Cholesterol and mevalonic acid are independent requirements for the in vitro proliferation of human bone marrow granulocyte progenitor cells: studies using ML-236B.
ML-236B is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the key regulatory enzyme in the sequence that catalyzes the conversion of acetate to mevalonic acid in cholesterol biosynthesis. This compound caused marked inhibition of human bone marrow granulocyte progenitor cell (CFU-C) proliferation, the 50% inhibitory concentration (IHD50) being 2.0 X 10(6)M. Inhibition of colony formation was reversed by mevalonic acid but not by cholesterol. ML-236B also inhibited DNA synthesis and acetate incorporation into cholesterol in marrow mononuclear cells (IHD50 = 5.6 x 10(6)M and 3.2 x 10(7)M, respectively). No inhibition of mevalonate incorporation into cholesterol was observed. These results differ from those observed with 25-hydroxycholesterol, another inhibitor of HMG CoA reductase. The latter compound also inhibited CFU-C proliferation and cholesterol biosynthesis from acetate; inhibition of colony formation was reversed by cholesterol but not by mevalonic acid. In addition, 25-hydroxycholesterol inhibited cholesterol synthesis from mevalonic acid precursor. We conclude that: (1) ML-236B is a potent inhibitor of CFU-C proliferation, DNA synthesis, and cholesterol biosynthesis from acetate precursor in marrow mononuclear cells; (2) the effects of ML-236B are completely reversed by mevalonic acid but not by cholesterol, suggesting that mevalonic acid per se or one or more of its nonsterol products are critical for cell growth; (3) the inhibitory effects of 25-hydroxycholesterol on CFU-C proliferation and cholesterol biosynthesis are not solely a result of its inhibition of HMG CoA reductase, but are due in part to inhibition of enzymatic steps distal to mevalonic acid in the sterol synthetic pathway; and (4) mevalonic acid and cholesterol are independent requirements for CFU-C proliferation and differentiation in vitro.


Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson's disease patients.
The pathogenesis of Parkinson's disease (PD) involves both genetic susceptibility and environmental factors, with focus on the mutation in the alpha-synuclein gene (SNCA).Objective To analyse the polymorphism SNCA-A53T in patients with familial PD (FPD) and sporadic PD (SPD). A total of 294 individuals were studied, regardless of sex and with mixed ethnicity. The study group with 154 patients with PD, and the control group included 140 individuals without PD. The genotyping of SNCA-A53T was performed by PCR/RFLP. Significance level was p < 0.05. Among all patients, 37 (24%) had FPD and 117 (75.9%) had SPD. The absence of SNCA-A53T mutation was observed in all individuals. SPD is notably observed in patients. However, the SNCA-A53T mutation was absent in all individuals, which does not differ controls from patients. This fact should be confirmed in a Brazilian study case with a more numerous and older population.


Business management and the environment of care standards.
In summary, the entire JCAHO manual is built around the concept of "know thyself." This expectation creates the need to engage in a substantial rework of existing practices to remove communication barriers and to eliminate turf warfare. The focus of the standards is on the patient. All aspects of the patient-care delivery cycle are examined during survey, as are key elements of the business-management activities. The EC standards are a case study of business management. They expect leadership and planning, development of human resources, management of information, and improvement of performance. They expect that all four of these management tools will be exercised by all managers and staff members who have an impact on or are impacted by the seven elements of the EC function. The primary focus is on teamwork among providers and maximizing benefits to patients.


Impact of the uremic milieu on the osteogenic potential of mesenchymal stem cells.
Human mesenchymal stem cells (hMSCs), the precursors of osteoblasts during osteogenesis, play a role in the balance of bone formation and resorption, but their functioning in uremia has not been well defined. To study the effects of the uremic milieu on osteogenic properties, we applied an in vitro assay culturing hMSCs in osteogenic medium supplemented with serum from healthy donors and from uremic patients on hemodialysis. Compared to control, serum from uremic patients induces, in hMSC cultures, a modification of several key regulators of bone remodeling, in particular a reduction of the ratio Receptor Activator of Nuclear factor Kappa B Receptor (RANKL) over osteoprotegerin, indicating an adaptive response of the system to favor osteogenesis over osteoclastosis. However, the levels of osteopontin, osteocalcin, and collagen type I, are increased in cell medium, while BMP-2, and alizarin red staining were decreased, pointing to a reduction of bone formation favoring resorption. Selected uremic toxins, such as p-cresylsulfate, p-cresylglucuronide, parathyroid hormone, indoxyl sulfate, asymmetric dimethylarginine, homocysteine, were able to mimic some of the effects of whole serum from uremic patients. Serum from cinacalcet-treated patients antagonizes these effects. Hydrogen sulfide (H2S) donors as well as hemodialysis treatment are able to induce beneficial effects. In conclusion, bone modifications in uremia are influenced by the capability of the uremic milieu to alter hMSC osteogenic differentiation. Cinacalcet, H2S donors and a hemodialysis session can ameliorate the hampered calcium deposition.


[Nature of the diabetogenic factor of blood plasma in clinical and experimental diabetes].
A homogeneous diabetogenic factor (HDF), an albumin with the molecular mass of 60 000 daltons, was isolated from the blood of people and animals with diabetes mellitus. An i.v. injection of HDF to intact rats resulted in a prolonged and stable hyperglycemia. HDF hyperglycemic activity was completely blocked in the recipients by the injection of appropriate heparin doses.


Ureteroscopic cytologic diagnosis of upper tract lesions.
The definitive diagnosis of upper urinary tract lesions often relies on providing adequate tissue samples for cytopathologic review. Uretreopyeloscopy allows direct examination of these lesions and enables tissue sampling under visual control. A retrospective analysis of 11 patients with 13 abnormal upper tracts was performed, comparing sampling techniques performed under endoscopic vision (brush biopsy, fine-needle aspiration [FNA], and forceps biopsy) with standard retrograde catheter lavage. Forceps biopsy was the most accurate of the direct vision sampling methods (100%), although it provided adequate tissue only 56% of the time. Direct vision brush biopsy and FNA were better than forceps biopsy at providing adequate tissue but were less accurate, at 83% and 89%, respectively. Surprisingly, retrograde catheter lavage was superior to direct vision sampling methods. These results may be attributable to patient selection bias in that five of seven upper tracts found to have malignancy had multifocal disease. One patient developed a distal ureteral stricture from instrumentation that was managed successfully with an endoureterotomy.


Promoting professional behaviour in undergraduate medical, dental and veterinary curricula in the Netherlands: evaluation of a joint effort.
From 2002 onwards, a nationwide working group of representatives from all medical (8), dental (3) and veterinary medicine (1) schools collaborated in order to develop and implement recommendations for teaching and assessing professional behaviour. The aim of this article is to describe the outcomes of this process, including hurdles encountered and challenges to be met. By a qualitative survey, information was requested on teaching professional behaviour, assessment, instruments used, consequences of unprofessional behaviour and faculty training. All schools have adopted at least parts of the 2002 recommendations. Differences exist mainly in the organisational structure of teaching and assessment as well as in the assessment instruments used. In all schools a longitudinal assessment of professional behaviour was accomplished. All schools involved have made progress since 2002 with regard to teaching and assessment of professional behaviour, resulting in a shift from an instrumental to a cultural change for some schools. A stimulating factor was society's call to focus on patient safety and therefore on assessment of unprofessional behaviour. Hurdles yet to be taken are the involvement of students in the assessment process, teacher confidence in personal assessment capacities, remediation programmes and logistic and administrative support.


Protective effects of L-carnosine on CCl4 -induced hepatic injury in rats.
The present study was undertaken to investigate the possible protective effect of L-carnosine (CAR), an endogenous dipeptide of alanine and histidine, on carbon tetrachloride (CCl4)-induced hepatic injury. Liver injury was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injections of CCl4, twice weekly for six weeks. CAR was administered to rats daily, at dose of 250 mg/kg, i.p. At the end of six weeks, blood and liver tissue specimens were collected. Results show that CAR treatment attenuated the hepatic morphological changes, necroinflammation and fibrosis induced by CCl4, as indicated by hepatic histopathology scoring. In addition, CAR treatment significantly reduced the CCl4-induced elevation of liver-injury parameters in serum. CAR treatment also combatted oxidative stress; possibly by restoring hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) levels. Moreover, CAR treatment prevented the activation of hepatic stellate cells (HSCs), as indicated by reduced α-smooth muscle actin (α-SMA) expression in the liver, and decreased hepatic inflammation as demonstrated by a reduction in hepatic tumor necrosis factor-α (TNF-α) and restoration of interleukin-10 (IL-10) levels. In conclusion, CCl4-induced hepatic injury was alleviated by CAR treatment. The results suggest that these beneficial, protective effects are due, at least in part, to its anti-oxidant, anti-inflammatory and anti-fibrotic activities.


[The change of mothers with autistic children: from analyzing the process of support group].
The purpose of this study was to analyze the processes by which support groups assist mothers with autistic children, in order to understand how mothers adapt themselves and reestablish relationships within the environment of the support group. In this qualitative study, eight mothers were recruited to form a support group. The group met for 10 sessions, each lasting 90 minutes. All the sessions were recorded in full on both audio and video tape. The data were analysed by the content analysis method. The results were used to analyze the process of change within mothers who took care of their autistic children, including transitions involving the termination of a fond dream, emerging from confusion, finding hope and seeking help; facing the family--reversing the course of events and taking responsibility; facing society--respecting life. The results show the changes in mothers caused by the group experience and the effects on them of interaction between themselves and their spouse, relatives and the autistic child since the time of the child's birth. The results should help health workers to gain a deeper understanding of mothers with autistic children.


Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.
Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration. We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers. We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene. Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.


Defective O-antigen polymerization in tolA and pal mutants of Escherichia coli in response to extracytoplasmic stress.
We have previously shown that the TolA protein is required for the correct surface expression of the Escherichia coli O7 antigen lipopolysaccharide (LPS). In this work, delta tolA and delta pal mutants of E. coli K-12 W3110 were transformed with pMF19 (encoding a rhamnosyltransferase that reconstitutes the expression of O16-specific LPS), pWQ5 (encoding the Klebsiella pneumoniae O1 LPS gene cluster), or pWQ802 (encoding the genes necessary for the synthesis of Salmonella enterica O:54). Both DeltatolA and delta pal mutants exhibited reduced surface expression of O16 LPS as compared to parental W3110, but no significant differences were observed in the expression of K. pneumoniae O1 LPS and S. enterica O:54 LPS. Therefore, TolA and Pal are required for the correct surface expression of O antigens that are assembled in a wzy (polymerase)-dependent manner (like those of E. coli O7 and O16) but not for O antigens assembled by wzy-independent pathways (like K. pneumoniae O1 and S. enterica O:54). Furthermore, we show that the reduced surface expression of O16 LPS in delta tolA and delta pal mutants was associated with a partial defect in O-antigen polymerization and it was corrected by complementation with intact tolA and pal genes, respectively. Using derivatives of W3110 delta tolA and W3110 delta pal containing lacZ reporter fusions to fkpA and degP, we also demonstrate that the RpoE-mediated extracytoplasmic stress response is upregulated in these mutants. Moreover, an altered O16 polymerization was also detected under conditions that stimulate RpoE-mediated extracytoplasmic stress responses in tol+ and pal+ genetic backgrounds. A Wzy derivative with an epitope tag at the C-terminal end of the protein was stable in all the mutants, ruling out stress-mediated proteolysis of Wzy. We conclude that the absence of TolA and Pal elicits a sustained extracytoplasmic stress response that in turn reduces O-antigen polymerization but does not affect the stability of the Wzy O-antigen polymerase.


Ultrasound-assisted transthoracic biopsy: cells or sections?
Physicians increasingly use transthoracic ultrasound (US) as an aid for diagnostic procedures. At the bedside, US helps to visualize neoplasms in the chest wall, pleura, peripheral lung, and anterior mediastinum involving or abutting the pleura. Histology specimens from cutting-needle biopsies have been shown to be safe and effective. This prospective study determined the yield and safety of US-guided fine-needle aspiration biopsy (FNAB) as a first-line bedside investigation. We recruited 97 consecutive patients, and of these, 85 underwent both cutting-needle biopsy and FNAB. These were adequate for diagnosis in 81.2% and 80% of cases, respectively, with a combined yield of 90%. Measured with a novel semiquantitative score, FNAB allowed a diagnosis with fewer special investigations than cutting biopsy. US-guided FNAB by pulmonologists performed best in lung carcinoma and can be recommended as a first-line investigation in patients with a high clinical suspicion of this diagnosis.


National tuberculosis spending efficiency and its associated factors in 121 low-income and middle-income countries, 2010-19: a data envelopment and stochastic frontier analysis.
Maximising the efficiency of national tuberculosis programmes is key to improving service coverage, outcomes, and progress towards End TB targets. We aimed to determine the overall efficiency of tuberculosis spending and investigate associated factors in 121 low-income and middle-income countries between 2010 and 2019. In this data envelopment and stochastic frontier analysis, we used data from the WHO Global TB report series on tuberculosis spending as the input and treatment coverage as the output to estimate tuberculosis spending efficiency. We investigated associations between 25 independent variables and overall efficiency. We estimated global tuberculosis spending efficiency to be between 73·8% (95% CI 71·2-76·3) and 87·7% (84·9-90·6) in 2019, depending on the analytical method used. This estimate suggests that existing global tuberculosis treatment coverage could be increased by between 12·3% (95% CI 9·4-15·1) and 26·2% (23·7-28·8) for the same amount of spending. Efficiency has improved over the study period, mainly since 2015, but a substantial difference of 70·7-72·1 percentage points between the most and least efficient countries still exists. We found a consistent significant association between efficiency and current health expenditure as a share of gross domestic product, out-of-pocket spending on health, and some Sustainable Development Goal (SDG) indicators such as universal health coverage. To improve efficiency, treatment coverage will need to be increased, particularly in the least efficient contexts where this might require additional spending. However, progress towards global End TB targets is slow even in the most efficient countries. Variables associated with TB spending efficiency suggest efficiency is complimented by commitments to improving health-care access that is free at the point of use and wider progress towards the SDGs. These findings support calls for additional investment in tuberculosis care. None.


Folding processes of the B domain of protein A to the native state observed in all-atom ab initio folding simulations.
Reaching the native states of small proteins, a necessary step towards a comprehensive understanding of the folding mechanisms, has remained a tremendous challenge to ab initio protein folding simulations despite the extensive effort. In this work, the folding process of the B domain of protein A (BdpA) has been simulated by both conventional and replica exchange molecular dynamics using AMBER FF03 all-atom force field. Started from an extended chain, a total of 40 conventional (each to 1.0 micros) and two sets of replica exchange (each to 200.0 ns per replica) molecular dynamics simulations were performed with different generalized-Born solvation models and temperature control schemes. The improvements in both the force field and solvent model allowed successful simulations of the folding process to the native state as demonstrated by the 0.80 A C(alpha) root mean square deviation (RMSD) of the best folded structure. The most populated conformation was the native folded structure with a high population. This was a significant improvement over the 2.8 A C(alpha) RMSD of the best nativelike structures from previous ab initio folding studies on BdpA. To the best of our knowledge, our results demonstrate, for the first time, that ab initio simulations can reach the native state of BdpA. Consistent with experimental observations, including Phi-value analyses, formation of helix II/III hairpin was a crucial step that provides a template upon which helix I could form and the folding process could complete. Early formation of helix III was observed which is consistent with the experimental results of higher residual helical content of isolated helix III among the three helices. The calculated temperature-dependent profile and the melting temperature were in close agreement with the experimental results. The simulations further revealed that phenylalanine 31 may play critical to achieve the correct packing of the three helices which is consistent with the experimental observation. In addition to the mechanistic studies, an ab initio structure prediction was also conducted based on both the physical energy and a statistical potential. Based on the lowest physical energy, the predicted structure was 2.0 A C(alpha) RMSD away from the experimentally determined structure.


Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences.
The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is secreted by the thyroid gland. These pathways ensure regulation of the availability of the biologically active molecule T3, which occurs in a time-and tissue-specific fashion. In addition, because cells and plasma are in equilibrium and deiodination affects central thyroid hormone regulation, these local deiodinase-mediated events can also affect systemic thyroid hormone economy, such as in the case of non-thyroidal illness. Heightened interest in the field has been generated following the discovery that the deiodinases can be a component in both the Sonic hedgehog signaling pathway and the TGR-5 signaling cascade, a G-protein-coupled receptor for bile acids. These new mechanisms involved in deiodinase regulation indicate that local thyroid hormone activation and inactivation play a much broader role than previously thought.


Genograms of exile and return families in Croatia--a medical anthropological approach.
This article presents the most important results of an applied anthropological long-term study of the prolonged exile and return that many families are currently undergoing in Croatia. The results are elaborated with a special reflection upon two important overlapping issues concerning the methodological approach that was applied: firstly, it discusses the crucial questions which motivated the search for a tool that will not distort the experiences, reality and suffering of exile families; and secondly, it critically describes the application of the genogram (a tool borrowed from systemic family therapy) in the exile setting. This tool was not only useful in the clinical sense of psychotherapeutically helping the families, but was also a very flexible part of the methodology orientated towards evoking family history and providing valid knowledge about different family and living circumstances.


Second-sphere tethering of rare-earth ions to cucurbit[6]uril by iminodiacetic acid involving carboxylic group encapsulation.
The reaction of rare-earth nitrates with iminodiacetic acid (H(2)IDA) in the presence of cucurbit[6]uril (CB6) in water at room temperature yields a family of isomorphous complexes, [M(H(2)IDA)(NO(3))(H(2)O)(6)](NO(3))(2)·CB6·14H(2)O with M = Y (1), Ce (2), Nd (3), Eu (4), Dy (5), Er (6), Tm (7), and Yb (8). In these compounds, the trivalent metal ion is bound to one nitrate ion, six water molecules, and one zwitterionic H(2)IDA molecule. The latter is further partly included in the CB6 cavity, with the ammonium group forming two hydrogen bonds with oxygen atoms of one portal. The uncoordinated carboxylic group is thus encapsulated in CB6 and hydrogen-bonded to the other portal via a water molecule. CB6 is a second-sphere ligand in these complexes, but direct bonding of the metal ion to CB6 can be enforced by using a ligand more deeply imbedded in the cavity, such as 2-pyridylacetate (PA) in [Eu(PA)(CB6)(NO(3))(H(2)O)(5)](NO(3))·10H(2)O (11). When the reaction with H(2)IDA is performed with Lu(III) or Cu(II), no metal complex is isolated, but the inclusion compounds [(H(3)IDA)(2)(CB6)](NO(3))(2)·xH(2)O with x = 6 (9) or 8 (10) are obtained instead, in which the two H(3)IDA(+) cations are attached to the CB6 portals by ammonium-carbonyl hydrogen bonds and are linked to one another inside the cavity by hydrogen bonding between the carboxylic groups. These complexes are compared to that comprising a dicarboxylic acid devoid of an ammonium functionality, [(H(2)AZ)(CB6)]·6H(2)O (12), where H(2)AZ is azelaic acid. The metal ion complexes 1-8 and the organic complexes 9 and 10 display the unprecedented feature of inclusion of carboxylic groups inside the CB6 cavity, with the CB6/acid stoichiometry and the finer details of the host-guest interactions being dependent on the presence of the metal ion.


Rapid destruction of the hip joint associated with enlarged iliopsoas bursa in a patient with refractory rheumatoid arthritis.
A case of refractory rheumatoid arthritis with a rapid destruction of the hip joint and an enlarged iliopsoas bursa is presented. Rapidly destructive coxarthrosis, chondrocalcinosis, suppurative arthritis, and pigmented villonodular synovitis were the differential diagnoses. Radiological examination showed that rheumatoid arthritis was most likely diagnosis. The patient was treated with total hip arthroplasty and etanercept, with good results.


Spatial and temporal variability in costs and effectiveness in phosphorus loss mitigation at farm scale: A scenario analysis.
Current policy instruments under the EU Water Framework Directive (WFD) to mitigate phosphorus (P) loss require that P use on farms is managed through regulation of farm gate P balances. Regulation at farm scale does not account for spatial variability in nutrient use and soil fertility at field scale, affecting the costs and effectiveness of farm gate measures. This study simulated the implementation of a P loss mitigation measure coupled with improving soil fertility so that farm productivity would not be compromised. The measure was simulated at field scale and the costs and effectiveness assessed at farm scale. Effectiveness was expressed as the time taken for excessive soil P levels to decline to levels that matched off-takes and this varied temporally and spatially within and between farms ranging from 1 to 8 years. Sub-optimum soil fertility was corrected on all fields across both farms, with applications of other soil nutrients and lime to protect productivity. An increase in costs ranging from 1.5 to 116% was predicted in the first two years of the measure on both farms after-which savings of 15-31% were predicted for each subsequent year until the measure was effective in year 9. Despite initial cost increase, there was no statistically significant difference in costs over the time taken for the measure to be effective, when compared to baseline costs. Successful implementation of measures should consider the impact on farm costs and time taken for measures to environmentally effective. Adoption of measures could improve if demonstrating to farmers that costs will not vary significantly from current practice and in time may results in savings if measures are paired with correcting soil fertility and increasing yields. This 'win-win' approach could be used into the future to ensure successful implementation and uptake of measures within the farming community.


Lipid transfer proteins enhance cell wall extension in tobacco.
Plant cells are enclosed by a rigid cell wall that counteracts the internal osmotic pressure of the vacuole and limits the rate and direction of cell enlargement. When developmental or physiological cues induce cell extension, plant cells increase wall plasticity by a process called loosening. It was demonstrated previously that a class of proteins known as expansins are mediators of wall loosening. Here, we report a type of cell wall-loosening protein that does not share any homology with expansins but is a member of the lipid transfer proteins (LTPs). LTPs are known to bind a large range of lipid molecules to their hydrophobic cavity, and we show here that this cavity is essential for the cell wall-loosening activity of LTP. Furthermore, we show that LTP-enhanced wall extension can be described by a logarithmic time function. We hypothesize that LTP associates with hydrophobic wall compounds, causing nonhydrolytic disruption of the cell wall and subsequently facilitating wall extension.


Omega-3 Polyunsaturated Fatty Acids and Oxylipins in Neuroinflammation and Management of Alzheimer Disease.
Alzheimer disease (AD) is becoming one of the most prevalent neurodegenerative conditions worldwide. Although the disease progression is becoming better understood, current medical interventions can only ameliorate some of the symptoms but cannot slow disease progression. Neuroinflammation plays an important role in the advancement of this disorder, and n-3 (ω-3) polyunsaturated fatty acids (PUFAs) are involved in both the reduction in and resolution of inflammation. These effects may be mediated by the anti-inflammatory and proresolving effects of bioactive lipid mediators (oxylipins) derived from n-3 PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in fish oil. Although interventions have generally used fish oil containing both EPA and DHA, several studies that used either EPA or DHA alone or specific oxylipins derived from these fatty acids indicate that they have distinct effects. Both DHA and EPA can reduce neuroinflammation and cognitive decline, but EPA positively influences mood disorders, whereas DHA maintains normal brain structure. Fewer studies with a plant-derived n-3 PUFA, α-linolenic acid, suggest that other n-3 PUFAs and their oxylipins also may positively affect AD. Further research identifying the unique anti-inflammatory and proresolving properties of oxylipins from individual n-3 PUFAs will enable the discovery of novel disease-management strategies in AD.


An innovative approach to the medical management of the nursing home resident: the EverCare experience.
Providing quality medical care to the frail elderly who reside permanently in nursing homes is associated with a variety of problems and impediments. This article describes the solution devised by two geriatric nurse practitioners who created a program of care called EverCare. This program, now a Health Care Financing Administration (HCFA) demonstration project, incorporates the nurse practitioner in a collaborative relationship with the primary care physician to provide early detection and intervention for myriad health and medical problems found in the nursing home population and to enhance the care of the frail elderly overall.


Exploring the role of ectomycorrhizal fungi in soil carbon dynamics.
The extent to which ectomycorrhizal (ECM) fungi enable plants to access organic nitrogen (N) bound in soil organic matter (SOM) and transfer this growth-limiting nutrient to their plant host, has important implications for our understanding of plant-fungal interactions, and the cycling and storage of carbon (C) and N in terrestrial ecosystems. Empirical evidence currently supports a range of perspectives, suggesting that ECM vary in their ability to provide their host with N bound in SOM, and that this capacity can both positively and negatively influence soil C storage. To help resolve the multiplicity of observations, we gathered a group of researchers to explore the role of ECM fungi in soil C dynamics, and propose new directions that hold promise to resolve competing hypotheses and contrasting observations. In this Viewpoint, we summarize these deliberations and identify areas of inquiry that hold promise for increasing our understanding of these fundamental and widespread plant symbionts and their role in ecosystem-level biogeochemistry.


Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals.
The SNP rs12252-C allele alters the function of interferon-induced transmembrane protein-3 increasing the disease severity of influenza virus infection in Caucasians, but the allele is rare. However, rs12252-C is much more common in Han Chinese. Here we report that the CC genotype is found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. Specifically, the CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. More importantly, because the risk genotype occurs with such a high frequency, its effect translates to a large population-attributable risk of 54.3% for severe infection in the Chinese population studied compared with 5.4% in Northern Europeans. Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.


Late-onset chronic mucocutaneous and ocular candidiasis and malignant thymoma.
Late-onset chronic mucocutaneous candidiasis (CMCC) is part of a spectrum of candidal infections. It usually develops during or after the fourth decade of life and is often associated with an underlying neoplasm, especially thymoma. A 56-year-old man with late-onset CMCC and thymoma had several unusual features. His malignant thymoma seemed to be more widespread than the thymomas of previously described patients. Ocular infection was present in addition to extensive involvement of the skin, nails, and oral mucosa. To our knowledge, this is the first report of ocular involvement in this syndrome. We also believe that this is the first patient with thymoma-associated late-onset CMCC to be treated effectively with ketoconazole.


TCM differential treatment of child hood persisting pneumonia--a report of 52 cases.
According to TCM differentiation of the symptoms and signs, 52 children with presisting pneumonia were divided into the following four types: 1) deficiency of body fluid due to accumulation of heat in the lung, 2) earth failing to generate metal, 3) deficiency of the Ying and Wei systems, and 4) excessiveness of pathogens due to qi deficiency. After treatment for 2-3 weeks, 40-cases were cured, 8 improved, and 4 ineffective.


The effects of sympathectomy and dexamethasone in rats ingesting sucrose.
Both high-sucrose diet and dexamethasone (D) treatment increase plasma insulin and glucose levels and induce insulin resistance. We showed in a previous work (Franco-Colin, et al. Metabolism 2000; 49:1289-1294) that combining both protocols for 7 weeks induced less body weight gain in treated rats without affecting mean daily food intake. Since such an effect may be explained by an increase in caloric expenditure, possibly due to activation of the sympathetic nervous system by sucrose ingestion, in this work, and using 10% sucrose in the drinking water, male Wistar rats were divided into 4 groups. Two groups were sympathectomized using guanethidine (Gu) treatment for 3 weeks. One of these groups of rats received D in the drinking water. Of the 2 groups not receiving Gu, one was the control (C) and the other received D. After 8 weeks a glucose tolerance test was done. The rats were sacrificed and liver triglyceride (TG), perifemoral muscle lipid, and norepinephrine (NE) levels in the liver spleen, pancreas, and heart were determined. Gu-treated rats (Gu and Gu+D groups) showed less than 10% NE concentration compared to C and D rats, less daily caloric intake and body-weight gain, more sucrose intake, and better glucose tolerance. The area under the curve after glucose administration correlated significantly with the mean body weight gain of the rats, except for D group. Groups D (D and Gu+D) also showed less caloric intake and body-weight gain but higher liver weight and TG concentration and lower peripheral muscle mass. The combination of Gu+D treatments showed some peculiar results: negative body weight gain, a fatty liver, and low muscle mass. Though the glucose tolerance test had the worst results for the D group, it showed the best results in the Gu+D group. There were significant interactions for Guan X Dex by two-way ANOVA test for the area under the curve in the glucose tolerance test, muscle mass, and muscle lipids. The results suggest that dexamethasone catabolic effect is not caused by sympathetic activation.


Factors in Placement and Enrollment of Primary Care Patients in YMCA's Diabetes Prevention Program, Bronx, New York, 2010-2015.
The reach of the New York State YMCA's Diabetes Prevention Program (DPP) to at-risk populations may be increased through integration with primary care settings. Although considerable effort has been made in the referral and retention of patients, little is known about the factors associated with the placement of potential participants into YMCA's DPP. Among Montefiore Health System (MHS) patients referred to YMCA's DPP (n = 1,249) from July 10, 2010, through November 11, 2015, we identified demographic factors (eg, age, preferred language) and primary care practice-level factors (eg, time between referral and start of session, session season) associated with placement into a session and subsequent drop-out. We also evaluated factors associated with weight loss. Patients were predominantly female (71%) and aged 45 years or older (71%). Patients preferring sessions in Spanish were less often placed in sessions. Patients aged 18 to 44 years were less often placed (P = .01) and enrolled (P = .001) than patients aged 60 years or older. Sessions conducted in the summer and spring had higher enrollment than fall and winter months. Patients who started the YMCA's DPP within 2 months of their referral date were more often enrolled (54.4%) than patients who waited 4 or more months (21.6%) to start their sessions. Patients aged 45 to 59 years lost marginally less weight than those aged 60 years or older (-3.1% vs -3.8%; P = .07). Although this evaluation gives some insight into the barriers to placement and enrollment in YMCA's DPP, challenges remain. Efforts are under way to increase referral of patients to community-based DPPs.


Weaving pathways: talking with our Elders.
While there exists a relative paucity of completed healthcare directives nationally in the USA, even fewer exist within minority populations. This report describes one model for bringing advance care planning and discussions to American Indian and Alaska Native (AIAN) communities. In 2018, Honoring Choices of Minnesota approached the Center of American Indian and Minority Health (CAIMH), housed in the University of Minnesota Medical School, to collaborate on a project to increase healthcare directives in AIAN communities. CAIMH assembled AIAN students, faculty and community members to identify and address barriers to healthcare directive completion and discussions about end-of-life choices. The project team decided upon a two-pronged approach: culturally informed provider training paralleling culturally relevant community engagement. We aimed to empower AIAN to engage with healthcare providers on decisions impacting their care. To further support AIAN patients and their providers, a toolkit was created and will soon be available for dissemination.


Mental health profiles and the related socio-demographic predictors in Hong Kong university students under the COVID-19 pandemic: A latent class analysis.
While the COVID-19 pandemic has brought about significant challenges to mental health of university students, there is limited research in this area. Particularly, few studies examined the person-centered mental health symptom profiles such as depression and anxiety and the related socio-demographic predictors. Using Latent Class Analysis (LCA), this study investigated the symptom profiles of depression and anxiety in university students in Hong Kong under the COVID-19 pandemic and the socio-demographic predictors. A total of 978 undergraduate students completed an online questionnaire including socio-demographic factors and measures of depression and anxiety during the summer of 2022. The LCA identified three latent classes: "normal" group, "moderate comorbid depression and anxiety" group and "severe comorbid depression and anxiety" group. Multinominal logistic regression showed that comparing with the "normal" group and the "moderate symptom" group, the "severe symptom" group had higher personal financial difficulties and individual/family member unemployment during the pandemic. In contrast, other socio-demographic factors (age, gender, year of study, living status, and COVID-19 infection status) had no significant association with group status. The study contributes to understanding of person-centered depression and anxiety symptom profiles and the risk role of personal financial difficulty in mental health of university students under the pandemic.


Clinical outcomes of low-pressure pneumoperitoneum in minimally invasive urological surgery.
The adoption of minimally invasive laparoscopic techniques has revolutionised urological practice. This necessitates a pneumoperitoneum (PNP) and the impact the PNP pressure has on post-operative outcomes is uncertain. During the current COVID-19 era guidance has suggested the utilisation of lower PNP pressures to mitigate the risk of intra-operative viral transmission. Review the current literature regarding the impact of pneumoperitoneum pressure, within the field of urology, on post-operative outcomes. A search of the PubMed, Medline and EMBASE databases was undertaken to identify studies that met the inclusion criteria. The Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines were adhered to. Ten studies, that included both randomised controlled trials and retrospective case series reviews, were identified that met the inclusion criteria. The effect of PNP pressure on outcomes following prostatectomy, live donor nephrectomy, partial nephrectomy and a variety of benign upper tract procedures were discussed. Low pressure PNP appears safe when compared to high pressure PNP, potentially reducing post-operative pain and rates of ileus. When compared to general surgery, there is a lack of quality evidence investigating the impact of PNP pressures on outcomes within urology. Low pressure PNP appears non-inferior to high pressure PNP. More research is required to validate this finding, particularly post-cystectomy and nephrectomy.


[Proxy informant reliability and bias in epidemiological research: analysis of a screening questionnaire for mental disorders].
To evaluate the reliability, magnitude and direction of the resulting bias in the application of a screening instrument for mental disorders by considering proxy informants in comparison to primary informants. Data are taken from a general morbidity community-based survey carried out in 520 randomly selected households of an industrial area of the Metropolitan Region of Salvador, the capital of Bahia state, Brazil. During the pilot phase, the first 70 families of the total sample were asked to participate in the evaluation of research instruments. The Questionnaire of Adult Psychiatric Morbidity, QAPM, consists of 44 questions about psychiatric symptoms widely used in Brazil. The husbands and wives of the selected families answered QAPM questions regarding themselves and their respective partners. One family refused to participate. The Kappa index was estimated for each QAPM question. To assess the magnitude and direction of bias, the proportional variation of prevalence was estimated from proxy and primary respondents. Each informant was analyzed as a primary informant when answering about his/her own symptoms and as a proxy informant when answering those about his/her partner. Proxy informants as compared to primary informants show weak reliability, as measured by the Kappa Index, particularly when husbands reported on their wives' symptoms. An overall underestimation of prevalence estimates was found, which reveals the potential negative bias with the use of proxy informants for psychological symptoms. No bias was found for only two questions (lack of appetite and globus hystericus) when women were taken as proxy informants for their husbands. In addition, departures of proxy informants from primary informant-based estimates were greater among men than to women. Proxy informants underestimate the occurrence of psychological symptoms in this community-based study. When the feasibility of a research project, based on the QAPM depends on the use of proxies, wives may be recommended as better informants than their husbands.


In vitro and in vivo effects of rat kidney vascular endothelial cells on osteogenesis of rat bone marrow mesenchymal stem cells growing on polylactide-glycoli acid (PLGA) scaffolds.
It is well established that vascularization is critical for osteogenesis. However, adequate vascularization also remains one of the major challenges in tissue engineering of bone. This problem is further accentuated in regeneration of large volume of tissue. Although a complex process, vascularization involves reciprocal regulation and functional interaction between endothelial and osteoblast-like cells during osteogenesis. This prompted us to investigate the possibility of producing bone tissue both in vitro and ectopically in vivo using vascular endothelial cells because we hypothesized that the direct contact or interaction between vascular endothelial cells and bone marrow mesenchymal stem cells are of benefit to osteogenesis in vitro and in vivo. For that purpose we co-cultured rat bone marrow mesenchymal stem cells (MSC) and kidney vascular endothelial cells (VEC) with polylactide-glycolic acid scaffolds. In vitro experiments using alkaline phosphatase and osteocalcin assays demonstrated the proliferation and differentiation of MSC into osteoblast-like cells, especially the direct contact between VEC and MSC. In addition, histochemical analysis with CD31 and von-Willebrand factor staining showed that VEC retained their endothelial characteristics. In vivo implantation of MSC and VEC co-cultures into rat's muscle resulted in pre-vascular network-like structure established by the VEC in the PLGA. These structures developed into vascularized tissue, and increased the amount and size of the new bone compared to the control group (p < 0.05). These results suggest that the vascular endothelial cells could efficiently stimulate the in vitro proliferation and differentiation of osteoblast-like cells and promote osteogenesis in vivo by the direct contact or interaction with the MSC. This technique for optimal regeneration of bone should be further investigated.


Generation of monoclonal antibodies specific for desmoglein family members.
Desmosomes are the most prominent cell-cell junctions in most epithelial cells and serve to link the intermediate filament cytoskeletons of adjacent cells. Desmogleins and desmocollins are the transmembrane core of the desmosome and both are members of the cadherin family of cell-cell adhesion molecules. In the skin, the three desmoglein gene products (Dsg 1, 2, and 3) are expressed in a stratification dependent manner, and therefore contribute to compositionally different desmosomes throughout the differentiating layers. In this study we generated a panel of monoclonal antibodies (MAbs) specific for each of the desmoglein gene products and evaluated their usefulness in a number of immunological procedures including immunoblotting, immunoprecipitation, and immunofluorescence. In addition, we showed that these antibodies are useful for immunoprecipitating desmogleins from cell extracts prepared in 0.1% Empigen BB, a zwitterionic detergent capable of solubilizing the desmosomal structure. Identification of conditions that solubilize the desmosome and allow the use of immunological reagents will help facilitate an increased understanding of desmosome assembly and regulation.


Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1).
Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function. Wild-type (σR1⁺/⁺), heterozygous (σR1⁺/⁻), and homozygous (σR1⁻/⁻, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis. Cornea and lens of σR1⁻/⁻ mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the σR1⁻/⁻ mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in σR1⁻/⁻ mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of σR1⁻/⁻ mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in σR1⁻/⁻ mice. These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.


[A comparative study of 2 methods of preparation for colonoscopic procedure].
Although ingestion of polyethylene glycol solution has become the standard preparation for colonoscopy since 1980, there is investigation of new safe, comfortable and cheap methods. We carried out a prospective study in order to compare the utility and tolerance related to the preparation of the colon for colonoscopy, using a dioctyl sodium sulfosuccinate enema (SD) versus our conventional preparation. Group A was prepared the day previous to the study with liquid diet, oral laxative and application of an SD, prior to the endoscopy received another SD. Group B was prepared three days with liquid diet, the day previous to the colonoscopy they ingested oral laxative and used a water enema (W(e)), and they used another W(e) the day of the procedure. The patients' tolerance in each case was compared using a scale assigned as good, fair and poor. The cleaning obtained in the colon was also evaluated in a scale of good, regular and bad, considering three colon segments. Forty-four patients had been studied, 19 men and 25 women; each group with 22 patients. In group A: the preparation tolerance was good in 14 cases (63.6%), fair in seven (31.8%) and poor in one (4.5%); also, the obtained cleaning up to the cecum was good in nine cases (40.9%) and fair in 13 (59%). In group B: the tolerance was good in five cases (22.7%) fair in 12 (54.5%) and poor in five (22.7%); the obtained cleaning in this group up to the cecum was good in two cases (9%), fair in 19 (86.3%) and poor in one (4.5%). The SD preparation was better tolerated and more effective in order to achieve the cleaning of the colon than the conventional one.


High microsatellite diversity and differential structuring among populations of the introduced common brushtail possum, Trichosurus vulpecula, in New Zealand.
An understanding of genetic variation and structure of pest populations has the potential to improve the efficiency of measures to control them. Genetic analysis was undertaken at five microsatellite loci in four native Australian and 14 introduced New Zealand populations of the common brushtail possum Trichosurus vulpecula in order to document these parameters. Genetic variation in New Zealand populations, and phylogenetic relationships among Australian and New Zealand populations, were largely predicted by the recorded introduction history. Populations on the two main islands of New Zealand had only slightly lower genetic diversity than did Australian populations, except that allelic richness on the South Is. was significantly lower. Diversity was higher in North Is. than in South Is. populations (although not significantly so) and mainland New Zealand populations as a group were significantly more diverse than offshore islands that represented secondary population size bottlenecks. In phylogenetic analyses South Is. and offshore island populations grouped with Tasmania, while North Is. populations grouped either with mainland Australia or were intermediate between the two Australian sources. This scheme was supported by admixture coefficients showing that North and South Is./offshore island populations were largely mainland Australian and Tasmanian in origin, respectively. Population structure differed markedly between the North and South Islands: populations were typically more genetically differentiated on the former than the latter, which also showed significant isolation-by-distance. Substantial linkage disequilibrium in most sampled New Zealand but no Australian population between microsatellite loci Tv16 and Tv27 suggests they may be physically linked.


Corrections and clarifications.
The image in the Table of Contents for the issue of 23 October (p. 523) illustrating the report by G. D. Schellenberg et al. (p. 668) and the Research News article by Jean Marx (p. 550) about early-onset familial Alzheimer's disease being linked to chromosome 14 was incorrect. The correct figure appears on page 668 of the same issue.


Conversational Therapy through Semi-Immersive Virtual Reality Environments for Language Recovery and Psychological Well-Being in Post Stroke Aphasia.
Aphasia is a highly disabling acquired language disorder generally caused by a left-lateralized brain damage. Even if traditional therapies have been shown to induce an adequate clinical improvement, a large percentage of patients are left with some degree of language impairments. Therefore, new approaches to common speech therapies are urgently needed in order to maximize the recovery from aphasia. The recent application of virtual reality (VR) to aphasia rehabilitation has already evidenced its usefulness in promoting a more pragmatically oriented treatment than conventional therapies (CT). In the present study, thirty-six chronic persons with aphasia (PWA) were randomly assigned to two groups. The VR group underwent conversational therapy during VR everyday life setting observation, while the control group was trained in a conventional setting without VR support. All patients were extensively tested through a neuropsychological battery which included not only measures for language skills and communication efficacy but also self-esteem and quality of life questionnairies. All patients were trained through a conversational approach by a speech therapist twice a week for six months (total 48 sessions). After the treatment, no significant differences among groups were found in the different measures. However, the amount of improvement in the different areas was distributed over far more cognitive and psychological aspects in the VR group than in the control group. Indeed, the within-group comparisons showed a significant enhancement in different language tasks (i.e., oral comprehension, repetition, and written language) only in the VR group. Significant gains, after the treatment, were also found, in the VR group, in different psychological dimensions (i.e., self-esteem and emotional and mood state). Given the importance of these aspects for aphasia recovery, we believe that our results add to previous evidence which points to the ecological validity and feasibility of VR treatment for language recovery and psychosocial well-being.


[Ultrastructure of Salmonella typhimurium forms with unbalanced growth induced by lithium chloride].
The action of 1.0 and 1.5 M LiCl on S. typhimurium induces the appearance of unbalanced growth forms capable of growing and multiplication, when subcultured in a medium with this preparation. In this culture the prevalence of cells differing in their structure from the initial Salmonella cells and from stable L-form cultures is observed. Cells characteristic of the initial culture and cells resembling the L-forms occur in lesser numbers. LiCl seems to affect peptidoglycan and the cytoplasmic membrane, which brings about disturbances in the permeability of the surface structures of the cell.


Prevention and treatment of HIV infections in minorities in the US military: a review of military research.
The prevalence and incidence of HIV-1 infection in the U.S. military has been higher in minorities than in whites. In order to understand the reason for this disproportionate impact of the epidemic, military HIV research efforts were reviewed for race/ethnic-specific differences in a conference held in July 1993. Studies presented were from the areas of epidemiology, natural history, treatment, and prevention. This report summarizes the presentations made at that conference. Few race/ethnic-related differences were identified in this setting of early diagnosis of HIV-1 infection and equal access to a quality health care system. More information of this type will be needed to allow the targeting of interventions for maximal effect in decreasing the risk of HIV infection.


Branched and linear fatty acid esters of hydroxy fatty acids (FAHFA) relevant to human health.
Fatty acid esters of hydroxy fatty acids (FAHFAs) represent a complex lipid class that contains both signaling mediators and structural components of lipid biofilms in humans. The majority of endogenous FAHFAs share a common chemical architecture, characterized by an estolide bond that links the hydroxy fatty acid (HFA) backbone and the fatty acid (FA). Two structurally and functionally distinct FAHFA superfamilies are recognized based on the position of the estolide bond: omega-FAHFAs and in-chain branched FAHFAs. The existing variety of possible HFAs and FAs combined with the position of the estolide bond generates a vast quantity of unique structures identified in FAHFA families. In this review, we discuss the anti-diabetic and anti-inflammatory effects of branched FAHFAs and the role of omega-FAHFA-derived lipids as surfactants in the tear film lipid layer and dry eye disease. To emphasize potential pharmacological targets, we recapitulate the biosynthesis of the HFA backbone within the superfamilies together with the degradation pathways and the FAHFA regioisomer distribution in human and mouse adipose tissue. We propose a theoretical involvement of cytochrome P450 enzymes in the generation and degradation of saturated HFA backbones and present an overview of small-molecule inhibitors used in FAHFA research. The FAHFA lipid class is huge and largely unexplored. Besides the unknown biological effects of individual FAHFAs, also the enigmatic enzymatic machinery behind their synthesis could provide new therapeutic approaches for inflammatory metabolic or eye diseases. Therefore, understanding the mechanisms of (FA)HFA synthesis at the molecular level should be the next step in FAHFA research.


Japanese Structure Survey of Radiation Oncology in 2011.
We evaluated the evolving structure of radiation oncology in Japan in terms of equipment, personnel, patient load and geographic distribution to identify and overcome any existing limitations. From March 2012 to August 2015, the Japanese Society for Radiation Oncology conducted a questionnaire based on the Japanese national structure survey of radiation oncology in 2011. Data were analyzed based on the institutional stratification by the annual number of new patients treated with radiotherapy per institution. The estimated annual numbers of new and total (new plus repeat) patients treated with radiation were 211 000 and 250 000, respectively. Additionally, the estimated cancer incidence was 851 537 cases with approximately 24.8% of all newly diagnosed patients being treated with radiation. The types and numbers of treatment devices actually used included linear accelerator (LINAC; n = 836), telecobalt (n = 3), Gamma Knife (n = 46), 60Co remote afterloading system (RALS; n = 24), and 192Ir RALS (n = 125). The LINAC system used dual-energy functions in 619 units, 3D conformal radiotherapy functions in 719 and intensity-modulated radiotherapy (IMRT) functions in 412. There were 756 JRS or JASTRO-certified radiation oncologists, 1018.5 full-time equivalent (FTE) radiation oncologists, 2026.7 FTE radiotherapy technologists, 149.1 FTE medical physicists, 141.5 FTE radiotherapy quality managers and 716.3 FTE nurses. The frequency of IMRT use significantly increased during this time. To conclude, although there was a shortage of personnel in 2011, the Japanese structure of radiation oncology has clearly improved in terms of equipment and utility.


Recombinant Brucella abortus proteins that induce proliferation and gamma-interferon secretion by CD4+ T cells from Brucella-vaccinated mice and delayed-type hypersensitivity in sensitized guinea pigs.
Optimal protective immunity to Brucella abortus infection is dependent on a coordinate interaction between different T-cell subsets which leads to an antigen-specific T-lymphocyte-mediated activation of macrophages, the main cellular reservoir for the bacterium. As an initial step in the identification of bacterial proteins that mediate cellular immunity, we have subcloned the B. Abortus ssb, uvrA, GroES, and GroEL genes into the prokaryotic expression vector pMAL-c2 using PCR. Escherichia coli DH5 alpha was transformed with the pMAL-ssb, pMAL-uvrA, pMAL-GroES, and pMAL-GroEL constructs separately, and gene expression was induced by isopropyl-beta-D-thiogalactopyranoside. The resulting fusion proteins were purified by affinity chromatography and confirmed by Western blot analysis using an anti-maltose-binding protein antibody. Furthermore, we have examined the pattern of T helper (Th) cell response from vaccinated BALB/c mice after in vitro stimulation with the recombinant (r) fusion proteins. In addition to T-cell proliferative responses, CD4+ T cells were tested for interleukin-2 (IL-2), IL-4, and gamma interferon (IFN-gamma) secretion. Primed CD4+ T cells proliferated to the rUvrA, rGroES, and rGroEL, but not to rSsb. The cytokine profile of the proliferating cells was characteristic of a Th1 type, as we detected IL-2 and IFN-gamma but not IL-4 in the T-cell culture supernatants. The recombinant B. abortus proteins were also screened in vivo to their ability to elicit DTH reaction in Brucella-sensitized guinea pigs. Moreover, the results of this study suggest that B. abortus rUvrA, rGroES, and rGroEL might be important sources of potentially protective molecules.


Cloning, expression and purification of functionally active human angiopoietin-like protein 2.
Angiopoietin-like protein 2 (Angptl2) is a secreted glycoprotein that has been implicated in angiogenesis, inflammation and atherosclerosis as well as enhancing the survival of human hematopoietic stem cells. Glycosylation of Angptl2 is required for biological activity and studies of angiopoietin-like protein 2 have been hindered by the lack of a source for the mature form of this protein. We describe a system that permits purification of the glycosylated form of human Angptl2 from conditioned media of stably transfected HEK 293 cells. To facilitate purification while retaining the integrity of Angptl2's endogenous N-terminal secretion signal peptide, GST was fused downstream of the Angptl2 coding sequence. Secreted Angptl2-GST was purified using a one-step glutathione-affinity purification scheme. The purity and identity of the resulting protein were confirmed by SDS-PAGE, immunoblotting, and mass spectrometry. N-Glycosidase treatment reduced the apparent molecular mass of Angptl2-GST on SDS-PAGE, confirming its glycosylation state. Purified human Angptl2-GST stimulated both HUVEC migration and microtubule formation in vitro. The yield of Angptl2-GST obtained was in quantities suitable for multiple applications including functional in vitro and in vivo assays.


Baclofen for binge eating: an open-label trial.
Baclofen is a GABA-B agonist that may be useful in the treatment of substance use disorders, and also reduces 'binge-like' eating in rodents. We hypothesized that baclofen might be effective in reducing binge eating episodes in binge eating disorder (BED) and bulimia nervosa (BN). Seven women with BED (n = 4) or BN (n = 3) took baclofen (60 mg/day) for 10 weeks. Six out of seven patients completed the full 10-week trial. Five out of seven participants (3 BED; 2 BN) demonstrated 50% or greater reduction of frequency of binge eating from beginning to end of the study. Three out of seven participants (2 BED; 1 BN) were free of binge eating at study end. Four out of seven participants elected to continue baclofen at study end. Baclofen was well tolerated by the participants. In this open-label trial, baclofen was associated with decreased binge eating frequency in patients with BED and BN.


Temporal dynamics of pro-inflammatory cytokines and serum corticosterone following acute sleep fragmentation in male mice.
Obstructive sleep apnea is increasing worldwide, leading to disordered sleep patterns and inflammatory responses in brain and peripheral tissues that predispose individuals to chronic disease. Pro-inflammatory cytokines activate the inflammatory response and are normally regulated by glucocorticoids secreted from adrenal glands. However, the temporal dynamics of inflammatory responses and hypothalamic-pituitary-adrenal (HPA) axis activation in relation to acute sleep fragmentation (ASF) are undescribed. Male C57BL/6J mice were exposed to ASF or control conditions (no ASF) over specified intervals (1, 2, 6, or 24 h) and cytokine gene expression (IL-1β, TNF-α) in brain and peripheral tissues as well as serum glucocorticoid and interleukin-6 (IL-6) concentration were assessed. The HPA axis was rapidly activated, leading to elevated serum corticosterone from 1-24 h of ASF compared with controls. This activation was followed by elevated serum IL-6 concentration from 6-24 h of ASF. The tissue to first exhibit increased pro-inflammatory gene expression from ASF was heart (1 h of ASF). In contrast, pro-inflammatory gene expression was suppressed in hypothalamus from 1 h of ASF, but elevated at 6 h. Because the HPA axis was activated throughout ASF, this suggests that brain, but not peripheral, pro-inflammatory responses were rapidly inhibited by glucocorticoid immunosuppression.


The reading process and learning to read.
This paper provides a description of two models of the reading process and the relation of these models to learning to read, reading instruction and the identification and treatment of reading problems.


Platelet-rich concentrate in serum free medium enhances osteogenic differentiation of bone marrow-derived human mesenchymal stromal cells.
Previous studies have shown that platelet concentrates used in conjunction with appropriate growth media enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs). However, their potential in inducing osteogenesis of hMSCs when cultured in serum free medium has not been explored. Furthermore, the resulting osteogenic molecular signatures of the hMSCs have not been compared to standard osteogenic medium. We studied the effect of infrequent supplementation (8-day interval) of 15% non-activated platelet-rich concentrate (PRC) in serum free medium on hMSCs proliferation and differentiation throughout a course of 24 days, and compared the effect with those cultured in a standard osteogenic medium (OM). Cell proliferation was analyzed by alamar blue assay. Gene expression of osteogenic markers (Runx2, Collagen1, Alkaline Phosphatase, Bone morphogenetic protein 2, Osteopontin, Osteocalcin, Osteonectin) were analyzed using Q-PCR. Immunocytochemical staining for osteocalcin, osteopontin and transcription factor Runx2 were done at 8, 16 and 24 days. Biochemical assays for the expression of ALP and osteocalcin were also performed at these time-points. Osteogenic differentiation was further confirmed qualitatively by Alizarin Red S staining that was quantified using cetylpyridinium chloride. Results showed that PRC supplemented in serum free medium enhanced hMSC proliferation, which peaked at day 16. The temporal pattern of gene expression of hMSCs under the influence of PRC was comparable to that of the osteogenic media, but at a greater extent at specific time points. Immunocytochemical staining revealed stronger staining for Runx2 in the PRC-treated group compared to OM, while the staining for Osteocalcin and Osteopontin were comparable in both groups. ALP activity and Osteocalcin/DNA level were higher in the PRC group. Cells in the PRC group had similar level of bone mineralization as those cultured in OM, as reflected by the intensity of Alizarin red stain. Collectively, these results demonstrate a great potential of PRC alone in inducing proliferation of hMSCs without any influence from other lineage-specific growth media. PRC alone has similar capacity to enhance hMSC osteogenic differentiation as a standard OM, without changing the temporal profile of the differentiation process. Thus, PRC could be used as a substitute medium to provide sufficient pool of pre-differentiated hMSCs for potential clinical application in bone regeneration.


Effect of taurochenodeoxycholate or tauroursodeoxycholate upon biliary output of phospholipids and plasma-membrane enzymes, and the extent of cell damage, in isolated perfused rat livers.
Isolated perfused rat livers were used to study the effects of taurochenodeoxycholate (TCDC) and tauroursodeoxycholate (TUDC) upon some aspects of biliary composition. After depletion of the endogenous bile salt pool of the liver, introduction of either bile salt brought about increases in bile flow, bile salt output and biliary phospholipid output. Taurochenodeoxycholate needed a lower biliary concentration to produce phospholipid output than did tauroursodeoxycholate. TCDC perfusion caused a substantial output of plasma-membrane enzymes (5'-nucleotidase and alkaline phosphodiesterase) into the bile, whereas TUDC caused little output of either enzyme; this may represent a characteristic difference between the effects of the two bile salts on the hepatobiliary system. The results from TUDC perfusion indicate also that much of the output of biliary phospholipid promoted by bile salts, may be independent of the output of plasma-membrane enzymes promoted by bile salts.


Conformational transitions of cinnamoyl CoA reductase 1 from Leucaena leucocephala.
Conformational transitions of cinnamoyl CoA reductase, a key regulatory enzyme in lignin biosynthesis, from Leucaena leucocephala (Ll-CCRH1) were studied using fluorescence and circular dichroism spectroscopy. The native protein possesses four trp residues exposed on the surface and 66% of helical structure, undergoes rapid structural transitions at and above 45 °C and starts forming aggregates at 55 °C. Ll-CCRH1 was transformed into acid induced (pH 2.0) molten globule like structure, exhibiting altered secondary structure, diminished tertiary structure and exposed hydrophobic residues. The molten globule like structure was examined for the thermal and chemical stability. The altered secondary structure of L1-CCRH1 at pH 2.0 was stable up to 90 °C. Also, in presence of 0.25 M guanidine hydrochloride (GdnHCl), it got transformed into different structure which was stable in the vicinity of 2M GdnHCl (as compared to drastic loss of native structure in 2M GdnHCl) as seen in far UV-CD spectra. The structural transition of Ll-CCRH1 at pH 2.0 followed another transition after readjusting the pH to 8.0, forming a structure with hardly any similarity to that of native protein.


Correlation of aberrations with visual symptoms using wavefront analysis in eyes after laser in situ keratomileusis.
To evaluate the information assessed with the Alcon LADARWave wavefront measurement device and correlate it with visual symptoms in eyes previously treated with laser in situ keratomileusis (LASIK), and to analyze the influence of scotopic pupil size on visual symptoms. One hundred and five eyes of 58 patients who underwent LASIK were evaluated. Wavefront measurements were assessed using the Alcon LADARWave device. Visual symptoms were correlated to higher order aberrations in three different pupil sizes (5 mm, 7 mm, and scotopic pupil size). Generalized estimating equations were used for statistical analysis. In eyes after LASIK, visual symptoms analysis showed positive correlation of double vision with total coma and with horizontal coma for the 5-mm and 7-mm pupil sizes, negative correlation between starburst and total coma for the 7-mm pupil size, positive correlation of double vision with horizontal coma, and glare and starburst with spherical aberration and with total aberrations. Scotopic pupil size had a positive association with starburst and negative association with double vision. The LADARWave wavefront measurement device is a valuable diagnostic tool in measuring ocular aberrations in eyes after LASIK. A strong correlation between visual symptoms and ocular aberrations, such as monocular diplopia with coma, and starburst and glare with spherical aberration, suggest this device is valuable in diagnosing symptomatic LASIK-induced aberrations. Horizontal coma was correlated with double vision, while vertical coma was not, demonstrating a greater sensitivity with horizontally oriented multifocality.


Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.
Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).


Perils and pointers in the evaluation and management of back pain.
This article examines the current treatment of low back pain in light of the recent Agency for Health Care Practice and Research (AHCPR) guidelines on the acute management of low back pain (the AHCPR is an agency of the federal government). The article describes the most important history questions, the most helpful physical signs, and the most practical examination techniques. Considerable emphasis is placed on ruling out the "red flag" diagnoses that require immediate treatment. The article agrees with the AHCPR that if the red flags of cancer, infection, fracture, and neurologic deficit are ruled out, most of the remaining causes of acute back pain are largely self-healing over 4-8 weeks. Emphasis is placed on using the history and physical examination rather than expensive studies to rule out the red flag cases, so that cost-effective management of low back pain is possible. The author also reviews the ten top causes of low back pain and their evaluation and treatment.


Taking action against ocean acidification: a review of management and policy options.
Ocean acidification has emerged over the last two decades as one of the largest threats to marine organisms and ecosystems. However, most research efforts on ocean acidification have so far neglected management and related policy issues to focus instead on understanding its ecological and biogeochemical implications. This shortfall is addressed here with a systematic, international and critical review of management and policy options. In particular, we investigate the assumption that fighting acidification is mainly, but not only, about reducing CO2 emissions, and explore the leeway that this emerging problem may open in old environmental issues. We review nine types of management responses, initially grouped under four categories: preventing ocean acidification; strengthening ecosystem resilience; adapting human activities; and repairing damages. Connecting and comparing options leads to classifying them, in a qualitative way, according to their potential and feasibility. While reducing CO2 emissions is confirmed as the key action that must be taken against acidification, some of the other options appear to have the potential to buy time, e.g. by relieving the pressure of other stressors, and help marine life face unavoidable acidification. Although the existing legal basis to take action shows few gaps, policy challenges are significant: tackling them will mean succeeding in various areas of environmental management where we failed to a large extent so far.


Metabolic acidosis stimulates the production of the antimicrobial peptide cathelicidin in rabbit urine.
Intercalated cells of the collecting duct (CD) are critical for acid-base homeostasis and innate immune defense of the kidney. Little is known about the impact of acidosis on innate immune defense in the distal nephron. Urinary tract infections are mainly due to Escherichia coli and are an important risk factor for development of chronic kidney disease. While the effect of urinary pH on growth of E. coli is well established, in this study, we demonstrate that acidosis increases urine antimicrobial activity due, at least in part, to induction of cathelicidin expression within the CD. Acidosis was induced in rabbits by adding NH4Cl to the drinking water and reducing food intake over 3 days or by casein supplementation. Microdissected CDs were examined for cathelicidin mRNA expression and antimicrobial activity, and cathelicidin protein levels in rabbit urine were measured. Cathelicidin expression in CD cells was detected in kidney sections. CDs from acidotic rabbits expressed three times more cathelicidin mRNA than those isolated from normal rabbits. Urine from acidotic rabbits had significantly more antimicrobial activity (vs. E. coli) than normal urine, and most of this increased activity was blocked by cathelicidin antibody. The antibody had little effect on antimicrobial activity of normal urine. Urine from acidotic rabbits had at least twice the amount of cathelicidin protein as did normal urine. We conclude that metabolic acidosis not only stimulates CD acid secretion but also induces expression of cathelicidin and, thereby, enhances innate immune defense against urinary tract infections via induction of antimicrobial peptide expression.


The application of errorless learning to aphasic disorders: A review of theory and practice.
Recently, there has been great interest in errorless learning as a new intervention technique. This may be because there are data from both basic neuroscience and clinical application that suggest it is superior to more traditional trial and error methods. In the contemporary literature the most prominent investigations of errorless learning are those designed for rehabilitation of memory impairments. These studies include numerous demonstrations of effective amelioration of word finding difficulties using errorless intervention. The aphasic literature contains no examples of purely errorless learning methods, however, some studies have successfully treated anomia using error reducing techniques. This suggests that errorless learning could be advantageous for treating aphasic disorders, in particular anomia. To explore this idea, we discuss previous research and review two current theories of errorless learning. We provide our own framework for thinking about errorless and errorful learning. In addition, a review of the anomia treatment literature (from 1985 to the present) is presented and conclusions drawn on the methods of treating the word finding difficulties of patients with aphasia.


Inhibitory transmission in the basolateral amygdala.
1. Intracellular recording techniques were used to characterize synaptic inhibitory postsynaptic potentials (IPSPs) recorded from neurons of the basolateral nucleus of the amygdala (BLA). Bipolar electrodes positioned in the stria terminalis (ST) or lateral amygdala (LA) were used to evoke synaptic responses at a frequency of 0.25 Hz. 2. Two synaptic waveforms having IPSP components could be evoked by electrical stimulation of either pathway: a biphasic, excitatory postsynaptic potential (EPSP), fast-IPSP (f-IPSP) waveform, and a multiphasic, EPSP, f-IPSP, and subsequent slow-IPSP (s-IPSP) waveform. Expression of either waveform was dependent on the site of stimulation. ST stimulation evoked a similar number of biphasic (45%) and multiphasic (50%) synaptic responses. In contrast, stimulation of the LA pathway evoked mainly (80%) multiphasic synaptic responses. 3. Both the f- and s-IPSP elicited by ST stimulation could be reduced in amplitude in the presence of the glutamatergic, N-methyl-D-aspartate (NMDA) antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV, 50 microM), and were abolished by the glutamatergic, non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). In contrast, a CNQX-resistant f-IPSP was evoked with LA stimulation and abolished by subsequent addition of bicuculline methiodide (BMI), a gamma-aminobutyric acid (GABAA) receptor antagonist, suggesting direct inhibition of BLA neurons by GABAergic LA interneurons. The sensitivity of the s-IPSPs and the f-IPSPs to glutamatergic antagonists suggests the presence of feed-forward inhibition onto BLA neurons. 4. The f-IPSP possessed characteristics of potentials mediated by GABAA receptors linked to Cl- channels, namely, a reversal potential of -70 mV, a decrease in membrane resistance (13.5 M omega) recorded at -60 mV, a block by BMI, and potentiation by sodium pentobarbital (NaPB). 5. The s-IPSP was associated with a resistance decrease of 4.5 M omega, a reversal potential of -95 mV, and was reversibly depressed (approximately 66%) by 2-hydroxy-saclofen (100 microM), suggesting activation of GABAB receptors. 6. The large resistance change associated with the f-IPSP, its temporal overlap with evoked EPSPs, and the development of both spontaneous and evoked burst firing in the presence of BMI suggests that the f-IPSP determines the primary state of excitability in BLA neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


The E-Textile for Biomedical Applications: A Systematic Review of Literature.
The use of e-textile technologies spread out in the scientific research with several applications in both medical and nonmedical world. In particular, wearable technologies and miniature electronics devices were implemented and tested for medical research purposes. In this paper, a systematic review regarding the use of e-textile for clinical applications was conducted: the Scopus and Pubmed databases were investigate by considering research studies from 2010 to 2020. Overall, 262 papers were found, and 71 of them were included in the systematic review. Of the included studies, 63.4% focused on information and communication technology studies, while the other 36.6% focused on industrial bioengineering applications. Overall, 56.3% of the research was published as an article, while the remainder were conference papers. Papers included in the review were grouped by main aim into cardiological, muscular, physical medicine and orthopaedic, respiratory, and miscellaneous applications. The systematic review showed that there are several types of applications regarding e-textile in medicine and several devices were implemented as well; nevertheless, there is still a lack of validation studies on larger cohorts of subjects since the majority of the research only focuses on developing and testing the new device without considering a further extended validation.


A comparative study of machine learning methods for time-to-event survival data for radiomics risk modelling.
Radiomics applies machine learning algorithms to quantitative imaging data to characterise the tumour phenotype and predict clinical outcome. For the development of radiomics risk models, a variety of different algorithms is available and it is not clear which one gives optimal results. Therefore, we assessed the performance of 11 machine learning algorithms combined with 12 feature selection methods by the concordance index (C-Index), to predict loco-regional tumour control (LRC) and overall survival for patients with head and neck squamous cell carcinoma. The considered algorithms are able to deal with continuous time-to-event survival data. Feature selection and model building were performed on a multicentre cohort (213 patients) and validated using an independent cohort (80 patients). We found several combinations of machine learning algorithms and feature selection methods which achieve similar results, e.g. C-Index = 0.71 and BT-COX: C-Index = 0.70 in combination with Spearman feature selection. Using the best performing models, patients were stratified into groups of low and high risk of recurrence. Significant differences in LRC were obtained between both groups on the validation cohort. Based on the presented analysis, we identified a subset of algorithms which should be considered in future radiomics studies to develop stable and clinically relevant predictive models for time-to-event endpoints.


Genetics of human obesity.
The rapid development of new concepts and tools has led to a change in the way in which researchers carry out nutrition-related research. Obesity is determined by the interaction between predisposing genetic and environmental aspects, but at present the gene-gene and gene-environment interactions contributing to the development of this complex disease cannot be analysed in detail. The purpose of the present paper is to provide some examples of the knowledge that is available in the field of obesity genetics, and also the new strategies being developed that are aimed at studying the relative contribution of numerous genes to obesity and their responses to environmental changes. In the rare cases of monogenic obesities in which a major gene is the cause the molecular approach has proved extremely powerful in the identification of the genes responsible and in defining new syndromes. However, in the common forms of obesity (polygenic obesity) most studies have analysed genotype-phenotype associations without sometimes taking into account the influence of environmental factors (diet, sedentary lifestyle). Among the aspects limiting this integrated approach to obesity are the difficulty of having large enough samples and the expansion of biocomputing tools developed for accessing the question of multiple interactions with no a priori hypotheses. This picture is rapidly changing. Large databases of clinical data and DNA and biological sample banks with more precise environmental information and patient phenotypes are being compiled. The capacity for studying multiple genes simultaneously at the DNA or RNA levels is also possible. Finally, the tremendous progress in biocomputing will allow the integration of these different types of data (relating to environment, phenotype, genotype, gene expression) and will improve the ability to deal with this complex disease.


Null alleles are ubiquitous at microsatellite loci in the Wedge Clam (Donax trunculus).
Recent studies have reported an unusually high frequency of nonamplifying alleles at microsatellite loci in bivalves. Null alleles have been associated with heterozygous deficits in many studies. While several studies have tested for its presence using different analytical tools, few have empirically tested for its consequences in estimating population structure and differentiation. We characterised 16 newly developed microsatellite loci and show that null alleles are ubiquitous in the wedge clam, Donax trunculus. We carried out several tests to demonstrate that the large heterozygous deficits observed in the newly characterised loci were most likely due to null alleles. We tested the robustness of microsatellite genotyping for population assignment by showing that well-recognised biogeographic regions of the south Atlantic and south Mediterranean coast of Spain harbour genetically different populations.


Contorted and ordinary body postures in the human brain.
Social interaction and comprehension of non-verbal behaviour requires a representation of people's bodies. Research into the neural underpinnings of body representation implicates several brain regions including extrastriate and fusiform body areas (EBA and FBA), superior temporal sulcus (STS), inferior frontal gyrus (IFG) and inferior parietal lobule (IPL). The different roles played by these regions in parsing familiar and unfamiliar body postures remain unclear. We examined the responses of this body observation network to static images of ordinary and contorted postures by using a repetition suppression design in functional neuroimaging. Participants were scanned whilst observing static images of a contortionist or a group of objects in either ordinary or unusual configurations, presented from different viewpoints. Greater activity emerged in EBA and FBA when participants viewed contorted compared to ordinary body postures. Repeated presentation of the same posture from different viewpoints lead to suppressed responses in the fusiform gyrus as well as three regions that are characteristically activated by observing moving bodies, namely STS, IFG and IPL. These four regions did not distinguish the image viewpoint or the plausibility of the posture. Together, these data define a broad cortical network for processing static body postures, including regions classically associated with action observation.


A Novel Approach to Prenatal Measurement of the Fetal Frontal Lobe Using Three-Dimensional Sonography.
To assess the feasibility of a standardized approach to biometric measurement of the fetal frontal lobe and to construct frontal lobe growth trajectories throughout gestation. A sonographic 3-dimensional (3D) volume set was obtained and measured in 101 patients between 16.1 and 33.7 gestational weeks. Measurements were obtained by 2 independent raters. To model the relationship between gestational age and each frontal lobe measurement, flexible linear regression models were fit using penalized regression splines. The sample contained an ethnically diverse population (7.9% Native Americans, 45.5% Hispanics/Latinas). There was high interrater reliability (correlation coefficients 0.95, 1.0, and 0.87 for frontal lobe length, width, and height; p values <0.001). Graphs of the growth trajectories and corresponding percentiles were estimated as a function of gestational age. The estimated rates of frontal lobe growth were 0.096 cm/week, 0.247 cm/week, and 0.111 cm/week for length, width, and height, respectively. To our knowledge, this is the first study to examine fetal frontal lobe growth trajectories through 3D prenatal ultrasound examination. Such normative data will allow for future prenatal evaluation of a particular disease state by 3D ultrasound imaging.


Tracings of the north of Europe: Robert Chambers in search of the Ice Age.
Scottish publisher and naturalist Robert Chambers pursued an amateur interest in geology through much of his life. His early measurements of raised beaches in Scotland earned him membership in the Geological Society of London in 1844, a recognition much appreciated by the anonymous author of the 'scandalous' Vestiges published the same year. Although familiar with emerging ice age theories, Chambers remained with most British geologists a sceptic through the 1840s, even after a trip to the glaciers of the Alps in 1848, which nevertheless prepared him for the turning point, which came in 1849 during an extensive field trip in Norway and Sweden. Here a wealth of observations left him in no doubt that vast glaciers had formerly covered Scandinavia, polishing cliffs, scouring striations, depositing old moraines and erratic boulders. This also led him to a new glacial reading of the British landscape, and with the ardent conviction of a fresh convert he became one of the most vocal supporters of glacial theory in Britain in the 1850s at a time when the iceberg drift theory for boulder transport was still favoured by most prominent British geologists. While Chambers through his popular Chambers's Edinburgh Journal communicated his travels and ice age vision to a wide audience, and also pointed out ice age evidence on guided excursions around Edinburgh, he did not enter this new vision into subsequent editions of Vestiges, probably in order not to reveal its author. This paper explores Chambers's contributions to the ice age debate, his field trips and the genesis of his convictions, and evaluates his impact on the scientific debate.


Genomic aberrations in lung adenocarcinoma in never smokers.
Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide. We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity. The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers.


The construct of adaptive behavior: its conceptualization, measurement, and use in the field of intellectual disability.
This article updates the current conceptualization, measurement, and use of the adaptive behavior construct. Major sections of the article address an understanding of the construct, the current approaches to its measurement, four assessment issues and challenges related to the use of adaptive behavior information for the diagnosis of intellectual disability, and two future issues regarding the relations of adaptive behavior to multidimensional models of personal competence and the distribution of adaptive behavior scores. An understanding of the construct of adaptive behavior and its measurement is critical to clinicians and practitioners in the field because of its role in understanding the phenomenon of intellectual disability, diagnosing a person with intellectual disability, providing a framework for person-referenced education and habilitation goals, and focusing on an essential dimension of human functioning.


Ionizing radiation-induced mitogen-activated protein (MAP) kinase activation in DU145 prostate carcinoma cells: MAP kinase inhibition enhances radiation-induced cell killing and G2/M-phase arrest.
These studies examine the role(s) played by the mitogen-activated protein kinase (MAPK) pathway after exposure of DU145 prostate carcinoma cells to radiation. Radiation (2 Gy) was found to cause both immediate primary (0-30 min) and prolonged secondary activations (90-1440 min) of the MAPK pathway. These activations of the MAPK pathway were abolished by inhibition of epidermal growth factor receptor (EGFR) function. The secondary activation was also abolished by addition of a neutralizing monoclonal antibody against transforming growth factor alpha (TGFA). Activation of the MAPK pathway could be induced in nonirradiated cells by the transfer of medium from irradiated cultures. Neutralizing antibody to TGFA blocked this effect, indicating that radiation causes secondary activation of the MAPK pathway by release of TGFA in DU145 cells. Radiation induced a transient G(2)/M-phase growth arrest that was prolonged for up to 24 h by inhibition of the MAPK pathway. Inhibition of the MAPK pathway significantly increased the ability of radiation to cause apoptosis 24 h after exposure. The ability of DU145 cells to proliferate after irradiation became dependent on MAPK signaling. When cells were subjected to single doses or fractionated radiation exposure, continuous inhibition of the MAPK pathway significantly decreased clonogenic survival. Only a small fraction of this cell killing could be accounted for by apoptosis within the first 96 h. Thus inhibition of the MAPK pathway increased radiation-induced cell killing likely by both apoptotic and nonapoptotic mechanisms. Collectively, our findings indicate that disruption of the TGFA/EGFR/MAPK pathway may represent a strategy that could be exploited to manipulate prostate carcinoma growth and cell survival after irradiation.