patient of 21.5 for SEG and 21.2 for TAC. With advancing age, SEG becomes a more favorable strategy. Results of our model were most sensitive to the utility state of TAC (relative to SEG), rates of metachronous occurrence, and stage of cancer at the time of such occurrence. SEG and TAC are approximately equivalent strategies for patients with colon cancer and Lynch syndrome. The decision regarding which operation is preferable should be made on the basis of patient factors and preferences, with special emphasis on age and the ability of the patient to utilize intensive surveillance.


The antidyskinetic action of dihomo-gamma-linolenic acid in the rodent.
The antidyskinetic action of dihomo-gamma-linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea-pig by dopamine injected into the striatum (200 micrograms bilateral 2 h after nialamide, 75 mg kg-1, i.p.) and in the guinea-pig and rat by 2-di-n-propylamino-5, 6-dihydroxytetralin (tetralin), 0.025 mg kg-1, s.c. Dopamine and tetralin-induced dyskinesias in the guinea-pig were reduced or abolished by DHLA given i.p., 30-100 mg kg-1, given once daily for 5-10 days. Tetralin-induced dyskinesias were antagonized by DHLA given orally to the guinea-pig (50-200 mg kg-1, 5 days) or in the diet to the rat (approximately 200 mg kg-1 daily for 10-14 days). DHLA injected into the striatum (2.5-20 micrograms bilateral, 2-4 days) also antagonized tetralin-induced dyskinesias in the rat. The antidyskinetic action of DHLA given i.p. to the guinea-pig could be antagonized by aspirin or eicosa-5,8,11,14-tetraynoic acid (100 mg kg-1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25-100 mg kg-1, i.p.) dose-dependently antagonized the antidyskinetic activity of 5 and 20 micrograms DHLA given bilaterally into the striatum (2 days). DHLA (100 mg kg-1 i.p.) given daily for 10 days or approximately 200 mg kg-1 DHLA (daily for 10-14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg-1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg-1 i.p. 7 It is suggested that the selective inhibition of dyskinesias in the rodent by DHLA may reflect a striatal effect with a dependency on conversion to prostaglandins.


Mono(ADP-ribosyl)transferase genes and diabetes in NOD mice. Is there a relationship?
The answer to the question posed by the title (is there a relationship between aberrant Art gene expression and IDDM pathogenesis in NOD mice?) remains elusive. Conclusions are currently based almost entirely upon analysis of mRNA transcript levels rather than on T-cell-specific mono-ADP ribosylation activities. Our unpublished data, as well as data published in abstract form by Dr. L. Chatenoud and colleagues (48) indicate that gene transcription is not impaired in splenic leukocytes of older NOD mice, including those with spontaneous IDDM development. Based upon the limited data showing that there may be reduced expression of Art gene products in the earliest T cell immigrants from the NOD thymus, one would have to surmise that If there is a regulatory defect, it may be in allowing single positive thymic T cells to emigrate before they are fully mature. Therefore, development of anti-Art monoclonal antibody together with further studies regarding functions of mono(ADP-ribosyl)transferase in immunoregulation of different subpopulation of T-cells, may finally resolve the role that altered mono(ADP-ribosyl)transferase activities play in the pathogenesis of IDDM in NOD mice.


Fisetin Enhances the Cytotoxicity of Gemcitabine by Down-regulating ERK-MYC in MiaPaca-2 Human Pancreatic Cancer Cells.
Pancreatic cancer is a highly lethal malignancy with a poor prognosis. This study was set up to investigate the combined effect of gemcitabine and fisetin, a natural flavonoid from plants, on human pancreatic cancer cells. Meterials and Methods: Cytotoxic effect of fisetin in combination with gemcitabine on MiaPaca-2 cells was evaluated by the MTT assay, caspase 3/7 assay and propidium iodide/Annexin V. Extracellular signal-regulated kinase (ERK)-v-myc avian myelocytomatosis viral oncogene homolog (MYC) pathway was investigated by western blotting and quantitative real-time polymerase chain reaction. Combination treatment with fisetin and gemcitabine inhibited the proliferation of pancreatic cancer cells within 72 h and induced apoptosis, as indicated by activation of caspase 3/7. Fisetin down-regulated ERK at the protein and mRNA levels, and reduced ERK-induced MYC instability at the protein level. Fisetin sensitized human pancreatic cancer cells to gemcitabine-induced cytotoxicity through inhibition of ERK-MYC signaling. These results suggest that the combination of fisetin and gemcitabine could be developed as a novel potent therapeutic.


The Northern Swedish Population Health Study (NSPHS)--a paradigmatic study in a rural population combining community health and basic research.
Health care and research in rural populations are often limited due to poor infrastructure and small sample sizes. However, such populations have a need for medical care and can be of great value when studying the health effects of lifestyle and genetic factors. The Northern Sweden Population Health Study (NSPHS) is a paradigmatic study that combines a survey of the health status and specific needs of the community with basic research into the environmental and genetic determinants of non-communicable diseases. This article presents the NSPHS results on lifestyle, subclinical, and clinical measures and gives a review of the past contributions of this study to our understanding of the genetic determinants of disease in international collaborations. A population-representative, cross-sectional sample (n=656) was examined from the Karesuando parish in Northern Sweden north of the Arctic Circle. The population consists of individuals living a traditional, subsistence-based lifestyle (TLS, n=96), mainly based on reindeer herding, hunting and fishing, and others following a modern, more industrialized lifestyle (MLS, n=560), similar to other western European countries. Subgroups with a modern versus traditional lifestyle were compared separately in men and women, highlighting differences in lifestyle (eg diet, physical activity), subclinical (eg blood circulation, blood lipids, lung function) and clinical measures (eg disorders of the cardiovascular, metabolic, and musculoskeletal system). TLS men and women consumed much more game meat (Men: 71 vs 194 g/day, p=0.0011; Women: 56 vs 140 g/day, p=0.0020) and less non-game meat (Men: 88 vs 42 g/day, p=1.4x10(-7); Women: 81 vs 42 g/day, p=0.026) compared with the respective MLS group. TLS men consumed less milk (p=4.2x10(-4)), and TLS women less vegetables (p=0.042). TLS men reported more physical activity at work (p=0.042) and TLS women less physical activity at leisure (p=0.0023). Total cholesterol (Men: 220 vs 244 mg/dl, p=0.0031; Women: 225 vs 246 mg/dl, (p=0.049) and LDL cholesterol levels (Men: 134 vs 153 mg/dl, p=0.012; Women: 133 vs 146 mg/dl, p>0.05) were higher in the blood serum of TLS men and women than in the MLS comparison group. While TLS women showed a higher rate of myocardial infarction (5% vs 16%, p=0.024), TLS men reported a dramatically higher frequency of body pain consistently, for example in the lower back (0% vs 25%; p>0.05). A consistent pattern was found of differences between individuals living a traditional versus modern lifestyle and between the sexes, identifying specific health risks for each group. Women with a traditional lifestyle were exposed to a greater risk for cardiovascular disease (especially myocardial infarction) and men with a traditional lifestyle reported higher rates of orthopedic symptoms (eg body pain). We also show that studies of rural populations can make a substantial contribution to basic research into understanding the environmental and genetic determinants of disease. The European Special Populations Research Network (EUROSPAN) provided an excellent example of a platform combining studies of rural populations from different parts of Europe that can leverage these for collaboration with large international consortia.


Identification and quantification of caffeic and rosmarinic acid in complex plant extracts by the use of variable-temperature two-dimensional nuclear magnetic resonance spectroscopy.
A combination of advanced nuclear magnetic resonance (NMR) methodologies for the analysis of complex phenolic mixtures that occur in natural products is described, with particular emphasis on caffeic acid and its ester derivative, rosmarinic acid. The combination of variable-temperature two-dimensional proton-proton double quantum filter correlation spectroscopy (1H-1H DQF COSY) and proton-carbon heteronuclear multiple quantum coherence (1H-13C HMQC) gradient NMR spectroscopy allows the identification and tentative quantification of caffeic and rosmarinic acids at 243 K in extracts from plants of the Lamiaceae family, without resorting to previous chromatographic separation of the components. The use of proton-carbon heteronuclear multiple bond correlation (1H-13C HMBC) gradient NMR spectroscopy leads to the complete assignment of the correlations of the spins of H2a and H3a with the ester and carboxyl carbons of rosmarinic and caffeic acid, even at room temperature, and confirms the results of the above methodology Quantitative results are in reasonable agreement with reverse phase HPLC measurements.


Scanning electron microscopy of epididymal ducts in the Japanese monkey (Macacus fuscatus) with special reference to the architectural analysis of stereocilia.
The luminal surface of the initial segment of the epididymal duct in the Japanese monkey was observed under a field emission type scanning electron microscope. The long, slender stereocilia projecting from the apical surface of the columnar cells were found to be closely arranged in a funnel-like form opening to the lumen. The funnels formed by stereocilia were also confirmed by observation of thin sections cut from the same specimen used for scanning electron microscopy and their bottom was located in the center of the vertex of each columnar cell.


The chirality of imazethapyr herbicide selectively affects the bacterial community in soybean field soil.
The chiral herbicide imazethapyr (IM) is frequently used to control weeds in soybean fields in northeast China. However, the impact of IM enantiomers on microbial communities in soil is still unknown. Genetic markers (16S rRNA V3-V4 regions) were used to characterize and evaluate the variation of the bacterial communities potentially effected by IM enantiomers. Globally, the bacterial community structure based on the OTU profiles in (-)-R-IM-treated soils was significantly different from those in (+)-S-IM-treated soils, and the differences were enlarged with the treatment dose increasing. Interestingly, the Rhizobiaceae family and several other beneficial bacteria, including Bradyrhizobium, Methylobacterium, and Paenibacillus, were strongly enriched in (-)-R-IM treatment compared to (+)-S-IM treatment. In contrast, the pathogenic bacteria, including Erwinia, Pseudomonas, Burkholderia, Streptomyces, and Agrobacterium, were suppressed in the presence of (-)-R-IM compared to (+)-S-IM. Furthermore, we also observed that the bacterial community structure in (-)-R-IM-treated soils was more quickly restored to its original state compared with those in (+)-S-IM-treated soils. These findings unveil a new role of chiral herbicide in the development of soil microbial ecology and provide theoretical support for the application of low-persistence, high-efficiency, and eco-friendly optical rotatory (-)-R-IM.


Light-efficient, quantum-limited interferometric wavefront estimation by virtual mode sensing.
We describe and analyze an interferometer-based virtual modal wavefront sensor (VMWS) that can be configured to measure, for example, Zernike coefficients directly. This sensor is particularly light efficient because the determination of each modal coefficient benefits from all the available photons. Numerical simulations show that the VMWS outperforms state-of-the-art phase unwrapping at low light levels. Including up to Zernike mode 21, aberrations can be determined with a precision of about 0.17 rad (lambda/37) using low resolution (65 x 65 pixels) images and only about 400 photons total.


Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination.
Intrathecal immunoglobulin G (IgG) synthesis, cerebrospinal fluid (CSF) oligoclonal IgG bands and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Both the specific targets and pathogenic effects of MS antibodies remain poorly characterized. We produced IgG1 monoclonal recombinant antibodies (rAbs) from clonally-expanded plasmablasts recovered from MS patient CSF. Among these were a subset of myelin-specific MS rAbs. We examined their immunoreactivity to mouse organotypic cerebellar slices by live binding and evaluated tissue injury in the presence and absence of human complement. Demyelination, glial and neuronal viability, and complement pathway activation were assayed by immunofluorescence microscopy and compared to the effects of an aquaporin-4 water channel (AQP4)-specific rAb derived from a neuromyelitis optica (NMO) patient. MS myelin-specific rAbs bound to discrete surface domains on oligodendrocyte processes and myelinating axons. Myelin-specific MS rAbs initiated complement-dependent cytotoxicity to oligodendrocytes and induced rapid demyelination. Demyelination was accompanied by increased microglia activation; however, the morphology and survival of astrocytes, oligodendrocyte progenitors and neurons remained unaffected. In contrast, NMO AQP4-specific rAb initiated complement-dependent astrocyte damage, followed by sequential loss of oligodendrocytes, demyelination, microglia activation and neuronal death. Myelin-specific MS antibodies cause oligodendrocyte loss and demyelination in organotypic cerebellar slices, which are distinct from AQP4-targeted pathology, and display seminal features of active MS lesions. Myelin-specific antibodies may play an active role in MS lesion formation through complement-dependent mechanisms.


[Screening for autoimmune polyglandular syndrome in a cohort of patients with type 1 diabetes mellitus].
To characterize a cohort of patients with type 1 diabetes mellitus (T1DM) on the presence of other autoimmune disorders that could establish the diagnosis of autoimmune polyglandular syndrome (APS). We included 151 patients with T1DM. The following clinical parameters were analyzed: gender, current age, disease duration, previous history of autoimmune disorders, and familial history for diabetes mellitus. Each patient was analyzed to detect autoimmune markers of thyroiditis, adrenocortical insufficiency, gastritis, and celiac disease, as well as possible associated dysfunctions. A cohort with 51.7% males, average current age of 33.4 ± 13 years and disease duration of 14.4 ± 9.6 years was analyzed. Previous history of autoimmunity was found in 2%, and familial history for diabetes mellitus in 31.1% of the cohort. Frequency of autoimmune markers was 24% for thyroiditis, 9.4% for adrenocortical insufficiency, 17.2% for gastritis, and 2% for celiac disease. APS was diagnosed on 25.2% of the patients. APS and autoimmune thyroiditis risk was higher in females. Disease duration correlated directly with gastric autoantibodies, and inversely with positive islet cell, glutamic acid decarboxylase, and tyrosine phosphatase antibodies. We noticed a correlation between autoimmune markers for thyroiditis and gastritis, as well as between celiac disease and adrenocortical insufficiency. Considering APS prevalence and prognosis, the need for APS screening in patients with T1DM is emphasized. Early diagnosis of other autoimmune disorders will enable us to adjust each patient treatment and follow-up.


Ameliorating effects of anti-Dll4 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease.
We examined the role of Notch ligand Delta-like 4 (Dll4) in the development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). Treatment with mAb to Dll4, especially during the effector phase, resulted in significant suppression of the disease development both clinically and histologically. The number of infiltrating mononuclear inflammatory cells in the spinal cords was also decreased in mice treated with anti-Dll4 mAb. Semi-quantitative analysis of mRNA by using real-time PCR revealed that mRNAs of T(h)1-derived cytokines such as IFN-gamma and T(h)17-derived cytokines such as IL-17 were decreased in mice treated with anti-Dll4 mAb, whereas those of T(h)2-derived cytokines such as IL-4 and IL-10 were not. Flow cytometric analysis of cytokines indicated that there were no significant differences between mAb-treated mice and control mice in the relative frequency of splenic T(h)1 and T(h)2. However, absolute cell numbers of T(h)1-derived cytokine-producing cells in spinal cord were markedly decreased in mice treated with anti-Dll4 mAb in effector phase compared with control mice treated with non-specific IgG. These data suggest that Dll4 is critically involved in the pathogenesis of TMEV-IDD and that antibodies to Dll4 could be used as a novel therapeutic treatment of demyelinating diseases such as human multiple sclerosis.