Population attributable fractions and joint effects of key risk factors for multiple sclerosis.
We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.


A trans-Golgi network resident protein, golgin-97, accumulates in viral factories and incorporates into virions during poxvirus infection.
Poxviruses are the only DNA viruses known to replicate and assemble in the cytoplasm of infected cells. Poxvirus morphogenesis is a complicated process in which four distinct infectious forms of the virus are produced: intracellular mature virus, intracellular enveloped virus, cell-associated enveloped virus, and extracellular enveloped virus. The source of primary membrane wrapping the intracellular mature virus, the first infectious form, is still unknown. Although the membrane was suggested to originate from the endoplasmic reticulum-Golgi intermediate compartment, none of the marker proteins from this or any other cell compartments has been found in the intracellular mature virus. Thus, it was hypothesized that the membrane is either extensively modified by the virus or synthesized de novo. In the work described here, we demonstrate that a host cell protein residing in the trans-Golgi network membrane, golgin-97, is transported to the sites of virus replication and assembly and becomes incorporated into the virions during poxvirus infection. Inside the virion, golgin-97 is associated with the insoluble core protein fraction. Being able to adopt a long rod-like structure, the protein apparently extends through the virion envelope and protrudes from its surface. Here we discuss the potential role and functions of golgin-97 in poxvirus replication and propose two working models.


Influence of ghrelin on energy balance and endocrine physiology.
Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor. It is mainly secreted by stomach cells but has also been shown to be present in the hypothalamus, pituitary, gonads and many other organs. Ghrelin is a regulator of energy homeostasis and GH secretion. Many studies have been done examining the influence of ghrelin on different organs. Ghrelin may play an important role in pathophysiology of some endocrine diseases. The relationship between ghrelin and pituitary, gonads and thyroid function appears to be specially interesting.


Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy.
In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.


Associations between alcohol use and alcohol-related negative consequences among black and white college men and women.
The gender gap in alcohol use has been narrowing among young adults, while race differences in alcohol problems change throughout the life course, with Whites experiencing more problems before middle adulthood and Blacks experiencing more after. Yet, there is a paucity of research on the intricate relationship among gender, race, alcohol use, and alcohol problems in emerging adults. The present study addressed this gap in the literature. The sample included White (n = 14,772) and Black (n = 458) college students from multiple colleges across the United States (59% female; 51% freshmen; Mage = 20 years). With alcohol use levels adjusted for, women were more likely to report consequences related to damage to self and dependence-like symptoms than men. There were no significant race differences in either the type or the number of alcohol problems. Further, there was no Race × Alcohol Use interaction in relation to alcohol problems. We found a statistically significant interaction between gender and alcohol use in predicting alcohol problems, suggesting that, at higher levels of drinking, the risk for women to experience alcohol problems was significantly greater than that for men. The reverse race gap in alcohol use and problems may not surface until young adulthood or may not be relevant for those who attend college. College interventions should help both Black and White students reduce problems associated with drinking and focus on limiting harm among female students.


Vocational rehabilitation services for patients with cancer: design of a feasibility study incorporating a pilot randomised controlled trial among women with breast cancer following surgery.
Due to improvements in cancer survival the number of people of working age living with cancer across Europe is likely to increase. UK governments have made commitments to reduce the number of working days lost to ill-health and to improve access to vocational rehabilitation (VR) services. Return to work for people with cancer has been identified as a priority. However, there are few services to support people to remain in or return to work after cancer and no associated trials to assess their impact. A pilot randomised controlled trial among women with breast cancer has been designed to assess the feasibility of a larger definitive trial of VR services for people with cancer. Patients are being recruited from three clinical sites in two Scottish National Health Service (NHS) Boards for 6 months. Eligible patients are all women who are: (1) aged between 18 and 65 years; (2) in paid employment or self-employed; (3) living or working in Lothian or Tayside, Scotland, UK; (4) diagnosed with an invasive breast cancer tumour; (5) treated first with surgery. Patients are randomly allocated to receive referral to a VR service or usual care, which involves no formal employment support. The primary outcome measure is self-reported sickness absence in the first 6 months following surgery. Secondary outcome measures include changes in quality of life (FACT-B), fatigue (FACIT-Fatigue) and employment status between baseline and 6- and 12-months post-surgery. A post-trial evaluation will be conducted to assess the acceptability of the intervention among participants and the feasibility of a larger, more definitive, trial with patients with lung and prostate cancer. To our knowledge this is the first study to determine the feasibility of a randomised controlled trial of the effectiveness of VR services to enable people with cancer to remain in or return to employment. The study will provide evidence to assess the relevance and feasibility of a larger future trial involving patients with breast, prostate or lung cancer and inform the development of appropriate VR services for people living with cancer.


Light-responsive polymers for microfluidic applications.
While the microfluidic device itself may be small, often the equipment required to control fluidics in the chip unit is large e.g. pumps, valves and mixing units, which can severely limit practical use and functional scalability. In addition, components associated with fluidic control of the device, more specifically the valves and pumps, contribute significantly to the overall unit cost. Here we sketch the problem of a gap between high end accurate, but expensive sensor platforms, versus less accurate, but widely employable hand-held low-cost devices. Recent research has shown that the integration of light-responsive materials within microfluidic devices can provide the function of expensive fluidic components, and potentially enable sophisticated measurements to be made using much less expensive equipment. An overview of the most recent developments will be presented for valves, mixers, transport and sample handling inside microfluidic devices.


Magselectofection: an integrated method of nanomagnetic separation and genetic modification of target cells.
Research applications and cell therapies involving genetically modified cells require reliable, standardized, and cost-effective methods for cell manipulation. We report a novel nanomagnetic method for integrated cell separation and gene delivery. Gene vectors associated with magnetic nanoparticles are used to transfect/transduce target cells while being passaged and separated through a high gradient magnetic field cell separation column. The integrated method yields excellent target cell purity and recovery. Nonviral and lentiviral magselectofection is efficient and highly specific for the target cell population as demonstrated with a K562/Jurkat T-cell mixture. Both mouse and human enriched hematopoietic stem cell pools were effectively transduced by lentiviral magselectofection, which did not affect the hematopoietic progenitor cell number determined by in vitro colony assays. Highly effective reconstitution of T and B lymphocytes was achieved by magselectofected murine wild-type lineage-negative Sca-1(+) cells transplanted into Il2rg(-/-) mice, stably expressing GFP in erythroid, myeloid, T-, and B-cell lineages. Furthermore, nonviral, lentiviral, and adenoviral magselectofection yielded high transfection/transduction efficiency in human umbilical cord mesenchymal stem cells and was fully compatible with their differentiation potential. Upscaling to a clinically approved automated cell separation device was feasible. Hence, once optimized, validated, and approved, the method may greatly facilitate the generation of genetically engineered cells for cell therapies.


Prospective study comparing skin impedance with EEG parameters during the induction of anaesthesia with fentanyl and etomidate.
Sympathetic stimulation leads to a change in electrical skin impedance. So far it is unclear whether this effect can be used to measure the effects of anaesthetics during general anaesthesia. The aim of this prospective study is to determine the electrical skin impedance during induction of anaesthesia for coronary artery bypass surgery with fentanyl and etomidate. The electrical skin impedance was measured with the help of an electro-sympathicograph (ESG). In 47 patients scheduled for elective cardiac surgery, anaesthesia was induced with intravenous fentanyl 10 mug/kg and etomidate 0.3mg/kg. During induction, the ESG (Electrosympathicograph), BIS (Bispectral IndeX), BP (arterial blood pressure) and HR (heart rate) values of each patient were recorded every 20 seconds.The observation period from administration of fentanyl to intubation for surgery lasted 4 min. - The ESG recorded significant changes in the electrical skin impedance after administration of fentanyl and etomidate(p <0.05). During induction of anaesthesia, significant changes of BIS, HR and blood pressure were observed as well (p <0.05). The electrical skin impedance measurement may be used to monitor the effects of anesthetics during general anaesthesia.


Capnocytophaga ochracea chronic blepharoconjunctivitis.
A 70-year-old woman presented with a 10-month history of chronic blepharoconjunctivitis that had been unresponsive to multiple methods of treatment. The patient was not immunocompromised and had no history of corneal disease, ocular trauma, or lacrimal duct obstruction. Gram and Giemsa staining of conjunctival smears resulted in visualization of slender, fusiform bacilli. Culture of conjunctival scrapings led to the recovery of a fastidious isolate identified as Capnocytophaga ochracea. The same microorganism was also recovered from cultures of the patient's gingiva. The blepharoconjunctivitis responded well to treatment with fortified cefazolin eye drops. Awareness of this easily overlooked bacterial species should prompt the use of smear and cultural techniques.


Unravelling the electronic structure and dynamics of an isolated molecular rotary motor in the gas-phase.
Light-driven molecular motors derived from chiral overcrowded alkenes are an important class of compounds in which sequential photochemical and thermal rearrangements result in unidirectional rotation of one part of the molecule with respect to another. Here, we employ anion photoelectron spectroscopy to probe the electronic structure and dynamics of a unidirectional molecular rotary motor anion in the gas-phase and quantum chemistry calculations to guide the interpretation of our results. We find that following photoexcitation of the first electronically excited state, the molecule rotates around its axle and some population remains on the excited potential energy surface and some population undergoes internal conversion back to the electronic ground state. These observations are similar to those observed in time-resolved measurements of rotary molecular motors in solution. This work demonstrates the potential of anion photoelectron spectroscopy for studying the electronic structure and dynamics of molecular motors in the gas-phase, provides important benchmarks for theory and improves our fundamental understanding of light-activated molecular rotary motors, which can be used to inform the design of new photoactivated nanoscale devices.


Effect of defunctionalization on colon carcinogenesis in the rat.
to examine the effect of fecal absence on experimental colon carcinogenesis in both male and female rats. a total of 138 10-week-old Sprague-Dawley, male and female rats were divided into five groups: A) 20 rats, no treatment; B) 26 rats, colonic defunctionalization; C) 30 rats, 18 weekly doses of dimethylhydrazine (DMH), 21 mg/kg body weight each, from the beginning of the study; D) 20 rats, ethylen-diamine-tetraacetic acid for 18 weeks; and E) 42 rats, same surgical procedure as rats in group B plus DMH injections at the same doses as rats in group C. Animals were sacrificed after 25-27 weeks. Number of tumors, their location, and pathological findings were all compared between groups. no tumors developed in the dimethylhydrazine-free groups. No differences were obtained either in number of tumors or tumors per rat for group C as compared to group E. Fecal absence was associated with smaller-sized tumors (p = 0.007), greater numbers of non-mucinous tumors (p = 0.00009), better differentiation (p = 0.0054), and lesser penetration into the wall (p = 0.015) for group E as compared to group C. In the dimethylhydrazine group, fecal absence altered the number of tumors developing in males as compared to female rats (p = 0.025). Moreover, this fecal absence showed no inhibitory effect on right colonic tumors (p = 0.0065). fecal absence alters the DMH-carcinogenic pattern in the defunctionalized colon when using an experimental model in both male and female rats.


Acute effects of fenthion on certain oxidative stress biomarkers in various tissues of frogs (Rana ridibunda).
This study was aimed mainly to assess the effects of fenthion on certain oxidative stress biomarkers in various tissues of frogs (Rana ridibunda). Biomarkers selected for stress monitoring were malondialdehyde (MDA) and antioxidant defense system (ADS) such as reduced glutathione (GSH) level, glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), and superoxide dismutase (SOD) activities in the liver, kidney, heart, and brain of frogs exposed to 10 and 20 ppm dosages of fenthion for 24, 48, 72, and 96 h. The results demonstrate an increase in MDA levels in selected tissues following exposure to both concentrations of fenthion. The ADS, GSH-Px, GST, SOD activities and GSH levels also fluctuated after 24, 48, 72, and 96 h in all the treatment groups compared with controls. From the evidence obtained here, it is concluded that the exposure of frogs to fenthion induced an increase in MDA combined with fluctuated ADS. This may reflect the potential role of these parameters as useful biomarkers for oxidative stress in amphibian species.


Assessing the Impact and Equity of an Integrated Rural Sanitation Approach: A Longitudinal Evaluation in 11 Sub-Saharan Africa and Asian Countries.
Few rural sanitation programs have documented large increases in sanitation coverage or have assessed if interventions equitably increase sanitation coverage for vulnerable groups. We characterize the impact of the Sustainable Sanitation and Hygiene for All (SSH4A) approach on key program WASH (water, sanitation, and hygiene) indicators, and also assess if these increases in WASH coverage are equitably reaching vulnerable groups. The SSH4A approach was administered in 12 program areas in 11 countries, including Bhutan, Ethiopia, Ghana, Indonesia, Kenya, Mozambique, Nepal, South Sudan, Tanzania, Uganda, and Zambia. Repeated cross-sectional household surveys were administered over four rounds at annual follow-up rounds from 2014 to 2018. Surveys were conducted in an average of 21,411 households at each round of data collection. Overall, sanitation coverage increased by 53 percentage points between baseline and the final round of data collection (95% CI: 52%, 54%). We estimate that 4.8 million people gained access to basic sanitation in these areas during the project period. Most countries also demonstrated movement up the sanitation ladder, in addition to increases in handwashing stations and safe disposal of child feces. When assessing equity-if sanitation coverage levels were similar comparing vulnerable and non-vulnerable groups-we observed that increases in coverage over time were generally comparable between vulnerable groups and non-vulnerable groups. However, the increase in sanitation coverage was slightly higher for higher wealth households compared to lower wealth households. Results from this study revealed a successful model of rural sanitation service delivery. However, further work should be done to explore the specific mechanisms that led to success of the intervention.


A functional genomics resource for Brassica napus: development of an EMS mutagenized population and discovery of FAE1 point mutations by TILLING.
Two ethylmethanesulfonate (EMS) mutant populations of the semi-winter rapeseed cv. Ningyou7 were constructed with high mutant load, to provide a TILLING platform for functional genomics in Brassica napus, and for introduction of novel allelic variation in rapeseed breeding. Forward genetic screening of mutants from the M2 populations resulted in identification of a large number of novel phenotypes. Reverse genetic screening focused on the potentially multi-paralogous gene FAE1 (fatty acid elongase1), which controls seed erucic acid synthesis in rapeseed. A B. napus BAC library was screened, and loci in a reference mapping population (TNDH) were mapped to conclude that there are two paralogous copies of FAE1, one on each of the B. napus A and C genomes. A new procedure is demonstrated to identify novel mutations in situations where two or more very similar paralogous gene copies exist in a genome. The procedure involves TILLING of single plants, using existing SNPs as a positive control, and is able to distinguish novel mutations based on primer pairs designed to amplify both FAE1 paralogues simultaneously. The procedure was applied to 1344 M2 plants, with 19 mutations identified, of which three were functionally compromised with reduced seed erucic acid content.


The diagnosis and management of cystic lesions of the pancreas.
Cystic lesions of the pancreas are radiographic findings that have a very broad histologic differential. This differential spans the spectrum from benign to cancerous, and includes non-neoplastic pseudocysts, benign neoplastic cysts, pre-malignant cysts, and cystic lesions with invasive carcinoma. This chapter will highlight the challenges with diagnosis and management of patients who present with cystic neoplasms of the pancreas.


Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis.
Advanced glycation end-product (AGE)-damaged IgG occurs as a result of hyperglycemia and/or oxidative stress. Autoantibodies to IgG-AGE were previously demonstrated in patients with severe, longstanding rheumatoid arthritis (RA). We investigated whether IgG-AGE and anti-IgG-AGE antibodies were present early in the course of RA and other inflammatory arthropathies. We prospectively followed a cohort of 238 patients with inflammatory arthritis of duration less than 1 year. Patients were evaluated clinically and serologically, and radiographs were obtained at initial and 1-year visits. Sera were assayed for IgG-AGE and anti-IgG-AGE antibodies by enzyme-linked immunosorbent assay (ELISA). Rheumatoid factor (RF) was determined by nephelometry and ELISA. Of all patients, 29% had RF-positive RA, 15% had RF-negative RA, 18% had spondyloarthropathy, and 38% had undifferentiated arthritis. IgG-AGE was present in 19% of patients, and was similar in amount and frequency in all groups. Patients with elevated IgG-AGE levels had significantly higher levels of the inflammatory markers C-reactive protein and erythrocyte sedimentation rate, but there was no correlation with blood glucose levels. Overall, 27% of the patients had IgM anti-IgG-AGE antibodies. These antibodies were highly significantly associated with RFs (P < 0.0001) and with swollen joint count (P < 0.01). In early onset arthritis, IgG damaged by AGE was detected in all patient groups. The ability to make IgM anti-IgG-AGE antibodies, however, was restricted to a subset of RF-positive RA patients with more active disease. The persistence of the anti-IgG-AGE response was more specific to RA, and was transient in the patients with spondyloarthropathy and with undifferentiated arthritis who were initially found to be positive for anti-IgG-AGE antibodies.


Food outlet availability, deprivation and obesity in a multi-ethnic sample of pregnant women in Bradford, UK.
The obesogenic environment model would suggest that increased availability or access to energy dense foods which are high in saturated fat may be related to obesity. The association between food outlet location, deprivation, weight status and ethnicity was analysed using individual level data on a sample of 1198 pregnant women in the UK Born in Bradford cohort using geographic information systems (GIS) methodology. In the non South Asian group 24% were obese as were 17% of the South Asian group (BMI > 30). Food outlet identification methods revealed 886 outlets that were allocated into 5 categories of food shops. More than 95% of all participants lived within 500 m of a fast food outlet. Women in higher areas of deprivation had greater access to fast food outlets and to other forms of food shops. Contrary to hypotheses, there was a negative association between BMI and fast food outlet density in close (250 m) proximity in the South Asian group. Overall, these women had greater access to all food stores including fast food outlets compared to the non South Asian group. The stronger association between area level deprivation and fast food density than with area level deprivation and obesity argues for more detailed accounts of the obesogenic environment that include measures of individual behaviour.


Effects of functionalized and nonfunctionalized single-walled carbon nanotubes on root elongation of select crop species.
Single-walled carbon nanotubes have many potential beneficial uses, with additional applications constantly being investigated. Their unique properties, however, create a potential concern regarding toxicity, not only in humans and animals but also in plants. To help develop protocols to determine the effects of nanotubes on plants, we conducted a pilot study on the effects of functionalized and nonfunctionalized single-walled carbon nanotubes on root elongation of six crop species (cabbage, carrot, cucumber, lettuce, onion, and tomato) routinely used in phytotoxicity testing. Nanotubes were functionalized with poly-3-aminobenzenesulfonic acid. Root growth was measured at 0, 24, and 48 h following exposure. Scanning-electron microscopy was used to evaluate potential uptake of carbon nanotubes and to observe the interaction of nanotubes with the root surface. In general, nonfunctionalized carbon nanotubes affected root length more than functionalized nanotubes. Nonfunctionalized nanotubes inhibited root elongation in tomato and enhanced root elongation in onion and cucumber. Functionalized nanotubes inhibited root elongation in lettuce. Cabbage and carrots were not affected by either form of nanotubes. Effects observed following exposure to carbon nanotubes tended to be more pronounced at 24 h than at 48 h. Microscopy images showed the presence of nanotube sheets on the root surfaces, but no visible uptake of nanotubes was observed.


Vibration over the larynx increases swallowing and cortical activation for swallowing.
Sensory input can alter swallowing control in both the cortex and brainstem. Electrical stimulation of superior laryngeal nerve afferents increases reflexive swallowing in animals, with different frequencies optimally effective across species. Here we determined 1) if neck vibration overlying the larynx affected the fundamental frequency of the voice demonstrating penetration of vibration into the laryngeal tissues, and 2) if vibration, in comparison with sham, increased spontaneous swallowing and enhanced cortical hemodynamic responses to swallows in the swallowing network. A device with two motors, one over each thyroid lamina, delivered intermittent 10-s epochs of vibration. We recorded swallows and event-related changes in blood oxygenation level to swallows over the motor and sensory swallowing cortexes bilaterally using functional near infrared spectroscopy. Ten healthy participants completed eight 20-min conditions in counterbalanced order with either epochs of continuous vibration at 30, 70, 110, 150, and 70 + 110 Hz combined, 4-Hz pulsed vibration at 70 + 110 Hz, or two sham conditions without stimulation. Stimulation epochs were separated by interstimulus intervals varying between 30 and 45 s in duration. Vibration significantly reduced the fundamental frequency of the voice compared with no stimulation demonstrating that vibration penetrated laryngeal tissues. Vibration at 70 and at 150 Hz increased spontaneous swallowing compared with sham. Hemodynamic responses to swallows in the motor cortex were enhanced during conditions containing stimulation compared with sham. As vibratory stimulation on the neck increased spontaneous swallowing and enhanced cortical activation for swallows in healthy participants, it may be useful for enhancing swallowing in patients with dysphagia.NEW & NOTEWORTHY Vibratory stimulation at 70 and 150 Hz on the neck overlying the larynx increased the frequency of spontaneous swallowing. Simultaneously vibration also enhanced hemodynamic responses in the motor cortex to swallows when recorded with functional near-infrared spectroscopy (fNIRS). As vibrotactile stimulation on the neck enhanced cortical activation for swallowing in healthy participants, it may be useful for enhancing swallowing in patients with dysphagia.


Nonphotic phase shifting in the old and the cold.
When confined to novel running wheels or when given injections of triazolam in their home cages, old hamsters do not become as active as young hamsters. Therefore, lack of nonphotic phase shifting following such manipulations may stem from insufficient activity or arousal. Phase advances can be obtained in some 10-month-old animals when wheel running during the pulse is increased by the presence of females in estrous condition and in most 18-month-old hamsters by combining confinement to a novel wheel with triazolam injections. These data suggest that there is relatively little if anything wrong in aging hamsters with the nonphotic phase-shifting mechanism itself. The reason why in certain situations old hamsters do not shift appears to be because the nonphotic inputs to these shifting mechanisms are not strong enough. However, when running in novel wheels is increased by carrying out the tests at cold temperatures, most old animals did not show subsequent phase shifts. Evidently it is not running per se that is critical for phase shifts, but probably the motivational context for such running.


Identification and characterization of a neutral endopeptidase activity in Aplysia californica.
Kidney plasma membranes of Aplysia californica were shown to contain an endopeptidase activity which cleaved [Leu]enkephalin (Tyr-Gly-Gly-Phe-Leu) and [Leu]enkephalinamide (Tyr-Gly-Gly-Phe-Leu-NH2) at the Gly3-Phe4 bond, as determined by reverse-phase h.p.l.c. analysis of metabolites. The optimal pH was shown to be 6.5. The bivalent cation chelating agent, 1,10-phenanthroline protected [Leu]enkephalin from degradation, suggesting that this enzyme is a metallopeptidase. The degradation of [Leu]enkephalin was also abolished by the neutral endopeptidase-24.11 inhibitors RB104 (2-[(3-iodo-4-hydroxyl)-phenylmethyl]-4-N-[3-(hydroxyamino-3-oxo-1- phenylmethyl)-propyl]amino-4-oxobutanoic acid), HABCO-Gly [(3-hydroxy-aminocarbonyl-2-benzyl-1-oxypropyl)glycine], phosphoramidon and thiorphan, with IC50 values of 1 nM, 1 microM, 20 microM and 30 microM respectively. By contrast, the angiotensin-converting enzyme inhibitor captopril and the serine proteinase inhibitor phenylmethanesulphonyl fluoride were without effect. Phase separation experiments using Triton X-114 showed that about 64% of the neutral endopeptidase activity in the Aplysia kidney membrane corresponds to an integral membrane protein. A specific radioiodinated inhibitor ([125I]RB104) was shown to bind the Aplysia endopeptidase with high affinity; the KD and Bmax. values were 21 +/- 5 pM and 20.3 +/- 5 fmol/mg of proteins respectively. This inhibitor was used to determine the molecular form of the enzyme, after separation of solubilized membrane proteins on SDS/PAGE and transfer on to nitrocellulose membranes. A single protein band with an apparent molecular mass of 140 kDa was observed. The labelling was abolished by specific neutral endopeptidase inhibitors. This study provides the first biochemical characterization of an endopeptidase with catalytic properties similar to those of neutral endopeptidase-24.11 in the mollusc Aplysia californica.


Piezo1, a mechanically activated ion channel, is required for vascular development in mice.
Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.


Retinal blood vessel segmentation using line operators and support vector classification.
In the framework of computer-aided diagnosis of eye diseases, retinal vessel segmentation based on line operators is proposed. A line detector, previously used in mammography, is applied to the green channel of the retinal image. It is based on the evaluation of the average grey level along lines of fixed length passing through the target pixel at different orientations. Two segmentation methods are considered. The first uses the basic line detector whose response is thresholded to obtain unsupervised pixel classification. As a further development, we employ two orthogonal line detectors along with the grey level of the target pixel to construct a feature vector for supervised classification using a support vector machine. The effectiveness of both methods is demonstrated through receiver operating characteristic analysis on two publicly available databases of color fundus images.


The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia.
We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.


Breast cancer screening: early recognition.
The epidemic of breast cancer and the availability of tools to increase early detection and decrease mortality require care and diligence on the part of every physician directly caring for patients. With the widespread implementation of managed care, primary care physicians are in the best position to recommend breast cancer screening. Educational programs to emphasize the primary care physician's role in breast cancer prevention and detection, to improve physical examination skills, and to implement office systems to facilitate screening should be available to primary care physicians, and may have a major impact on breast cancer mortality in the future.


Comparative performance of two mite-resistant stocks of honey bees (Hymenoptera: Apidae) in Alabama beekeeping operations.
The utility of USDA-developed Russian and varroa sensitive hygiene (VSH) honey bees, Apis mellifera L. (Hymenoptera: Apidae), was compared with that of locally produced, commercial Italian bees during 2004-2006 in beekeeping operations in Alabama, USA. Infestations of varroa mites, Varroa destructor Anderson & Truman (Acari: Varroidae), were measured twice each year, and colonies that reached established economic treatment thresholds (one mite per 100 adult bees in late winter; 5-10 mites per 100 adult bees in late summer) were treated with acaricides. Infestations of tracheal mites, Acarapis woodi (Rennie) (Acari: Tarsonemidae), were measured autumn and compared with a treatment threshold of 20% mite prevalence. Honey production was measured in 2005 and 2006 for colonies that retained original test queens. Throughout the three seasons of measurement, resistant stocks required less treatment against parasitic mites than the Italian stock. The total percentages of colonies needing treatment against varroa mites were 12% of VSH, 24% of Russian, and 40% of Italian. The total percentages requiring treatment against tracheal mites were 1% of Russian, 8% of VSH and 12% of Italian. The average honey yield of Russian and VSH colonies was comparable with that of Italian colonies each year. Beekeepers did not report any significant behavioral problems with the resistant stocks. These stocks thus have good potential for use in nonmigratory beekeeping operations in the southeastern United States.


Testing olfactory foraging strategies in an Antarctic seabird assemblage.
Procellariiform seabirds (petrels, albatrosses and shearwaters) forage over thousands of square kilometres for patchily distributed prey resources. While these birds are known for their large olfactory bulbs and excellent sense of smell, how they use odour cues to locate prey patches in the vast ocean is not well understood. Here, we investigate species-specific responses to 3-methyl pyrazine in a sub-Antarctic species assemblage near South Georgia Island (54 degrees 00 ' S, 36 degrees 00 ' W). Pyrazines are scented compounds found in macerated Antarctic krill (Euphausia superba), a primary prey item for many seabird species in this region. To examine behavioural attraction to this odour, we presented birds with either scented or 'unscented' vegetable oil slicks at sea. As a positive control for our experiments, we also compared birds' responses to a general olfactory attractant, herring oil. Responses to pyrazine were both highly species specific and consistent with results from earlier studies investigating responses to crude krill extracts. For example, Cape petrels (Daption capense), giant petrels (Macronectes sp.) and white-chinned petrels (Procellaria aequinoctialis) were sighted at least 1.8-4 times as often at pyrazine-scented slicks than at control slicks. Black-browed albatrosses (Diomedea melanophris) were only sighted at pyrazine-scented slicks and never at control slicks. Wilson's storm-petrels (Oceanites oceanicus), black-bellied storm-petrels (Fregetta tropica), great shearwaters (Puffinus gravis) and prions (Pachyptila sp.) were sighted with equal frequency at control and pyrazine-scented slicks. As expected, responses to herring oil were more common. With the exception of great shearwaters (Puffinus gravis), each of these species was sighted up to five times as often at slicks scented with herring oil compared with control slicks. Together, the results support the hypothesis that Antarctic procellariiforms use species-specific foraging strategies that are inter-dependent and more complex than simply tracking prey by scent.


Microplastics in coastal areas and seafood: implications for food safety.
Microplastics have become ubiquitous in the marine environment. Microplastics have been detected in many coastal environments and species, including commercial seafood. This triggers concern about potential economic impacts and the risks of dietary exposure, especially for coastal communities. However, data regarding the levels of microplastics in coastal seafood and their toxicological effects are still limited. Accordingly, the dietary risk is still poorly explored. This review summarizes and discusses recent scientific findings on (i) the presence of microplastics in coastal waters, (ii) the occurrence of microplastics in coastal seafood and the likelihood of trophic transfer, and (iii) the effects of microplastics on coastal fish and shellfish species. Human toxicity data are also reviewed, but the risks for human health are difficult to determine due to limited data. Based on available worldwide data, the estimation of microplastics intake through seafood consumption shows a huge variation. Additionally, a lack of standardized analytical methods complicates the comparison of results between studies and therefore seriously affects the reliability of risk assessments. It is concluded that more exposure and toxicity data are needed properly to assess human health risks of microplastics in coastal seafood, and the lack of data currently impede the derivation of a risk-based food safety standard. The pros and cons of an interim solution, i.e. setting a provisional action level, are being discussed.


Resting-state quantitative electroencephalography reveals increased neurophysiologic connectivity in depression.
Symptoms of Major Depressive Disorder (MDD) are hypothesized to arise from dysfunction in brain networks linking the limbic system and cortical regions. Alterations in brain functional cortical connectivity in resting-state networks have been detected with functional imaging techniques, but neurophysiologic connectivity measures have not been systematically examined. We used weighted network analysis to examine resting state functional connectivity as measured by quantitative electroencephalographic (qEEG) coherence in 121 unmedicated subjects with MDD and 37 healthy controls. Subjects with MDD had significantly higher overall coherence as compared to controls in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-20 Hz) frequency bands. The frontopolar region contained the greatest number of "hub nodes" (surface recording locations) with high connectivity. MDD subjects expressed higher theta and alpha coherence primarily in longer distance connections between frontopolar and temporal or parietooccipital regions, and higher beta coherence primarily in connections within and between electrodes overlying the dorsolateral prefrontal cortical (DLPFC) or temporal regions. Nearest centroid analysis indicated that MDD subjects were best characterized by six alpha band connections primarily involving the prefrontal region. The present findings indicate a loss of selectivity in resting functional connectivity in MDD. The overall greater coherence observed in depressed subjects establishes a new context for the interpretation of previous studies showing differences in frontal alpha power and synchrony between subjects with MDD and normal controls. These results can inform the development of qEEG state and trait biomarkers for MDD.


In vivo testing of gold nanoparticles using the Caenorhabditis elegans model organism.
Gold nanoparticles (AuNPs) are present in many man-made products and cosmetics and are also used by the food and medical industries. Tight regulations regarding the use of mammalian animals for product testing can hamper the study of the specific interactions between engineered nanoparticles and biological systems. Invertebrate models, such as the nematode Caenorhabditis elegans (C. elegans), can offer alternative approaches during the early phases of nanoparticle discovery. Here, we thoroughly evaluated the biodistribution of 11-nm and 150-nm citrate-capped AuNPs in the model organism C. elegans at multiple scales, moving from micrometric to nanometric resolution and from the organismal to cellular level. We confirmed that the nanoparticles were not able to cross the intestinal and dermal barriers. We investigated the effect of AuNPs on the survival and reproductive performance of C. elegans, and correlated these effects with the uptake of AuNPs in terms of their number, surface area, and metal mass. In general, exposure to 11-nm AuNPs resulted in a higher toxicity than the larger 150-nm AuNPs. NP aggregation inside C. elegans was determined using absorbance microspectroscopy, which allowed the plasmonic properties of AuNPs to be correlated with their confinement inside the intestinal lumen, where anatomical traits, acidic pH and the presence of biomolecules play an essential role on NP aggregation. Finally, quantitative PCR of selected molecular markers indicated that exposure to AuNPs did not significantly affect endocytosis and intestinal barrier integrity. This work highlights how the simple, yet information-rich, animal model C. elegans is ideally suited for preliminary screening of nanoparticles or chemicals mitigating most of the difficulties associated with mammalian animal models, namely the ethical issues, the high cost, and time constraints. This is of particular relevance to the cosmetic, food, and pharmaceutical industries, which all have to justify the use of animals, especially during the discovery, development and initial screening phases. This work provides a detailed and thorough analysis of 11-nm and 150-nm AuNPs at multiple levels of organization (the whole organism, organs, tissues, cells and molecules).


Comparison of automated volumetry of the hippocampus using NeuroQuant® and visual assessment of the medial temporal lobe in Alzheimer's disease.
Background Different clinically feasible methods for evaluation of medial temporal lobe atrophy exists and are useful in diagnostic work-up of Alzheimer's disease (AD). Purpose To compare the diagnostic properties of two clinically available magnetic resonance imaging (MRI)-based methods-an automated volumetric software, NeuroQuant® (NQ) (evaluation of hippocampus volume) and the Scheltens scale (visual evaluation of medial temporal lobe atrophy [MTA])-in patients with AD dementia, and subjective and mild cognitive impairment (non-dementia). Material and Methods MRIs from 56 patients (31 AD, 25 non-dementia) were assessed with both methods. Correlations between the methods were calculated and receiver operating curve (ROC) analyses that yield area under the curve (AUC) statistics were conducted. Results High correlations were found between the two MRI assessments for the total hippocampal volume measured with NQ and mean MTA score (-0.753, P < 0.001), for the right (-0.767, P < 0.001), and for the left (-0.675, P < 0.001) sides. The NQ total measure yielded somewhat higher AUC (0.88, "good") compared to the MTA mean measure (0.80, "good") in the comparison of patients with AD and non-dementia, but the accuracy was in favor of the MTA scale. Conclusion The two methods correlated highly and both methods reached equally "good" power.


Membrane insertion defects caused by positive charges in the early mature region of protein pIII of filamentous phage fd can be corrected by prlA suppressors.
The filamentous phage coat protein pIII has been used to display a variety of peptides and proteins to allow easy screening for desirable binding properties. We have examined the biological constraints that restrict the expression of short peptides located in the early mature region of pIII, adjacent to the signal sequence cleavage site. Many functionally defective pIII fusion proteins contained several positively charged amino acids in this region. These residues appear to inhibit proper insertion of pIII into the Escherichia coli inner membrane, blocking the assembly and extrusion of phage particles. Suppressor mutations in the prlA (secY) component of the protein export apparatus dramatically alleviate the phage growth defect caused by the positively charged residues. We conclude that insertion of pIII fusion proteins into the inner membrane can occur by a sec gene-dependent mechanism. The suppressor strains should be useful for increasing the diversity of peptides displayed on pIII in phage libraries.


The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer.
HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome. We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis. HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels. HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.


The association between the end of court-ordered school desegregation and preterm births among Black women.
Racial segregation, and in particular school segregation, likely plays an important role in affecting health outcomes. To examine this connection, this paper explores the relationship between the end of court-ordered school desegregation and preterm births among Blacks using birth certificate information between 1992 and 2002 (n = 183,178). The end of court-ordered oversight has important implications for the level of racial segregation in schools: If residential segregation remains high, neighborhood-based student assignment plans would naturally increase school segregation. A rise in school segregation may lead to worse educational, labor, and health outcomes among Blacks. Using multiple difference-in-differences framework that exploits variation in exposure to schools that declared unitary status, it finds that school districts' release from court oversight is associated with a 0.8 percentage point increase in preterm births among Black mothers. This paper contributes to literature that finds that the end of court-ordered school desegregation in the 1990s have negative implications for Blacks. More research should be conducted to understand the causal relationship between school segregation and infant health.


Real-time imaging and elemental mapping of AgAu nanoparticle transformations.
We report the controlled alloying, oxidation, and subsequent reduction of individual AgAu nanoparticles in the scanning transmission electron microscope (STEM). Through sequential application of electron beam induced oxidation and in situ heating and quenching, we demonstrate the transformation of Ag-Au core-shell nanoparticles into: AgAu alloyed, Au-Ag core-shell, hollow Au-Ag2O core-shell, and Au-Ag2O yolk-shell nanoparticles. We are able to directly image these morphological transformations in real-time at atomic resolution and perform energy dispersive X-ray (EDX) spectrum imaging to map changing elemental distributions with sub-nanometre resolution. By combining aberration corrected STEM imaging and high efficiency EDX spectroscopy we are able to quantify not only the growth and coalescence of Kirkendall voids during oxidation but also the compositional changes occurring during this reaction. This is the first time that it has been possible to track the changing distribution of elements in an individual nanoparticle undergoing oxidation driven shell growth and hollowing.


Impact of venous thromboembolism on mortality of elderly Medicare patients with stage III colon cancer.
The improvement in survival rates for patients with colon cancer has shifted the focus from examining cancer-specific mortality to exploring all-cause mortality. Adverse events such as venous thromboembolism (VTE) affect overall survival times and the net clinical benefit of cancer management strategies. This retrospective study used Surveillance, Epidemiology and End Results (SEER) Medicare data to examine VTE incidence and mortality rates for elderly patients with stage III colon cancer who were diagnosed in 2004 or 2005 and followed through 2007. The impact of VTE on mortality was estimated using multivariable Cox proportional hazards regression. In all, 20.7% of 4,985 elderly patients with stage III colon cancer had clinically diagnosed VTE following diagnosis. All-cause mortality risk was higher for patients with a VTE diagnosis (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.04-1.27), greater comorbidity burden, more advanced tumor depth and nodal involvement within stage III, advanced age, and male sex; the risk was lower for patients treated with chemotherapy. VTE was associated with higher mortality hazards (HR: 1.41, 95% CI: 1.21-1.64) for patients treated with adjuvant chemotherapy but not for untreated patients. A new diagnosis of VTE significantly reduced survival rates for elderly patients with stage III colon cancer and further reduced survival rates for patients treated with chemotherapy. Improved prevention and management of VTE for elderly patients with stage III colon cancer who are at risk for VTE is warranted, particularly for patients treated with chemotherapy.


Uptake of 99mTc-exametazime shown by single photon emission computerized tomography in obsessive-compulsive disorder compared with major depression and normal controls.
Twelve patients with obsessive-compulsive disorder (OCD) were investigated at rest using single photon emission computerized tomography with 99mTc-exametazime. The uptake of 99mTc-exametazime was expressed relative to calcarine/occipital cortex. Patients were matched for drug treatment with 12 patients with a major depressive episode and the patient groups were compared with a control group. Significant bilateral decreases in tracer uptake were confined to basal ganglia in the OCD group. There was a paradoxical positive correlation between anxiety ratings and tracer uptake to basal ganglia in the OCD group. The findings confirm that the functional topography of OCD implicates altered function in the basal ganglia.


First Report of Soybean Rust (Phakopsora pachyrhizi) in Nigeria.
Rust caused by Phakopsora pachyrhizi H. & P. Sydow was observed for the first time on soybean (Glycine max [L.] Merr.) in Nigeria during the 1999 main soybean growing season. The disease was first noticed on soybean farms in Oniyo and neighboring villages located about 20 km west of Ogbomoso (Long. 4° 02' E and Lat. 8° 06' N), Oyo State, Nigeria. The area falls under the moist savanna vegetation with a bimodal rainfall pattern (from April to July, September to November) and an annual mean rainfall of 1,370 mm. Commercial cultivation of soybean by farmers in the area started in 1986. A similar disease outbreak in 1999 on soybean in Benue state, the major area of soybean production in Nigeria, could not be confirmed to be rust. In the Oniyo area, soybean is commonly grown as an early season crop usually planted between March and April in small plots to produce seeds for the main crop, normally planted in July. Rust was not observed on the early season soybean crop grown in the area in 1999. Symptoms were first observed on leaves close to the ground in September 1999 as chlorotic spots, which progressed to reddish brown lesions, then uredia. The symptoms appeared further up the plant until all the leaves were infected. Pimple-like uredia observed in the lesions were more pronounced and numerous on the lower surface of the leaves than on the upper leaf surface. Uredia were noted to cluster together in clumps (1). The urediospores released from a central ostiole in the uredia were hyaline and oblong, 17 μm wide (15 to 18 μm) and 22 μm long (19 to 25 μm). Premature defoliation occurred on infected plants. Seed weight of TGX 1485-1D, TGX 1448-2E, and TGX 1440-1E was reduced by 28, 52, and 49%, respectively. Disease severity was higher on the medium maturing cultivars and all those that were planted late. Reference: (1) J. B. Sinclair. 1983. Compendium of Soybean Diseases, 2nd ed. The American Phytopathological Society, St. Paul, MN.


Coronary "balanced ischemia" with false negative regadenoson Technetium Tc99 m Sestamibi stress test subsequently diagnosed by FFRCT.
A 63-year-old female with multiple cardiovascular risk factors presented with a nontypical chest pain syndrome. Myocardial perfusion imaging (MPI) with a regadenoson (Lexiscan) Technetium Tc99 m (Sestamibi) stress test was interpreted as normal. The patient's chest pain syndrome continued, and subsequently, she presented to the emergency room. Cardiac computed tomographic angiography (CCTA) revealed a partially calcified left main coronary artery (LMCA) plaque with mild positive remodeling, having low attenuation (68 Hounsfield units-HU) in the noncalcified portion. In addition, a significant proximal left anterior descending coronary artery (LAD) noncalcified plaque was also noted. These lesions were hemodynamically significant by CCTA fractional flow reserve (FFRCT ) as evidenced by a significant drop across the LMCA, followed by the LAD and circumflex (CX) vessels. Stenting of the stenosis was performed with resolution of symptoms. The phenomenon of "balanced ischemia" was not readily detected with a regadenoson Technetium Tc99 m perfusion stress test but was readily documented by FFRCT .


Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-γ, IL-2 and IL-2R.
Complex interactions between effector T cells and Foxp3(+) regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression.


Comparative gene expression in sexual and apomictic ovaries of Pennisetum ciliare (L.) Link.
Limited emphasis has been given to the molecular study of apomixis, an asexual method of reproduction where seeds are produced without fertilization. Most buffelgrass (Pennisetum ciliare (L.) Link syn = Cenchrus ciliaris L.) genotypes reproduce by obligate apomixis (apospory); however, rare sexual plants have been recovered. A modified differential display procedure was used to compare gene expression in unpollinated ovaries containing ovules with either sexual or apomictic female gametophytes. The modification incorporated end-labeled poly(A)+ anchored primers as the only isotopic source, and was a reliable and consistent approach for detecting differentially displayed transcripts. Using 20 different decamers and two anchor primers, 2268 cDNA fragments between 200 and 600 bp were displayed. From these, eight reproducible differentially displayed cDNAs were identified and cloned. Based on northern analysis, one cDNA was detected in only the sexual ovaries, two cDNAs in only apomictic ovaries and one cDNA was present in both types of ovaries. Three fragments could not be detected and one fragment was detected in ovaries, stems, and leaves. Comparison of gene expression during sexual and apomictic development in buffelgrass represents a new model system and a strategy for investigating female reproductive development in the angiosperms.


Genetic influence on scar height and pliability after burn injury in individuals of European ancestry: A prospective cohort study.
After similar extent of injury there is considerable variability in scarring between individuals, in part due to genetic factors. This study aimed to identify genetic variants associated with scar height and pliability after burn injury. An exome-wide array association study and gene pathway analysis were performed on a prospective cohort of 665 patients treated for burn injury. Outcomes were scar height (SH) and scar pliability (SP) sub-scores of the modified Vancouver Scar Scale (mVSS). DNA was genotyped using the Infinium® HumanCoreExome-24 BeadChip. Associations between genetic variants (single nucleotide polymorphisms) and SH and SP were estimated using an additive genetic model adjusting for age, sex, number of surgical procedures and % total body surface area of burn in subjects of European ancestry. No individual genetic variants achieved the cut-off threshold of significance. Gene regions were analysed for spatially correlated single nucleotide polymorphisms and significant regions identified using comb-p software. This gene list was subject to gene pathway analysis to find which biological process terms were over-represented. Using this approach biological processes related to the nervous system and cell adhesion were the predominant gene pathways associated with both SH and SP. This study suggests genes associated with innervation may be important in scar fibrosis. Further studies using similar and larger datasets will be essential to validate these findings.


Psychosocial impact of perinatal loss among Muslim women.
Women of reproductive age are vulnerable to psychosocial problems, but these have remained largely unexplored in Muslim women in developing countries. The aim of this study was to explore and describe psychosocial impact and social support following perinatal loss among Muslim women. A qualitative study was conducted in a specialist centre among Muslim mothers who had experienced perinatal loss. Purposive sampling to achieve maximum variation among Muslims in relation to age, parity and previous perinatal death was used. Data was collected by focus group discussion and in-depth unstructured interview until the saturation point met. Sixteen mothers who had recent perinatal loss of wanted pregnancy, had received antenatal follow up from public or private health clinics, and had delivery in our centre participated for the study. All of them had experienced psychological difficulties including feelings of confusion, emptiness and anxiety over facing another pregnancy. Two out of sixteen showed anger and one felt guilt. They reported experiencing a lack of communication and privacy in the hospital during the period of grief. Family members and friends play an important role in providing support. The majority agreed that the decision makers were husbands and families instead of themselves. The respondents felt that repetitive reminder of whatever happened was a test from God improved their sense of self-worth. They appreciated this reminder especially when it came from husband, family or friends closed to them. Muslim mothers who had experienced perinatal loss showed some level of adverse psychosocial impact which affected their feelings. Husbands and family members were the main decision makers for Muslim women. Health care providers should provide psychosocial support during antenatal, delivery and postnatal care. On-going support involving husband should be available where needed.


Endemic burkholderia cepacia bacteraemia: clinical features and antimicrobial susceptibilities of isolates.
Burkholderia cepacia has emerged as a nosocomial pathogen, causing numerous outbreaks, particularly among cystic fibrosis (CF) patients. Reports of clinical features of endemic B. cepacia bacteraemia in non-CF patients are rare. Twenty-five patients with B. cepacia bacteraemia were matched with 25 controls with nosocomial Escherichia coli bacteraemia at China Medical College Hospital, Taichung, Taiwan, over a period of 3 y. Case-patients included 16 men and 9 women, from 13 to 75 y. All had severe underlying diseases, most commonly malignancy (44%). Twenty-four patients (96%) had nosocomial infections. Five patients (20%) had polymicrobial bacteraemia. Our controls included 11 men and 14 women, age range 18-80 y. The most common underlying disease was malignancy (44%). Multivariate analysis revealed that indwelling central venous catheter was the significant risk factor predisposing to B. cepacia bacteraemia (p= 0.025). Eleven case-patients met the definition of catheter-related bloodstream infection. Fifteen patients (60%) received appropriate antimicrobial therapy after notification of positive blood cultures and susceptibility patterns. The overall case-fatality rate was 12% (3/25), only 1 of whom died of B. cepacia bacteraemia. There was no statistically significant difference in overall mortality rate between case-patients and controls. All isolates were susceptible to ceftazidime, piperacillin and minocycline and 84% of the isolates were susceptible to imipenem. B. cepacia should be considered a potential pathogen in hospitalized patients with severe underlying diseases, particularly those with indwelling central venous catheters.


GaN-based light-emitting diodes on various substrates: a critical review.
GaN and related III-nitrides have attracted considerable attention as promising materials for application in optoelectronic devices, in particular, light-emitting diodes (LEDs). At present, sapphire is still the most popular commercial substrate for epitaxial growth of GaN-based LEDs. However, due to its relatively large lattice mismatch with GaN and low thermal conductivity, sapphire is not the most ideal substrate for GaN-based LEDs. Therefore, in order to obtain high-performance and high-power LEDs with relatively low cost, unconventional substrates, which are of low lattice mismatch with GaN, high thermal conductivity and low cost, have been tried as substitutes for sapphire. As a matter of fact, it is not easy to obtain high-quality III-nitride films on those substrates for various reasons. However, by developing a variety of techniques, distincts progress has been made during the past decade, with high-performance LEDs being successfully achieved on these unconventional substrates. This review focuses on state-of-the-art high-performance GaN-based LED materials and devices on unconventional substrates. The issues involved in the growth of GaN-based LED structures on each type of unconventional substrate are outlined, and the fundamental physics behind these issues is detailed. The corresponding solutions for III-nitride growth, defect control, and chip processing for each type of unconventional substrate are discussed in depth, together with a brief introduction to some newly developed techniques in order to realize LED structures on unconventional substrates. This is very useful for understanding the progress in this field of physics. In this review, we also speculate on the prospects for LEDs on unconventional substrates.


Age of Occurrence and Severity of Childhood Sexual Abuse: Impacts on Health Outcomes in Men Who Have Sex with Men and Transgender Women.
Childhood sexual abuse (CSA) is associated with a wide range of health outcomes and is more prevalent among men who have sex with men (MSM) compared to men who have sex with women exclusively and among transgender women (TW) compared to cisgender peers; however, there is a lack of consensus regarding an explanatory theoretical model. This analysis examined these models across health outcomes using baseline data from a longitudinal study of MSM and TW in Chicago (n = 1,035) collected from 2015 to 2019. Severity of CSA was measured for two age ranges (prior to 13 and 13-17). Logistic regression and negative binomial regressions were estimated. Teenage experiences of CSA were associated with alcohol problems, cannabis problems, suicide ideation/attempt, depression, condomless anal sex partners, rectal STI, and HIV. Pre-teenage CSA was associated with alcohol use and depressive symptoms. Significant interactions across age of experience of CSA were found for alcohol problems, cannabis problems, and condomless anal sex partners. Consistent with previous literature, this analysis found CSA to be a significant influence on various health outcomes. No single explanatory framework emerged; however, adolescent exposures may be more closely linked to health outcomes and risk behaviors than pre-teenage or cumulative exposures.


Decomposition of leaf litter from a native tree and an actinorhizal invasive across riparian habitats.
Dynamics of nutrient exchange between floodplains and rivers have been altered by changes in flow management and proliferation of nonnative plants. We tested the hypothesis that the nonnative, actinorhizal tree, Russian olive (Elaeagnus angustifolia), alters dynamics of leaf litter decomposition compared to native cottonwood (Populus deltoides ssp. wislizeni) along the Rio Grande, a river with a modified flow regime, in central New Mexico (U.S.A.). Leaf litter was placed in the river channel and the surface and subsurface horizons of forest soil at seven riparian sites that differed in their hydrologic connection to the river. All sites had a cottonwood canopy with a Russian olive-dominated understory. Mass loss rates, nutrient content, fungal biomass, extracellular enzyme activities (EEA), and macroinvertebrate colonization were followed for three months in the river and one year in forests. Initial nitrogen (N) content of Russian olive litter (2.2%) was more than four times that of cottonwood (0.5%). Mass loss rates (k; in units of d(-1)) were greatest in the river (Russian olive, k = 0.0249; cottonwood, k = 0.0226), intermediate in subsurface soil (Russian olive, k = 0.0072; cottonwood, k = 0.0031), and slowest on the soil surface (Russian olive, k = 0.0034; cottonwood, k = 0.0012) in a ratio of about 10:2:1. Rates of mass loss in the river were indistinguishable between species and proportional to macroinvertebrate colonization. In the riparian forest, Russian olive decayed significantly faster than cottonwood in both soil horizons. Terrestrial decomposition rates were related positively to EEA, fungal biomass, and litter N, whereas differences among floodplain sites were related to hydrologic connectivity with the river. Because nutrient exchanges between riparian forests and the river have been constrained by flow management, Russian olive litter represents a significant annual input of N to riparian forests, which now retain a large portion of slowly decomposing cottonwood litter with a high potential for N immobilization. As a result, retention and mineralization of litter N within these forests is controlled by hydrologic connectivity to the river, which affects litter export and in situ decomposition.


A wide diversity of bacteria from the human gut produces and degrades biogenic amines.
Background: Biogenic amines (BAs) are metabolites produced by the decarboxylation of amino acids with significant physiological functions in eukaryotic and prokaryotic cells. BAs can be produced by bacteria in fermented foods, but little is known concerning the potential for microbes within the human gut microbiota to produce or degrade BAs. Objective: To isolate and identify BA-producing and BA-degrading microbes from the human gastrointestinal tract. Design: Fecal samples from human volunteers were screened on multiple growth media, under multiple growth conditions. Bacterial species were identified using 16S rRNA sequencing and BA production or degradation was assessed using ultra-performance liquid chromatography. Results: In total, 74 BA-producing or BA-degrading strains were isolated from the human gut. These isolates belong to the genera Bifidobacterium, Clostridium, Enterococcus, Lactobacillus, Pediococcus, Streptococcus, Enterobacter, Escherichia, Klebsiella, Morganella and Proteus. While differences in production or degradation of specific BAs were observed at the strain level, our results suggest that these metabolic activities are widely spread across different taxa present within the human gut microbiota. Conclusions: The isolation and identification of microbes from the human gut with BA-producing and BA-degrading metabolic activity is an important first step in developing a better understanding of how these metabolites influence health and disease.


Synthesis of novel fluconazoliums and their evaluation for antibacterial and antifungal activities.
A series of novel fluconazoliums were synthesized and their bioactive evaluation as potential antibacterial and antifungal agents were described. Some target compounds displayed good and broad-spectrum antimicrobial activities with low MIC values ranging from 0.25 to 64 μg/mL against all the tested strains, including three Gram-positive bacteria (Staphylococcus aureus, MRSA and Bacillus subtilis), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Bacillus proteus) as well as two fungi (Candida albicans and Aspergillus fumigatus). Among all tested title compounds, the octyl, dichlorobenzyl, naphthyl and naphthalimino derivatives gave comparable or even better antibacterial and antifungal efficiency in comparison with the reference drugs Fluconazole, Chloromycin and Norfloxacin.


Evidence that electrostatic interactions between vesicle-associated membrane protein 2 and acidic phospholipids may modulate the fusion of transport vesicles with the plasma membrane.
The juxtamembrane domain of vesicle-associated membrane protein (VAMP) 2 (also known as synaptobrevin2) contains a conserved cluster of basic/hydrophobic residues that may play an important role in membrane fusion. Our measurements on peptides corresponding to this domain determine the electrostatic and hydrophobic energies by which this domain of VAMP2 could bind to the adjacent lipid bilayer in an insulin granule or other transport vesicle. Mutation of residues within the juxtamembrane domain that reduce the VAMP2 net positive charge, and thus its interaction with membranes, inhibits secretion of insulin granules in beta cells. Increasing salt concentration in permeabilized cells, which reduces electrostatic interactions, also results in an inhibition of insulin secretion. Similarly, amphipathic weak bases (e.g., sphingosine) that reverse the negative electrostatic surface potential of a bilayer reverse membrane binding of the positively charged juxtamembrane domain of a reconstituted VAMP2 protein and inhibit membrane fusion. We propose a model in which the positively charged VAMP and syntaxin juxtamembrane regions facilitate fusion by bridging the negatively charged vesicle and plasma membrane leaflets.


The role of beta cell heterogeneity in islet function and insulin release.
It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.


Tuberculosis case finding in first-degree relative contacts not living with index tuberculosis cases in Kampala, Uganda.
To assess the prevalence of pulmonary tuberculosis among first-degree relative (FDR) contacts not living with tuberculosis (TB) cases. A cross-sectional analysis of household contacts living with an index TB case and FDR contacts living outside of households in Kampala, Uganda, is presented. A total of 177 contacts (52 FDRs and 125 index household contacts) of 31 TB cases were examined. Compared with index household contacts, FDR contacts were older, more likely to be TB symptomatic (50% vs 33%), had a higher percentage of abnormal chest X-rays (19% vs 11%), sputum smear positive (15% vs 5%), and many similar epidemiologic risk factors, including HIV infection (13% vs 10%). Contact groups had similar pulmonary tuberculosis prevalence: 9.6% in FDR vs 10.4% in index household contacts and similar Mycobacterium tuberculosis infection: 62% in FDR vs 61% in index households. TB is common among FDR contacts. High TB prevalence justifies targeting FDRs during household contact investigations. Combining TB active-case finding among FDR contacts with household contact investigation in low-income setting is feasible. This should be part of national TB control program strategies for increasing TB case-detection rates and reducing community TB transmission and death.


Functional connectivity: integrating behavioral, diffusion tensor imaging, and functional magnetic resonance imaging data sets.
In the present study, we combined 2 types of magnetic resonance technology to explore individual differences on a task that required the recognition of objects presented from unusual viewpoints. This task was chosen based on previous work that has established the necessity of information transfer from the right parietal cortex to the left inferior cortex for its successful completion. We used reaction times (RTs) to localize regions of cortical activity in the superior parietal and inferior frontal regions (blood oxygen level-dependent [BOLD] response) that were more active with longer response times. These regions were then sampled, and their signal change used to predict individual differences in structural integrity of white matter in the corpus callosum (using diffusion tensor imaging). Results show that shorter RTs (and associated increases in BOLD response) are associated with increased organization in the splenium of the corpus callosum, whereas longer RTs are associated with increased organization in the genu.


Interspecific Hybridization of Meiotic Parthenogenetic Meloidogyne chitwoodi and M. fallax.
ABSTRACT Hybridization between two meiotic parthenogenetic species of root-knot nematodes, Meloidogyne chitwoodi and M. fallax, was investigated in two different crossing experiments on tomato plants grown in sand. The first experiment was a controlled cross between the two species. The second experiment was a bulk mating in a 1:1 mixture of two isolates. The haploid chromosome number of the parental isolates was n = 18. Successful interspecific hybridization was obtained, and the resulting hybrids produced egg masses. In eggs, cell division was observed, but most of them were without clear differentiation and consequently were sterile. Hatched F(2) juveniles were small in number, not viable, and showed morphological distortions. In the progeny of the isolate mixture of the bulk mating experiment, parental-type females of the two isolates were present in equal numbers, and 10% of all females were nonviable hybrids. Similar ratios of parental-type and hybrid females were detected in roots of test plants grown in soil from a field sample that contained a mixture of M. chitwoodi and M. fallax populations. In the controlled cross experiment, isozyme electrophoresis of malate dehydrogenase was applied to distinguish the two species and their hybrids. In the bulk mating experiment, malate dehydrogenase, esterase, and glucose 6-phosphate dehydrogenase were used as markers, two by two simultaneously on the same individual females, providing conclusive evidence for the occurrence of hybrids. This is the first report on interspecific hybridization in Meloidogyne. The possible role of interspecific hybridization in species differentiation and interspecific exchange of genetic material within Meloidogyne is discussed.


Effect of white tea consumption on serum leptin, TNF-α and UCP1 gene expression in ovariectomized rats.
Obesity and dyslipidemia due to estrogen deficiency are among the important health problems in menopausal women. Increasing evidence reports the anti-obesity and anti-hyperlipidemic properties of tea polyphenols. However, the effect of white tea (WT) with high polyphenol content on overweight and lipid profile is uncertain. Here, we aimed to examine the effects of long-term WT consumption on serum leptin, tumor necrosis factor- alpha (TNF-α) and uncoupling protein 1 (UCP1) mRNA gene expression in ovariectomized (OVX) rats. Adult rats were divided into four groups (n = 8): (i) sham, (ii) OVX, (iii) WT and (iv) OVX + WT. WT was given at a dose of 0.5% w/v for 12 weeks. In the study, body weight, serum leptin, TNF, estradiol (E2) levels, lipid profile and UCP1 mRNA gene expression in brown adipose tissue (BAT) were evaluated. There was a significant increase in body weight of OVX rats, which was decreased following WT consumption. While leptin and E2 levels decreased in the OVX group, TNF levels increased. There was no difference between the NF-kB levels of the groups. In addition, BAT UCP1 mRNA expression was significantly decreased in OVX groups, while WT treatment stimulated UCP1 activity. We explain the stimulatory effect of WT on weight loss mainly by the induction of UCP1 gene-mediated thermogenesis and suppression of inflammation. Therefore, we suggest that prolonged WT consumption may have beneficial effects in limiting excess weight gain caused by estrogen deficiency.


Self-assembled thermoresponsive nanostructures of hyaluronic acid conjugates for osteoarthritis therapy.
Under pathological conditions, joints and skin are often affected by an imbalance in the breakdown and production of hyaluronic acid (HA). The unique biochemical and biomechanical properties provided by HA must be restored for the long-term lubrication and cushioning effects. To overcome the inconvenience of repeated injections and the rapid degradation of exogenous HA treatments, HA is conjugated to a thermosensitive polymer, enabling the spontaneous formation of nanoparticles (HA Nano) at body temperature. Three HA Nano preparations are tested for their injectability, sensitivity to enzymatic degradation and cytocompatibility. One of them is delivered via subcutaneous and intra-articular injections to healthy mice and tested in a murine osteoarthritis (OA) model. It is found to be biocompatible, to offer a prolonged residence time at the injection site, have the ability to protect cartilage, to reduce pro-inflammatory cytokines and to preserve epiphysis thickness. In this study, HA Nano spontaneously forms nanoparticles at body temperature in vivo and is a promising candidate for the next generation of the sustainable/long-lasting treatment of OA and potentially also dermatological conditions.


MCI patients declining and not-declining at mid-term follow-up: FDG-PET findings.
Patients with Mild Cognitive Impairment (MCI) not converted to dementia at one to three years follow-up represent a heterogeneous group across studies, by including 'late converters' but also patients without any neurodegenerative disease. We tested the hypothesis that the combination of memory and brain metabolic assessment could identify subgroups of memory decliners (MCI/Decl) and non-decliners (MCI/noDecl) before a long follow-up time is available. From twenty-nine patients with amnestic MCI (aMCI) at baseline, three groups were identified at follow-up: 10 patients who converted to AD (MCI/AD); 10 patients either showing episodic memory worsening or reaching the floor effect on memory and declining in other key tests (MCI/Decl) and 9 patients showing no memory worsening or even improvement (MCI/noDecl). They were compared with a group of fourteen elderly controls (CTR) by means of basal FDG-PET voxel-based analysis (SPM2). Two hypometabolic clusters were found in MCI/AD versus CTR, including the bilateral posterior cingulate cortex, the left parietal precuneus and the left fusiform gyrus. MCI/AD showed also a large hypometabolic region, mainly including the left medium and superior temporal gyri and inferior parietal lobule, when compared to MCI/noDecl. The MCI/Decl showed a hypometabolic region in the left medial temporal lobe versus both CTR (hippocampus) and MCI/noDecl (parahippocampal gyrus and hippocampus). No significant difference was found in the comparison between CTR and MCI/noDecl, neither in the comparison between MCI/Decl and MCI/AD. Thus, non converter MCI patients comprised a sub-group of 'decliners' with AD-like metabolic and cognitive patterns, likely including 'late converters', and a sub-group lacking this pattern, with stable or improving memory function and a brain metabolic picture similar to that in healthy controls. Combining neuropsychological and FDG-PET information could be used for prognostic purposes in aMCI patients at medium-term follow-up.


Root caries on a Paranthropus robustus third molar from Drimolen.
Dental caries is often perceived as a modern human disease. However, their presence is documented in many early human groups, various nonhuman primates and, increasingly, our hominin ancestors and relatives. In this study, we describe an antemortem lesion on the root of a Paranthropus robustus third molar from Drimolen, South Africa, which likely represents another example of caries in fossil hominins. The molar, DNH 40, is dated to 2.0-1.5 Ma and displays a lesion on the mesial root surface, extending from the cementoenamel junction 3 mm down toward the apex. The position and severity of the lesion was macroscopically recorded and micro-CT scanned to determine the extent of dentine involvement. A differential diagnosis indicates root caries, as the lesion is indistinguishable from clinical examples. Although necrotic in appearance, external tertiary dentine is evident on a micro CT scan. Gingival recession and/or continuous eruption of the tooth as a result of extensive occlusal wear would have occurred to facilitate caries formation. Therefore, the lesion is likely linked to relative old age of this individual. This new example increases the total number of carious lesions described in P. robustus teeth to 10, on occlusal, interproximal, and now, root surfaces. Beyond the consumption of caries-causing food, caries formation would have also required the presence of requisite intraoral cariogenic bacteria in this individual and the species. Of interest, the presence of tertiary dentine on the outward surface suggests the DNH 40 lesion may have been arrested, that is, no longer active, perhaps relating to a change in diet or oral microbiome just prior to the individual's death.


Atmospheric refraction and lake monsters.
A survey of reported sightings of lake monster phenomena suggests that many of them may be attributable to atmospheric image distortion. The existence of the necessary conditions (surface temperature inversion and hence strong atmospheric refraction) can be inferred from most of the reports. Under such conditions familiar objects can easily take on unrecognizable form. Two photographs demonstrate the extent of the distortion that can occur.


Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists.
Recombinant thrombopoietin has been reported to stimulate megakaryocytopoiesis and thrombopoiesis and it may be quite useful to treat patients with low platelet counts after chemotherapy. As little is known regarding the possible activation of platelets by thrombopoietin, we examined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as an anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet aggregation induced by 2 micromol/L adenosine-diphosphate (ADP) in a dose dependent fashion. The enhancement was not affected by treatment of platelets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 micromol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 micromol/L), which does not induce platelet aggregation in hirudin platelet rich plasma (PRP), did so in the presence of thrombopoietin (10 ng/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggregation induced by collagen (0.5 micron.mL),. thrombin, serotonin, and vasopressin. Thrombopoietin does not induce any rise in cytosolic ionized calcium concentration nor activation of protein kinase C, as estimated by phosphorylation of preckstrin, indicating that the priming effects of thrombopoietin does not require those processes. The ADP- or thrombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm2)-induced platelet aggregation was also potentiated by thrombopoietin. The priming effect on epinephrine-induced platelet aggregation in hirudin PRP was unique to thrombopoietin, with no effects seen using interleukin-6 (IL-6), IL-11, IL-3, erythropoietin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functions may be necessary in the clinical trials of thrombopoietin.


Conditioning regimens for allotransplants for diffuse large B-cell lymphoma: myeloablative or reduced intensity?
The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.


The General Medical Council: frame of reference or arbiter of morals?
Many members of the public think of the General Medical Council (GMC) as the body which tries doctors: the doctors' law courts, as it were. And, except in the more sober of newspapers and news reports, the 'offences ' which receive the most publicity are those concerning alleged improper relations between doctors and patients. Professor Sir Denis Hill, in the following paper, which he read in the spring of this year to the annual conference of the London Medical Group devoted to a discussion of human sexuality, chose to examine the whole function of the General Medical Council as a frame of moral reference for doctors. Judging allegations of professional misconduct by doctors is the function of the Council's Disciplinary Committee. Judging sexual misconduct forms only a small part of their work. The GMC's responsibility covers the whole notion of morals and morality as it concerns doctors in their professional work. Sir Denis Hill stresses the modern thinking that morality must be learned and that attitudes are always shifting as society alters its norms of what is moral conduct. That is not to say that all that was previously considered not to be moral has now become acceptable but rather that other concepts have entered the field of moral debate. Therefore the GMC must constantly review the frame of reference it offers to doctors and the public may be surprised to learn that that process is never static. Sir Denis Hill in this paper is speaking personally and not as a member of the General Medical Council or of any of that body's special committees.


[Cytokine-mediated biological response to severe infections in surgical patients].
Cytokines serve to initiate the acute inflammatory response and to integrate nonspecific and specific immunological responses to infections occurring in perioperative patients. Microbial substances induce macrophages to produce pivotal cytokines (TNF-alpha and IL-1 beta). This results in an activation of other cytokine productions including IL-2, IL-3, IL-4, IL-6, chemokines, and IL-10. Also, other host-originated humoral mediators are released from macrophages, neutrophils, platelets, and endothelial cells Various cytokines are also produced by helper-T (Th) cells, and the Th1/Th2 balance is regulated by cytokines and stress hormones. This nonspecific inflammatory response and specific immunological response which are mediated by cytokines are crucial for the host defense against invading pathogens. On the other hand, the blood levels of TNF-alpha, IL-6, IL-8, and MIP-1 alpha were correlated with the severity and mortality in patients with sepsis. Also we found that in patients with inhalation injury the high IL-8 levels in bronchoalveolar lavage fluid on admission predicted the development of respiratory insufficiency. In severe infection, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines cause an autodestructive systemic inflammatory response syndrome (SIRS). This condition is termed "Cytokine Storm" by the author. In cytokine storm, not only proinflamamtory cytokines, but also anti-inflammatory cytokines appear in circulating blood, leading to septic shock, multiple organ dysfunction, and immunosuppression. With further understanding of the roles of cytokines in sepsis, modulation of cytokine responses could be a new modality of the treatment.


Histochemical studies on mucoproteins in nerve cells of the dog.
Autonomic and sensory ganglion cells in the senile dog contain a deposition of PAS-positive substances which has been shown to be mucoprotein in nature. Data are presented to show that this PAS-positive mucoprotein can be demonstrated by metachromatic staining with toluidine blue after the mucoprotein is sulfated. This procedure indicates that mucoprotein is also present in a granular form in all nerve cells in both senile and young dogs. The evidence for this is further substantiated by the use of the aldehyde-fuchsin stain following both periodic acid oxidation and sulfation. The granular and non-granular deposition can be demonstrated by the periodic acid-aldehyde-fuchsin method due to the affinity of the aldehyde-fuchsin stain for aldehydes. It can be demonstrated following the sulfation-aldehyde-fuchsin method owing to the affinity of the stain for the sulfuric group. The evidence for this latter phenomenon has been reported by Scott and Clayton (6). It is concluded that mucoprotein is present in a granular form in all nerve cells in both senile and young dogs but is not concentrated enough in the latter to be demonstrated by the PAS method.