Taxogenomics Resolves Conflict in the Genus Rhodobacter: A Two and Half Decades Pending Thought to Reclassify the Genus Rhodobacter.
The genus Rhodobacter is taxonomically well studied, and some members are model organisms. However, this genus is comprised of a heterogeneous group of members. 16S rRNA gene-based phylogeny of the genus Rhodobacter indicates a motley assemblage of anoxygenic phototrophic bacteria (genus Rhodobacter) with interspersing members of other genera (chemotrophs) making the genus polyphyletic. Taxogenomics was performed to resolve the taxonomic conflicts of the genus Rhodobacter using twelve type strains. The phylogenomic analysis showed that Rhodobacter spp. can be grouped into four monophyletic clusters with interspersing chemotrophs. Genomic indices (ANI and dDDH) confirmed that all the current species are well defined, except Rhodobacter megalophilus. The average amino acid identity values between the monophyletic clusters of Rhodobacter members, as well as with the chemotrophic genera, are less than 80% whereas the percentage of conserved proteins values were below 70%, which has been observed among several genera related to Rhodobacter. The pan-genome analysis has shown that there are only 1239 core genes shared between the 12 species of the genus Rhodobacter. The polyphasic taxonomic analysis supports the phylogenomic and genomic studies in distinguishing the four Rhodobacter clusters. Each cluster is comprised of one to seven species according to the current Rhodobacter taxonomy. Therefore, to address this taxonomic discrepancy we propose to reclassify the members of the genus Rhodobacter into three new genera, Luteovulum gen. nov., Phaeovulum gen. nov. and Fuscovulum gen. nov., and provide an emended description of the genus Rhodobacter sensu stricto. Also, we propose reclassification of Rhodobacter megalophilus as a sub-species of Rhodobacter sphaeroides.


Dacryocystitis following a nasolacrimal duct obstruction caused by an ectopic intranasal tooth in a dog.
To describe a nasolacrimal duct (NLD) obstruction secondary to an ectopic tooth in a 5-year-old male Border collie. The dog was presented with a 1-month history of mucopurulent discharge from the left eye (OS) preceded by a lifelong history of epiphora OS. Treatment with neomycin/polymyxin B/dexamethasone ophthalmic solution had not improved the clinical signs, and the NLD was not patent when irrigated by the referring veterinarian. A complete ophthalmologic examination was performed followed by dacryocystorhinography and computed tomography (CT). The ophthalmologic examination revealed marked mucopurulent discharge, mild conjunctivitis, slightly elevated STT measurements, and a negative Jones test OS. Both nasolacrimal puncta OS could be cannulated without resistance for approximately 1.5 cm. Upon irrigation, copious amounts of mucopurulent discharge were exited through the corresponding punctum, while no fluid could be detected at the nares. Dacryocystorhinography was performed. Radiographs revealed an ectopic left canine tooth within the left nasal cavity. A cystic dilation of the NLD was observed proximal to the ectopic tooth. Computed tomography was performed to determine the exact position of the tooth and possible involvement of adjacent structures; CT confirmed the previous imaging findings. Treatment with systemic antibiotics, NSAIDs, and ofloxacin ophthalmic solution led to resolution of the clinical signs within several days. Surgery was declined by the owner. This is the first case report describing a blocked NLD due to an ectopic tooth in a dog. Ectopic teeth should be included as a differential diagnosis in cases of dacryocystitis and chronic epiphora in dogs.


Lymphedema secondary to melanoma treatments: diagnosis, evaluation, and treatments.
Approximately 300,000 new cases of melanoma are annually diagnosed in the world. Advanced stage melanomas require sentinel lymph node biopsy (SLNB), sometimes lymph node dissections (LND). The development rate of lower extremity lymphedema ranges from 7.6% to 35.1% after inguinal SLNB, and from 48.8% to 82.5% after inguinal LND. Development rate of upper extremity lymphedema ranges from 4.4% to 14.6% after axillary LND. Lymphedema management has constantly improved but effective evaluation and surgical management such as supermicrosurgical lymphaticovenular anastomosis (LVA) are becoming common as minimally invasive lymphatic surgery. Diagnosis and new classification using indocyanine green lymphography allowing pre-clinical secondary lymphedema stage management are improving effectiveness of supermicrosurgical LVA and vascularized lymph node transfer. Lymphatic transfer with lymph-interpositional-flap can restore lymph flow after large oncologic excision even without performing lymphatic anastomosis. Since lymphatic reconstructive surgery may affect local to systemic dissemination of remnant tumor cells, careful consideration is required to evaluate indication of surgical treatments.


Increased potassium excretion in children with monosymptomatic nocturnal enuresis: could it be related to Kir 4.1- KCNJ10 gene polymorphism?
There are controversial results in the literature regarding urinary electrolytes, especially potassium, in enuretic children. KCNJ10 channel protein, a member of the Kir 4.1 family is expressed in renal distal tubules and has an important function in renal ion transport. We investigated whether KCNJ10 gene polymorphisms are associated with clinical and laboratory findings of a group of Turkish children with monosymptomatic primary nocturnal enuresis (MNE). Ninety-seven MNE children and 100 healthy controls were tested for three single nucleotide polymorphisms (SNPs) in the KCNJ10 gene. The transversions in SNPs were G to A for intron 1(SNP1), G to A for exon 2 (SNP2), and T to C transition for promoter (SNP3). All SNPs were genotyped by PCR-restriction fragment length polymorphism. SNP3 in promoter of KCNJ10 gene showed strong association with MNE children for distribution of genotype and allele frequency, while SNP1 in intron 1 and SNP2 in exon 2 were noninformative. The distribution of TT, TC, and CC genotypes for SNP3 was 66%, 26.8% and 7.2% respectively in MNE compared with 38%, 59% and 3% respectively in controls (p < 0.0001). In enuretic children, TT genotype was higher and there was an increased potassium excretion in children with TT genotype (P < 0.05). We conclude that KCNJ10 gene promoter polymorphism may have a role on potassium excretion in Turkish MNE children. This is the first study in literature evaluating KCNJ10 gene polymorphism in this patient population. Future studies investigating the other SNPs, mutations or altered regulation of Kir4.1 in larger samples would help clarify the role (s) of KCNJ10 gene in enuresis.


Social networks and homelessness among women heads of household.
To examine possible bidirectional relationships between homelessness and deficient social networks, we compared the networks of 251 mothers before, and approximately 5 years after, their families entered shelters with networks of 291 consistently housed poor mothers. At Time 1, more women on the verge of homelessness than housed women reported that they had mothers, grandmothers, friends, and relatives but fewer believed these network members were housing resources. At Time 2, after homeless women were rehoused, these network differences between consistently housed and formerly homeless women had largely disappeared. Contrary to prior research findings, formerly homeless mothers did not report smaller networks, more children or fewer partners. However, formerly homeless women did report fewer positive functions. Because of city policies, homeless mothers were frequently rehoused far from network members.


Gamma Knife radiosurgery for sellar and parasellar meningiomas: a multicenter study.
Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality. A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8-90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6-216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021). Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.


A high-throughput alphavirus-based expression cloning system for mammalian cells.
We have developed a widely applicable functional genomics strategy based on alphavirus expression vectors. The technology allows for rapid identification of genes encoding a functional activity such as binding of a defined ligand. Complementary DNA (cDNA) libraries were expressed in mammalian cells following infection with recombinant Sindbis virus (SIN replicon particles), a member of the Alphavirus genus. Virus-infected cells that specifically bound a ligand of choice were isolated using fluorescence-activated cell sorting (FACS). Replication-competent, infective SIN replicon particles harboring the corresponding cDNA were amplified in a next step. Within one round of selection, viral clones encoding proteins recognized by monoclonal antibodies or Fc-fusion molecules could be isolated and sequenced. Moreover, using the same viral libraries, a plaque-lift assay was established that allowed the identification of secreted, intracellular, and membrane proteins.


Pten loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis.
Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroid-stimulating hormone-induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter.


Atrial natriuretic peptide in multiple system atrophy.
Central nervous system feedback loops centered on hypothalamic neurons control atrial natriuretic peptide (ANP). We evaluated the ANP response to arterial hypotension, isotonic blood volume expansion, and increase in plasma osmolality in 14 patients with multiple system atrophy (MSA). Seven of the patients were characterized by a lack of vasopressin response to hypotension (MSA type B), suggesting chronic sinoaortic denervation, and seven by a preserved response (MSA type A). Orthostatic hypotension decreased ANP in controls and type A patients, whereas ANP in type B was not affected. Isotonic saline infusion increased ANP and diuresis in controls and type A patients, whereas it did not affect ANP in type B. Osmotic load increased plasma osmolality and vasopressin in controls and MSA patients and ANP in controls and type A but not in type B patients. In MSA patients with altered afferent control of vasopressin, ANP secretion is not stimulated by blood volume expansion, osmotic load, or blood pressure, suggesting that afferent excitatory control plays a role in the release of ANP.


Fluorescence incoherent color holography.
We present a new imaging method to record multicolor digital holograms from objects emitting fluorescent light. The fluorescent light specific to the emission wavelength of various fluorescent dyes after excitation of three dimensional (3D) objects is recorded on a digital monochrome camera after reflection from a diffractive optical element (DOE). For each wavelength of fluorescent emission, the camera sequentially records three holograms reflected from the DOE, each with a different phase factor of the DOE's function. The three holograms are superposed in a computer to create a complex valued Fresnel hologram of each fluorescent emission. The holograms for each fluorescent color are further combined in a computer to produce a multicolored fluorescence hologram and 3D color image.


Phase-sensitive, dual-acquisition, single-slab, 3D, turbo-spin-echo pulse sequence for simultaneous T2-weighted and fluid-attenuated whole-brain imaging.
Conventional T(2)-weighted turbo/fast spin echo imaging is clinically accepted as the most sensitive method to detect brain lesions but generates a high signal intensity of cerebrospinal fluid (CSF), yielding diagnostic ambiguity for lesions close to CSF. Fluid-attenuated inversion recovery can be an alternative, selectively eliminating CSF signals. However, a long time of inversion, which is required for CSF suppression, increases imaging time substantially and thereby limits spatial resolution. The purpose of this work is to develop a phase-sensitive, dual-acquisition, single-slab, three-dimensional, turbo/fast spin echo imaging, simultaneously achieving both conventional T(2)-weighted and fluid-attenuated inversion recovery-like high-resolution whole-brain images in a single pulse sequence, without an apparent increase of imaging time. Dual acquisition in each time of repetition is performed, wherein an in phase between CSF and brain tissues is achieved in the first acquisition, while an opposed phase, which is established by a sequence of a long refocusing pulse train with variable flip angles, a composite flip-down restore pulse train, and a short time of delay, is attained in the second acquisition. A CSF-suppressed image is then reconstructed by weighted averaging the in- and opposed-phase images. Numerical simulations and in vivo experiments are performed, demonstrating that this single pulse sequence may replace both conventional T(2)-weighted imaging and fluid-attenuated inversion recovery.


A randomised controlled trial of acceptance and commitment therapy (ACT) for psychosis: study protocol.
Cognitive behavior therapy for psychosis has been a prominent intervention in the psychological treatment of psychosis. It is, however, a challenging therapy to deliver and, in the context of increasingly rigorous trials, recent reviews have tempered initial enthusiasm about its effectiveness in improving clinical outcomes. Acceptance and commitment therapy shows promise as a briefer, more easily implemented therapy but has not yet been rigorously evaluated in the context of psychosis. The purpose of this trial is to evaluate whether Acceptance and Commitment Therapy could reduce the distress and disability associated with psychotic symptoms in a sample of community-residing patients with chronic medication-resistant symptoms. This is a single (rater)-blind multi-centre randomised controlled trial comparing Acceptance and Commitment Therapy with an active comparison condition, Befriending. Eligible participants have current residual hallucinations or delusions with associated distress or disability which have been present continuously over the past six months despite therapeutic doses of antipsychotic medication. Following baseline assessment, participants are randomly allocated to treatment condition with blinded, post-treatment assessments conducted at the end of treatment and at 6 months follow-up. The primary outcome is overall mental state as measured using the Positive and Negative Syndrome Scale. Secondary outcomes include preoccupation, conviction, distress and disruption to life associated with symptoms as measured by the Psychotic Symptom Rating Scales, as well as social functioning and service utilisation. The main analyses will be by intention-to-treat using mixed-model repeated measures with non-parametric methods employed if required. The model of change underpinning ACT will be tested using mediation analyses. This protocol describes the first randomised controlled trial of Acceptance and commitment therapy in chronic medication-resistant psychosis with an active comparison condition. The rigor of the design will provide an important test of its action and efficacy in this population. Australian New Zealand Clinical Trials Registry: ACTRN12608000210370. Date registered: 18 April 2008.


Increased levels of IgE and autoreactive, polyreactive IgG in wild rodents: implications for the hygiene hypothesis.
To probe the potential role of Th1 versus Th2 reactivity underlying the hygiene hypothesis, intrinsic levels of Th1-associated and Th2-associated antibodies in the serum of wild rodents were compared with that in various strains of laboratory rodents. Studies using rat lung antigens as a target indicated that wild rats have substantially greater levels of autoreactive, polyreactive immunoglobulin G (IgG), but not autoreactive, polyreactive IgM than do laboratory rats, both on a quantitative and qualitative basis. Increased levels of serum IgG and IgE were observed in both wild rats and wild mice relative to their laboratory-raised counterparts, with the effect being most pronounced for IgE levels. Further, wild rats had greater intrinsic levels of both Th1- and Th2-associated IgG subclasses than did lab rats. The habitat (wild versus laboratory raised) had a more substantial impact on immunoglobulin concentration than did age, strain or gender in the animals studied. The presence in wild rodents of increased intrinsic, presumably protective, non-pathogenic responses similar to both autoimmune (autoreactive IgG, Th1-associated) and allergic (IgE, Th2-associated) reactions as well as increased levels of Th1-associated and Th2-associated IgG subclasses points toward a generally increased stimulation of the immune system in these animals rather than a shift in the nature of the immunoreactivity. It is concluded that, at least to the extent that feedback inhibition is a controlling element of immunoreactivity, an overly hygienic environment may affect the threshold of both types of immune responses more so than the balance between the different responses.


Metabolic Scaling of Stress Hormones in Vertebrates.
Glucocorticoids (GCs) are stress hormones that can strongly influence physiology, behavior, and an organism's ability to cope with environmental change. Despite their importance, and the wealth of studies that have sought to understand how and why GC concentrations vary within species, we do not have a clear understanding of how circulating GC levels vary within and across the major vertebrate clades. New research has proposed that much interspecific variation in GC concentrations can be explained by variation in metabolism and body mass. Specifically, GC concentrations should vary proportionally with mass-specific metabolic rates and, given known scaling relationships between body mass and metabolic rate, GC concentrations should scale to the -1/4 power of body mass and to the power of 1 with mass-specific metabolic rate. Here, we use HormoneBase, the newly compiled database that includes plasma GC concentrations from free-living and unmanipulated vertebrates, to evaluate this hypothesis. Specifically, we explored the relationships between body mass or mass-specific metabolic rate and either baseline or stress-induced GC (cortisol or corticosterone) concentrations in tetrapods. Our phylogenetically-informed models suggest that, whereas the relationship between GC concentrations and body mass across tetrapods and among mammals is close to -1/4 power, this relationship does not exist in amphibians, reptiles, and birds. Moreover, with the exception of a positive association between stress-induced GC concentrations and mass-specific metabolic rate in birds, we found little evidence that GC concentrations are linked to metabolic rate, although the number of species sampled was quite limited for amphibians and somewhat so for reptiles and mammals. Nevertheless, these results stand in contrast to the generally accepted association between the two and suggest that our observed positive association between body mass and GC concentrations may not be due to the well-established link between mass and metabolism. Large-scale comparative approaches can come with drawbacks, such as pooling and pairing observations from separate sources. However, these broad analyses provide an important counterbalance to the majority of studies examining variation in GC concentrations at the population or species level, and can be a powerful approach to testing both long-standing and new questions in biology.


Bax deficiency in mice increases cartilage production during fracture repair through a mechanism involving increased chondrocyte proliferation without changes in apoptosis.
This study sought to determine the role of the pro-apoptotic gene, Bax, in fracture healing by comparing femoral fracture healing in Bax knockout (KO) and wild-type C57BL/6J (background strain) mice. Bax KO fractures were larger, had more bone mineral content, had approximately 2-fold larger cartilage area per callus area in the first and second weeks of fracture healing, and showed an increased osteoclast surface area in the third and fourth weeks of fracture healing compared to C57BL/6J fractures. The increased cartilage area in the Bax KO fracture callus was due to increases in number of both pre-hypertropic and hypertropic chondrocytes. TUNEL analysis showed no significant differences in the number of either chondrocyte or non-chondrocyte apoptotic cells between Bax KO and C57BL/6J fractures at 7 or 14 days post-fracture, indicating that the increased number of chondrocytes in Bax KO fractures was not due to reduced apoptosis. Analysis of expression of apoptotic genes revealed that although the expression levels of Bcl-2 and Bcl-xL were not different between the Bax KO and C57BL/6J mice at 7 or 14 days post-fracture, the expression of BH3-domain only Bak and "Bik-like" pro-apoptotic gene increased approximately 1.5-fold and approximately 2-fold, respectively, in Bax KO fractures at 7 and 14 days post-fracture, compared to C57BL/6J fractures, suggesting that up-regulation of the Bak and Bik-like pro-apoptotic genes in Bax KO mice might compensate for the lack of Bax functions in the context of apoptosis. Analysis by in vivo incorporation of bromodeoxyuridine into chondrocytes within the fracture tissues indicated a highly significant increase in chondrocyte proliferation in Bax KO fractures compared to C57BL/6J fractures at day 7. The increased expression of collagen 2alpha1 and 9alpha1 gene in Bax KO fractures during early healing was consistent with an increased chondrocyte proliferation. In conclusion, this study demonstrates for the first time that Bax has an important role in the early stage of fracture healing, and that the increased callus size and cartilage area in Bax KO fractures was due to increased chondrocyte proliferation and not to reduced apoptosis or increased chondrocyte hypertrophy. The unexpected effect of Bax deficiency on chondrocyte proliferation implicates a novel regulatory function for Bax on chondrocyte proliferation during fracture repair.


SCO-spondin derived peptide NX210 induces neuroprotection in vitro and promotes fiber regrowth and functional recovery after spinal cord injury.
In mammals, the limited regenerating potential of the central nervous system (CNS) in adults contrasts with the plasticity of the embryonic and perinatal periods. SCO (subcommissural organ)-spondin is a protein secreted early by the developing central nervous system, potentially involved in the development of commissural fibers. SCO-spondin stimulates neuronal differentiation and neurite growth in vitro. NX210 oligopeptide was designed from SCO-spondin's specific thrombospondin type 1 repeat (TSR) sequences that support the main neurogenic properties of the molecule. The objective of this work was to assess the neuroprotective and neuroregenerative properties of NX210 in vitro and in vivo for the treatment of spinal cord injury (SCI). In vitro studies were carried out on the B104 neuroblastoma cell line demonstrating neuroprotection by the resistance to oxidative damage using hydrogen peroxide and the measure of cell viability by metabolic activity. In vivo studies were performed in two rat models of SCI: (1) a model of aspiration of dorsal funiculi followed by the insertion of a collagen tube in situ to limit collateral sprouting; white matter regeneration was assessed using neurofilament immunostaining; (2) a rat spinal cord contusion model to assess functional recovery using BBB scale and reflex testing. We demonstrate for the first time that NX210 (a) provides neuroprotection to oxidative stress in the B104 neuroblastoma cells, (b) stimulates axonal regrowth in longitudinally oriented neofibers in the aspiration model of SCI and (c) significantly improves functional recovery in the contusive model of SCI.


Association between Abdominal Obesity and Incident Colorectal Cancer: A Nationwide Cohort Study in Korea.
We investigated the association of waist circumference (WC) and abdominal obesity with the incident colorectal cancer risk in Korean adults. This nationwide population-based cohort study was based on health insurance claims data. We analyzed data from 9,959,605 participants acquired through health check-ups of the Korean National Health Insurance Service in 2009 who were followed up until the end of 2017. We performed multivariable Cox proportional hazards regression analysis. During 8.3 years of follow up, 101,197 cases (1.0%) of colorectal cancer were recorded. After adjusting for potential confounders, there was a positive association between WC and colorectal cancer risk (p for trend <0.001). Abdominal obesity was associated with an increased risk of colorectal (hazard ratio: 1.10, (95% confidence interval: 1.08-1.12)), colon (1.11, 1.09-1.13), and rectal cancer (1.08, 1.05-1.10). These associations were independent of body mass index and were more pronounced in men and elderly individuals. We revealed that higher WC is related to colorectal cancer risk, thus suggesting that abdominal obesity may be a risk factor for colorectal cancer in this East Asian population.


Alcohol use, heavy episodic drinking and subsequent problems among adolescents in 23 European countries: does the prevention paradox apply?
According to the prevention paradox, a majority of alcohol-related problems in a population can be attributed to low to moderate drinkers simply because they are more numerous than heavy drinkers, who have a higher individual risk of adverse outcomes. We examined the prevention paradox in annual alcohol consumption, heavy episodic drinking (HED) and alcohol-related problems among adolescents in 23 European countries. Survey data from the 2007 European School Survey Project on Alcohol and Drugs (ESPAD) among 16-year-old students were analysed. A total of 38,370 alcohol-consuming adolescents (19,936 boys and 18,434 girls) from 23 European countries were included. The upper 10% and the bottom 90% of drinkers by annual alcohol intake, with or without HED, and frequency of HED, were compared for the distribution of 10 different alcohol-related problems. Although the mean levels of consumption and alcohol-related problems varied largely between genders and countries, in almost all countries the heavy episodic drinkers in the bottom 90% of consumers by volume accounted for most alcohol-related problems, irrespective of severity of problem. However, adolescents with three or more occasions of HED a month accounted for a majority of problems. The prevention paradox, based on measures of annual consumption and heavy episodic drinking, seems valid for adolescent European boys and girls. However, a minority with frequent heavy episodic drinking accounted for a large proportion of all problems, illustrating limitations of the concept. As heavy episodic drinking is common among adolescents, our results support general prevention initiatives combined with targeted interventions.


Change in the heterogeneous distribution of tubulin isotypes in mitotic microtubules of the sea urchin egg by treatment with microtubule depolymerizing or stabilizing drugs.
In the mitotic sea urchin egg, the spindle microtubules were composed of different tubulin isotypes from those of astral microtubules using monoclonal antibodies [Oka et al. (1990) Cell Motil. Cytoskeleton, 16, 239-250]. Three of the antibodies, D2D6, DM1B, and YL1/2, were specific for spindle microtubules, astral microtubules and reactive with both microtubules, respectively. The mitotic sea urchin egg was treated with microtubule depolymerizing (colcemid and nocodazole) and stabilizing (hexylene glycol) drugs and change in the heterogeneous distribution of the tubulin isotypes was investigated by the immunofluorescence procedure using these three monoclonal anti-tubulin antibodies. We observed that: (1) the microtubule depolymerizing drugs caused quick depolymerization of most mitotic microtubules, and a small number of spindle microtubules remaining were stained with all three antibodies; (2) hexylene glycol induced many microtubules in the mitotic apparatus, which was stained with D2D6 but was not stained with DM1B; (3) hexylene glycol also induced a great number of miniasters in the cytoplasm, and they were stained with three antibodies. These results suggest that these drugs altered the distribution of tubulin isotypes in the mitotic microtubules during depolymerization or polymerization within a short time.


Body mass index as a risk prediction and prevention factor for professional mixed low-intensity EMF burden.
The exposure conditions in the physiotherapy are characterized with various sources emitting electromagnetic fields (EMF) in different frequency ranges. Very little is known about the exposure modalities' influence on the operators. In this article, we present the effects of EMF on personnel morbidity profile dependent on the body mass index (BMI) increase. By cross-tabulation, the role of higher BMI on enhancing the EMF vulnerability potential is confirmed. The correlation of the higher BMI with some serious diseases and conditions' development has been evidenced statistically significant. Вy the whole-studied group, a general tendency for allergy, cardiovascular diseases, sleep disruption and age-shortened menopause, as well as allergy and leiomyoma in the expositional criteria subgroups (ESG), formed for the purposes of this study, is evidenced. The three ESGs are formed on work residence duration in the electrolight therapy section. The first - up to four working hour daily, the second - the entire working day (7 h) and the third group is not residenced in the electrolight therapy section. We hypothesize two signaling ways of interaction of the chronically low-intensity EMF and the higher BMI as the most likely: hormonal - by melatonin levels decrease due to estrogen levels increasing and endocrine - mast-cells auto replication and degranulation stimulation. Based on the results of the study, the BMI increase as an observed control factor in the prediction of the professional risk can be recommended.


Cross-cultural music phrase processing: an fMRI study.
The current study used functional magnetic resonance imaging (fMRI) to investigate the neural basis of musical phrase boundary processing during the perception of music from native and non-native cultures. German musicians performed a cultural categorization task while listening to phrased Western (native) and Chinese (non-native) musical excerpts as well as modified versions of these, where the impression of phrasing has been reduced by removing the phrase boundary marking pause (henceforth called "unphrased"). Bilateral planum temporale was found to be associated with an increased difficulty of identifying phrase boundaries in unphrased Western melodies. A network involving frontal and parietal regions showed increased activation for the phrased condition with the orbital part of left inferior frontal gyrus presumably reflecting working memory aspects of the temporal integration between phrases, and the middle frontal gyrus and intraparietal sulcus probably reflecting attention processes. Areas more active in the culturally familiar, native (Western) condition included, in addition to the left planum temporale and right ventro-medial prefrontal cortex, mainly the bilateral motor regions. These latter results are interpreted in light of sensorimotor integration. Regions with increased signal for the unfamiliar, non-native music style (Chinese) included a right lateralized network of angular gyrus and the middle frontal gyrus, possibly reflecting higher demands on attention systems, and the right posterior insula suggesting higher loads on basic auditory processing.


Subependymal Giant Cell Astrocytoma (SEGA) Treatment Update.
Rates of regrowth after resection of subependymal giant cell astrocytoma (SEGA) are low, making surgical resection a successful and permanent therapeutic strategy. In addition to surgical resection of SEGAs, other treatment options now include medications and Gamma Knife™ therapy. Advising patients on medical versus surgical management of SEGAs is currently not easy. SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.


An examination of periodontal treatment and per member per month (PMPM) medical costs in an insured population.
Chronic medical conditions have been associated with periodontal disease. This study examined if periodontal treatment can contribute to changes in overall risk and medical expenditures for three chronic conditions [Diabetes Mellitus (DM), Coronary Artery Disease (CAD), and Cerebrovascular Disease (CVD)]. 116,306 enrollees participating in a preferred provider organization (PPO) insurance plan with continuous dental and medical coverage between January 1, 2001 and December 30, 2002, exhibiting one of three chronic conditions (DM, CAD, or CVD) were examined. This study was a population-based retrospective cohort study. Aggregate costs for medical services were used as a proxy for overall disease burden. The cost for medical care was measured in Per Member Per Month (PMPM) dollars by aggregating all medical expenditures by diagnoses that corresponded to the International Classification of Diseases, 9th Edition, (ICD-9) codebook. To control for differences in the overall disease burden of each group, a previously calculated retrospective risk score utilizing Symmetry Health Data Systems, Inc. Episode Risk Groups (ERGs) were utilized for DM, CAD or CVD diagnosis groups within distinct dental services groups including; periodontal treatment (periodontitis or gingivitis), dental maintenance services (DMS), other dental services, or to a no dental services group. The differences between group means were tested for statistical significance using log-transformed values of the individual total paid amounts. The DM, CAD and CVD condition groups who received periodontitis treatment incurred significantly higher PMPM medical costs than enrollees who received gingivitis treatment, DMS, other dental services, or no dental services (p < .001). DM, CAD, and CVD condition groups who received periodontitis treatment had significantly lower retrospective risk scores (ERGs) than enrollees who received gingivitis treatment, DMS, other dental services, or no dental services (p < .001). This two-year retrospective examination of a large insurance company database revealed a possible association between periodontal treatment and PMPM medical costs. The findings suggest that periodontitis treatment (a proxy for the presence of periodontitis) has an impact on the PMPM medical costs for the three chronic conditions (DM, CAD, and CVD). Additional studies are indicated to examine if this relationship is maintained after adjusting for confounding factors such as smoking and SES.


Experimental contamination of Minims of fluorescein by Pseudomonas aeruginosa.
Contamination of fluorescein solutions by Pseudomonas aeruginosa has been a concern of ophthalmologists for many years because of the severity of pseudomonas keratitis. Attempts to prevent contamination have been directed at stringent sterility control during manufacture and the introduction of single-dose disposable containers such as Minims. Deliberate contamination of Minims fluorescein with Pseudomonas aeruginosa was attempted. Under conditions likely to be met with in clinical practice the contents remained sterile. However, under extreme conditions of immersion in pure broth culture of Pseudomonas aeruginosa contamination could be achieved. The relevance of these results to clinical practice is discussed.


A comparison of auditory hallucinations in a psychiatric and non-psychiatric group.
To compare auditory hallucinations in a psychiatric and non-psychiatric sample. Between-participants group design: a psychiatric group of 14 patients with schizophrenia, and a non-psychiatric group of 16 participants with tinnitus. Participants were interviewed using the Mental Health Research Institute Unusual Perceptions Scale (MUPS). The type of hallucinations differed: participants with tinnitus predominantly heard music, whereas the patients with schizophrenia heard voices speaking. The groups also differed in their explanations of the hallucinations. However, there were similarities in contributory factors, emotional responses and coping strategies. The study highlights the multi-dimensional nature of the auditory hallucinatory experience, and opportunities for intervention.


Efficacy of prior eccentric exercise in attenuating impaired exercise performance after muscle injury in resistance trained men.
Previous research has demonstrated that prior exercise may reduce the magnitude of muscle soreness and impaired function (i.e., repeated bout effect [RBE]) observed during subsequent eccentric exercise. Previous investigations have predominantly used research designs that include single-joint exercise performed by untrained individuals. It is unknown how resistance trained individuals respond to novel multi-joint eccentric actions of the upper body and whether prior exercise offers protection. Thirty-one resistance trained men (23.4 +/- 3.5 y, 177.2 +/- 5.1 cm, 86.4 +/- 16.5 kg, mean +/- SD) were randomly assigned to repeated bout ([RB] N = 15) or single bout ([CON] N = 16) conditions. Both groups performed 100 eccentric actions of the bench press ([ECC] at 70% concentric 1 repetition maximum) to induce muscle injury. Bilateral maximal isometric force, dynamic exercise performance (e.g., bench press throws), and muscle soreness were measured before, immediately after, and at 24 and 48 hours post-ECC. Total work, percent fatigue, and rating of perceived exertion (ECC) data were collected during ECC. Those assigned to RB condition exhibited less fatigue (9.5 vs. 22.6%) and lower RPE (14.8 vs. 17.1) during ECC. A significant interaction (p < 0.05) was found such that RB individuals experienced less soreness at 24 (6.5 vs. 4.9) and 48 (6.6 vs. 3.9) hours postexercise than the CON condition. No significant group differences (p < 0.05) were found for any measured performance variable. Although soreness, fatigue, and RPE suggest a RBE, this was not found in regards to exercise performance. It appears that in trained men, performing a strenuous high-volume eccentric exercise bout 2 weeks prior to an identical future bout offers no additional amelioration of impaired exercise performance.


Interactive video search tools: a detailed analysis of the video browser showdown 2015.
Interactive video retrieval tools developed over the past few years are emerging as powerful alternatives to automatic retrieval approaches by giving the user more control as well as more responsibilities. Current research tries to identify the best combinations of image, audio and text features that combined with innovative UI design maximize the tools performance. We present the last installment of the Video Browser Showdown 2015 which was held in conjunction with the International Conference on MultiMedia Modeling 2015 (MMM 2015) and has the stated aim of pushing for a better integration of the user into the search process. The setup of the competition including the used dataset and the presented tasks as well as the participating tools will be introduced . The performance of those tools will be thoroughly presented and analyzed. Interesting highlights will be marked and some predictions regarding the research focus within the field for the near future will be made.


[Registry of preventive activities in women: variability in Vizcaya, Spain].
Several studies have reported that there is a lack of preventive activities performance in Primary Health Care, however in Vizcaya, the situation is not known, so, we decided determine the percentage of preventive activities carried out on women by primary care physicians which are recorded in the Electronic Health Record (Osabide), and analyze the characteristics which determine differences in registration between regions and physicians. We conducted a cross-sectional study involving 425 women aged between 26 and 51 years who were to the general practitioners' consult at least twice, and who were again on April 28, 29 or 30, 2011. We colleted as primary variable the registries of contraceptives practices (group aged between 26 and 51 years), the registries of cervical cytologies during the last five years, as well as the registries of mammograms performed during the two last years, and compared the medical record between men and women practitioners, health regions and between areas with and without centers for women, using the chi-square statistic. In 139 (34.1%) of all women and in 99 (48.3%) of women aged between 26 and 51 years there was registry of cytologies and contraceptives practices respectively. The mammography performance was registered in 22 (10.7%) of women aged between 52 and 65 years. The registry of preventive activities on women is low. We have observed differences by practitioners' gender.


Effect of safety education on knowledge of and compliance with road safety signs among commercial motorcyclists in Uyo, Southern Nigeria.
Compliance with road safety signs is important in the reduction of motorcycle accidents. The aim of this study was to implement health education intervention and assess its impact on the knowledge of and compliance with road safety signs among commercial motorcyclists in Uyo, Southern Nigeria. This was an intervention study among motorcyclists in Uyo, Southern Nigeria, with a control group from a similar town. The instrument of data collection was a semi-structured interviewer administered questionnaire. Subjects were selected through multistage sampling method. Baseline data on compliance to road safety signs was collected from both groups. Motorcyclists in the intervention group were given education on the importance of compliance to road safety signs. Data was subsequently collected from both groups 3 months post intervention and analysed using the Statistical Package for the Social Sciences version 11. A total of 200 respondents participated in the study, 100 from each group. Following intervention, respondents with good knowledge score increased from 21% at baseline to 82% at 3 months post intervention in the intervention group (p<0.05) and from 19% to 21% in the control group. Compliance score in the intervention group increased from 15% to 70% (p<0.05) and from 12% to 18% in the control group. A significant increase in compliance to road safety signs was recorded among motorcyclists in the intervention group after safety education. All motorcyclists should therefore be given education on road safety signs as this will improve compliance and lead to safer road use among them.


Growth Mixture Modeling of Depression Symptoms Following Traumatic Brain Injury.
Growth Mixture Modeling (GMM) was used to investigate the longitudinal trajectory of groups (classes) of depression symptoms, and how these groups were predicted by the covariates of age, sex, severity, and length of hospitalization following Traumatic Brain Injury (TBI) in a group of 1074 individuals (696 males, and 378 females) from the Royal Hobart Hospital, who sustained a TBI. The study began in late December 2003 and recruitment continued until early 2007. Ages ranged from 14 to 90 years, with a mean of 35.96 years (SD = 16.61). The study also examined the associations between the groups and causes of TBI. Symptoms of depression were assessed using the Hospital Anxiety and Depression Scale within 3 weeks of injury, and at 1, 3, 6, 12, and 24 months post-injury. The results revealed three groups: low, high, and delayed depression. In the low group depression scores remained below the clinical cut-off at all assessment points during the 24-months post-TBI, and in the high group, depression scores were above the clinical cut-off at all assessment points. The delayed group showed an increase in depression symptoms to 12 months after injury, followed by a return to initial assessment level during the following 12 months. Covariates were found to be differentially associated with the three groups. For example, relative to the low group, the high depression group was associated with more severe TBI, being female, and a shorter period of hospitalization. The delayed group also had a shorter period of hospitalization, were younger, and sustained less severe TBI. Our findings show considerable fluctuation of depression over time, and that a non-clinical level of depression at any one point in time does not necessarily mean that the person will continue to have non-clinical levels in the future. As we used GMM, we were able to show new findings and also bring clarity to contradictory past findings on depression and TBI. Consequently, we recommend the use of this approach in future studies in this area.


Variational Bayesian mixture model on a subspace of exponential family distributions.
Exponential principal component analysis (e-PCA) has been proposed to reduce the dimension of the parameters of probability distributions using Kullback information as a distance between two distributions. It also provides a framework for dealing with various data types such as binary and integer for which the Gaussian assumption on the data distribution is inappropriate. In this paper, we introduce a latent variable model for the e-PCA. Assuming the discrete distribution on the latent variable leads to mixture models with constraint on their parameters. This provides a framework for clustering on the lower dimensional subspace of exponential family distributions. We derive a learning algorithm for those mixture models based on the variational Bayes (VB) method. Although intractable integration is required to implement the algorithm for a subspace, an approximation technique using Laplace's method allows us to carry out clustering on an arbitrary subspace. Combined with the estimation of the subspace, the resulting algorithm performs simultaneous dimensionality reduction and clustering. Numerical experiments on synthetic and real data demonstrate its effectiveness for extracting the structures of data as a visualization technique and its high generalization ability as a density estimation model.


Feasibility and Acceptability of Implementing the Integrated Care Plan for the Dying in the Indian Setting: Survey of Perspectives of Indian Palliative Care Providers.
Capacity to provide end-of-life care in India is scored as 0.6/100, and very few people in India have access to palliative and end-of-life care. Lack of end-of-life care provision in India has led to a significant number of people receiving inappropriate medical treatment at the end of life, with no access to pain and symptom control and high treatment costs. The International Collaborative for the Best Care for the Dying Person is an initiative that offers the opportunity to apply international evidence on the key factors required to provide best care for the dying in the Indian context. The aim of this study is to ascertain the perceptions of Indian palliative care providers regarding the feasibility and acceptability of implementing the international program in the Indian setting. Thirty participants from 16 palliative care centers who had participated in the foundation course of the International Collaborative for Best Care for the Dying Person were purposively chosen for the study. All participants were asked to complete the survey questionnaire that had both open- and close-ended questions. Twenty-three participants completed this survey. The majority of items in the international program were considered relevant, representative of end-of-life care and acceptable in Indian setting. However, participants felt that the concept of the multidisciplinary team (MDT) being responsible for recognizing death may not be possible in the existing Indian setting and a senior doctor may not always be available to document a MDT decision. Some participants felt that in the Indian setting, it was not always possible to communicate about the dying process and make patient aware of the same. A small number of participants felt that using leaflets for communicating end-of-life care process may not be always possible due to logistic reasons and cost. Six participants felt that giving the dying person the opportunity to discuss their wishes, feelings, faith, beliefs, and values may not be possible, representative, and not applicable in Indian setting. The majority of participants felt that using equipment such as a syringe driver for continuous infusion is relevant (n = 16) and representative (n = 13) of end-of-life care, however most thought that it could be challenging to apply in an Indian setting (n = 17), including concerns about lack of familiarity and knowledge and applicability in home care settings. Six participants had reservations regarding the limitation of life-sustaining treatment and felt that discussion and review of cardiopulmonary resuscitation should happen prior to patients entering their end-of-life phase. While most participants thought relevance, representation, and applicability of assessing skin integrity as important, a few participants felt this assessment challenging, especially in home setting, and recommended Braden scale to be used instead of Waterlow for assessing skin integrity. Most participants agreed on the importance of assisted hydration and nutrition; however, again a minority highlighted challenges in this area. Five participants felt that they would sometimes continue hydration under duress from a patient's family. Participants agreed unanimously on the relevance and representation of recording of physical symptoms by MDT-initial and ongoing-with a few participants indicating that frequent observations recommended in the care plan may not be feasible in home care setting. The majority also agreed on the relevance, representation (n = 21), and applicability (n = 18) of providing written information about after-death care, with a small number indicating challenges in the Indian setting, for example, very few unit currently having this information available (n = 2). Notifying general practitioners, primary care physicians, and other appropriate services on patients' death may not be easily applicable in the Indian setting. The survey of palliative care providers about the feasibility and acceptability of integrated care plan at end of life has shown that the international program is relevant, representative of end-of-life care, and acceptable in Indian setting. As would be expected, a number of items need careful consideration and appropriate modification to ensure relevance, representation, and applicability to Indian sociocultural context. The results also suggest that palliative care providers need additional training for the implementation of some of the items in the development of an India-specific document and supporting quality improvement program.


Taxa-area relationships for microbes: the unsampled and the unseen.
The recent observation of a power-law relationship, S proportional A(z), between number of taxa, S, and area, A, for microbial eukaryotes and bacteria suggests that this is one of the few generic relationships in ecology, applicable to plants, animals and microbes. However, the rate of increase in the number of species with area varies from approximately the fourth (z = 0.26) to as little as the 50th root (z = 0.0019) in microbes. This is an enormous range for which no quantitative explanation has been proffered. We show by sampling from synthetic populations that the disparity between sample and community sizes in microbial community surveys means z can be considerably underestimated and accrual of rare taxa with increasing area will not be detectable. Significant microbial taxa-area relationships will only be observed when changes in community structure within samples correlate with area. Thus, the very low z values observed recently cannot be used as the sole evidence in support of any particular community theory of community assembly. More generally, this suggests that our search for patterns and laws in the microbial world will be profoundly influenced and, potentially distorted by the sample sizes that are typical of microbial community surveys.


Electron-beam-initiated polymerization of poly(ethylene glycol)-based wood impregnants.
The current study demonstrates that methacrylate and acrylate poly(ethylene glycol) (PEG) functional oligomers can be effectively impregnated into wood blocks, and cured efficiently to high conversions without catalyst by e-beam radiation, allowing for less susceptibility to leaching, and favorable properties including higher Brinell hardness values. PEG based monomers were chosen because there is a long history of this water-soluble monomer being able to penetrate the cell wall, thus bulking it and decreasing the uptake of water which further protects the wood from fungal attack. Diacrylate, dimethacrylate, and dihydroxyl functional PEG of M(w) 550-575, of concentrations 0, 30, 60, and 100 wt % in water, were vacuum pressure impregnated into Scots Pine blocks of 15 × 25 × 50 mm in an effort to bulk the cell wall. The samples were then irradiated and compared with nonirradiated samples. It was shown by IR, DSC that the acrylate polymers were fully cured to much higher conversions than can be reached with conventional methods. Leaching studies indicated a much lower amount of oligomer loss from the cured vinyl functional PEG chains in comparison to hydroxyl functional PEG indicating a high degree of fastening of the polymer in the wood. The Brinell hardness indicated a significant increase in hardness to hardwood levels in the modified samples compared to the samples of hydroxyl functional PEG and uncured vinyl PEG samples, which actually became softer than the untreated Scots Pine. By monitoring the dimensions of the sample it was found by weight percent gain calculations (WPG %) that water helps to swell the wood structure and allow better access of the oligomers into the cell wall. Further, the cure shrinkage of the wood samples demonstrated infiltration of the oligomers into the cell wall as this was not observed for methyl methacrylate which is well-documented to remain in the lumen. However, dimensional stability of the vinyl polymer modified blocks when placed in water was not observed to the same extent as PEG.


Influence of malnutrition on intellectual development.
The relationship between malnutrition and intellectual performance was studied in 1336 rural primary school children (6-8 yr). Observations showed that the relative risk of having an IQ less than or equal to 89 in severe, moderate and mild malnutrition was 3.5, 2.7 and 1.4 times for boys and in girls it was 2.4, 1.7 and 1.4 times respectively. Mean full scale, verbal and performance IQ as well as the scores for various subtests decreased with the severity of malnutrition. However, though the decrease in IQ scores was significant, below average performance of malnourished children was observed only for performance IQ (87.6 +/- 9.13), and subtests information (87.9 +/- 10.5), digit span (79.6 +/- 11.9), picture completion (88.6 +/- 13.9), object assembly (81.1 +/- 18.1), and coding (80.5 +/- 14.4). Further, the stunted children had lower IQ scores as compared to those who were wasted. Multiple regression analysis showed that besides nutrition, socio-economic status had significant influence on verbal IQ; economic sufficiency on picture completion and block design, psychosocial and family environment on vocabulary and digit span subtests. However, the values of correlations obtained were too low to be used for prediction of scores. The overall observations demonstrate that even moderate degree of malnutrition influences the IQ scores and its effect is of a higher magnitude on immediate memory, visual perception, and visual motor integration as compared to verbal reasoning and comprehension.


Methods for the study of employment relations and health inequalities in a global context.
The authors describe the major methods and sources of information used in the EMCONET study for researching global, employment-related health inequalities. A systematic review of the literature provides valuable knowledge for research in this area. However, the limited number of studies, the poor quality of methods used, and a lack of theories or concepts have produced inconsistent results. To minimize bias from these limitations and to reach a comprehensive understanding of the complexity and health effects of global employment conditions, this article outlines key strategies for a synthetic, comprehensive, participatory approach: adapting transdisciplinary knowledge acquisition, building a theoretical model, employing multiple sources for data collection, and using a variety of methods (qualitative/ quantitative studies and narrative knowledge). This approach provides solutions to important research and policy needs regarding the global context of key employment relations, social mechanisms, and health inequalities. The strategies are adapted to synthesize input from several disciplines (epidemiology, sociology, and political science), social actors, and institutions. The study's main sources of information are a variety of digital, bibliographic databases; the authors reviewed the scientific literature from 1985 to 2008 and books, reports, and other documents from 2000 to 2008.


Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer.
We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.


A new arbovirus from Aedes albopictus, an Asian mosquito established in the United States.
Ten strains of a new arbovirus belonging to the Bunyamwera group (Bunyaviridae) were recovered from field-collected Aedes albopictus mosquitoes in Potosi, Missouri. This evidence indicates that this species may serve as an arbovirus vector in the United States. The urban-suburban distribution, aggressive biting behavior, and broad viral susceptibility of Ae. albopictus may lead to the transmission of viruses of known public health importance and perhaps of viruses hitherto not transmitted to humans because of the feeding pattern of their usual vectors.


Schmidtea mediterranea phylogeography: an old species surviving on a few Mediterranean islands?
Schmidtea mediterranea (Platyhelminthes, Tricladida, Continenticola) is found in scattered localities on a few islands and in coastal areas of the western Mediterranean. Although S. mediterranea is the object of many regeneration studies, little is known about its evolutionary history. Its present distribution has been proposed to stem from the fragmentation and migration of the Corsica-Sardinia microplate during the formation of the western Mediterranean basin, which implies an ancient origin for the species. To test this hypothesis, we obtained a large number of samples from across its distribution area. Using known and new molecular markers and, for the first time in planarians, a molecular clock, we analysed the genetic variability and demographic parameters within the species and between its sexual and asexual populations to estimate when they diverged. A total of 2 kb from three markers (COI, CYB and a nuclear intron N13) was amplified from ~200 specimens. Molecular data clustered the studied populations into three groups that correspond to the west, central and southeastern geographical locations of the current distribution of S. mediterranea. Mitochondrial genes show low haplotype and nucleotide diversity within populations but demonstrate higher values when all individuals are considered. The nuclear marker shows higher values of genetic diversity than the mitochondrial genes at the population level, but asexual populations present lower variability than the sexual ones. Neutrality tests are significant for some populations. Phylogenetic and dating analyses show the three groups to be monophyletic, with the west group being the basal group. The time when the diversification of the species occurred is between ~20 and ~4 mya, although the asexual nature of the western populations could have affected the dating analyses. S. mediterranea is an old species that is sparsely distributed in a harsh habitat, which is probably the consequence of the migration of the Corsica-Sardinia block. This species probably adapted to temperate climates in the middle of a changing Mediterranean climate that eventually became dry and hot. These data also suggest that in the mainland localities of Europe and Africa, sexual individuals of S. mediterranea are being replaced by asexual individuals that are either conspecific or are from other species that are better adapted to the Mediterranean climate.


Insect juvenile hormones: highly potent synthetic mimics.
The substitution of a 7-alkoxy group for the 6,7-epoxy moiety in aryl terpenoid ethers having high juvenile hormone activity has produced several compounds exceptionally active against Tenebrio molitor. The most potent compound [7-ethoxy-1-(p-ethylphenoxy)-3,7-dimethyl-2-octene, called JH-25] is active at the level of 10 picograms per insect, or about 100 times more active than other promising juvenile hormone mimics so far reported. Compound JH-25 was also active against Tribolium confusum.


The primary photoreaction of channelrhodopsin-1: wavelength dependent photoreactions induced by ground-state heterogeneity.
The primary photodynamics of channelrhodopsin-1 from Chlamydomonas augustae (CaChR1) was investigated by VIS-pump supercontinuum probe experiments from femtoseconds to 100 picoseconds. In contrast to reported experiments on channelrhodopsin-2 from Chlamydomonas reinhardtii (CrChR2), we found a clear dependence of the photoreaction dynamics on varying the excitation wavelength. Upon excitation at 500 and at 550 nm we detected different bleaching bands, and spectrally distinct photoproduct absorptions in the first picoseconds. We assign the former to the ground-state heterogeneity of a mixture of 13-cis and all-trans retinal maximally absorbing around 480 and 540 nm, respectively. At 550 nm, all-trans retinal of the ground state is almost exclusively excited. Here, we found a fast all-trans to 13-cis isomerization process to a hot and spectrally broad P1 photoproduct with a time constant of (100 ± 50) fs, followed by photoproduct relaxation with time constants of (500 ± 100) fs and (5 ± 1) ps. The remaining fraction relaxes back to the parent ground state with time constants of (500 ± 100) fs and (5 ± 1) ps. Upon excitation at 500 nm a mixture of both chromophore conformations is excited, resulting in overlapping reaction dynamics with additional time constants of <300 fs, (1.8 ± 0.3) ps and (90 ± 25) ps. A new photoproduct Q is formed absorbing at around 600 nm. Strong coherent oscillatory signals were found pertaining up to several picoseconds. We determined low frequency modes around 200 cm(-1), similar to those reported for bacteriorhodopsin.


Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations.
Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.


CD19 Chimeric Antigen Receptor Therapy for Refractory Aggressive B-Cell Lymphoma.
Anti-CD19-directed chimeric antigen receptor (CAR) T-cell therapy has had a resounding effect on the treatment of chemotherapy-insensitive aggressive B-cell non-Hodgkin lymphoma (B-NHL). There are now two US Food and Drug Administration (FDA)-approved products available for treating these patients, and a third product is expected to be approved in the coming months. The question remains: Is there a preferred or best product for my patient? However, answering that question is more complicated than simply balancing the reported efficacy and toxicity results. This review outlines potential confounding factors involving the three products and their pivotal clinical trials and highlights additional considerations of manufacturing reliability and overall cost that must be considered when weighing one product against another. It will also review the directions in which the field is moving and strategies being examined to improve efficacy as well as toxicity. Because a randomized three-arm clinical trial is unlikely, a product may have to be chosen on the basis of results from treatment centers that have experience with all three products. But by the time those results are available, they are likely to be outdated because, given the rapid evolution of the field, the next product will probably have been identified.


Tachykinins regulate the function of platelets.
Evidence has been mounting for peripheral functions for tachykinins, a family of neuropeptides including substance P (SP), neurokinin A, and neurokinin B, which are recognized for their roles in the central and peripheral nervous system. The recent discovery of 4 new members of this family, the endokinins (EKA, B, C, and D), which are distributed peripherally, adds support to the notion that tachykinins have physiologic/endocrine roles in the periphery. In the present study we report a fundamental new function for tachykinins in the regulation of platelet function. We show that SP stimulates platelet aggregation, and underlying this is the intracellular mobilization of calcium and degranulation. We demonstrate the presence of the tachykinin receptors NK1 and NK3 in platelets and present evidence for the involvement of NK1 in SP-mediated platelet aggregation. Platelets were found to contain SP-like immunoreactivity that is secreted upon activation implicating SP-like substances in the autocrine/paracrine regulation of these cells. Indeed, NK1-blocking antibodies inhibited aggregation in response to other agonists. Of particular note is the observation that EKA/B cross-react in the SP immunoassay and are also able to stimulate platelet activation. Together our data implicate tachykinins, specifically SP and EKA/B, in the regulation of platelet function.


Coronary venous retroinfusion of procainamide: a new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction.
The efficacy of retrograde coronary venous delivery of procainamide for the management of spontaneous and inducible sustained ventricular tachycardia was evaluated and compared with systemic intravenous procainamide administration in 22 conscious dogs with permanent left anterior descending coronary artery occlusion. Selective retrograde injection of procainamide was achieved through an autoinflatable balloon catheter placed in the great cardiac vein, with the tip positioned in the vicinity of the site of left anterior descending coronary occlusion. Great cardiac vein retroinfusion of procainamide was significantly (p less than 0.05) more effective than systemic intravenous injection against spontaneous ventricular tachycardia 1 day after coronary artery occlusion (13 dogs) and against electrically induced sustained ventricular tachycardia in the 3 to 12 day postocclusion period (9 dogs). Significantly lower doses of procainamide were used with retroinfusion as compared with systemic administration, that is, 19.6 +/- 8.8 versus 35 +/- 0 mg/kg body weight during spontaneous tachycardia and 13.4 +/- 4.1 versus 32.1 +/- 2 mg/kg during induced tachycardia (p less than 0.01). Retroinfusion of saline solution through the great cardiac vein had no effect on either type of tachycardia. Myocardial tissue procainamide levels measured in infarcted and ischemic zones of the left anterior ventricular wall were 9 to 100 times higher after great cardiac vein retroinfusion than after systemic injection. Great cardiac vein dye injection studies demonstrated a preferential distribution in left ventricular regions supplied by the occluded coronary artery. It is concluded that regional coronary venous procainamide retroinfusion in dogs with myocardial infarction is more effective than systemic intravenous injection against both spontaneous and inducible sustained ventricular tachycardia. The greater efficacy of great cardiac vein treatment appears to be primarily related to selectively increased delivery of procainamide to ischemic myocardial sites.


Gender-Specific HIV Prevention Interventions for Women Who Use Alcohol and Other Drugs: The Evolution of the Science and Future Directions.
The use of alcohol and other drugs (AODs) is an important driver of gender disparities in HIV prevalence. Consequently, there is a need for women-specific HIV interventions that are conceptualized to address (1) women's risk behavior, their roles in sexual relationships, and gender power dynamics and (2) other issues commonly faced by women who use AODs, such as gender-based violence and victimization. This article presents the evolution of HIV prevention intervention research with women who use AODs. It looks at 3 generations of women-focused HIV research interventions, including first-generation projects that started in the 1990s, second-generation efforts where projects expanded in scope and included adaptions of evidence-based interventions for global relevance, and finally third-generation projects currently underway that combine biobehavioral methods and are being implemented in real-world settings. Because women who use AODs continue to report risk behaviors related to HIV, emphasis should be placed on training scientists to conduct gender-specific studies, increasing funding for new studies, and advocating to ensure that stigma-free services are available for these at-risk women.


Influence of host origin on host choice of the parasitoid Dinarmus basalis: does upbringing influence choices later in life?
The aim of this study was to investigate the influence of volatile compounds from four secondary host plants on the ability of Dinarmus basalis Rond. (Hymenoptera: Pteromalidae) to locate, recognize, and parasitize its host, 4(th)instar larvae or pupae of Callosobruchus maculatus F. (Coleoptera: Chrysomelidae). To examine this, strains of D. basalis were transferred from cow-pea seeds (Vigna unguiculata (L.) Walp. (Fabales: Fabaceae)) to pigeon pea (Cajanus cajan (L.) Millsp.) and two varieties of Bambara groundnut (Vigna subterranea (L.) Verdc.) seeds. The ability of D. basalis females to recognize the volatile compounds emanating from their complex host plant was tested by using a Y-tube olfactometer and a three-dimensional device. The results suggest that when females have a choice between pure air and the air emanating from their complex host of origin, they are attracted to the air tainted by the volatile compounds they have become accustomed to. They spent significantly more time (p < 0.0001) in the branch of the tube leading to the odorous air than in the tube leading to the pure air. When females from pigeon pea seed hosts were offered a choice between cowpea and pigeon pea seeds, all containing 4(th)instar larvae, the familiar odor of pigeon pea seeds were most attractive. When females from Bambara groundnut (white and striped) seed hosts were offered a choice between cowpea and pigeon pea seeds, all containing 4(th)instar larvae, they were significantly attracted to the odour of cowpea seeds. In the three-dimensional system, the females from the four strains did not appear to have any preference for a given type of seed containing 4(th)instar larvae or pupae. The parasitism rate remained high on all four types of seeds used. These results show that the use of D. basalis as a biological control agent is possible in host changing situations where C. maculatus starts to attack other legumes. The results of this study also provide information supporting the behavioral plasticity of D. basalis. Understanding the mechanisms involved in the adaptive phenomena of biological control agents is discussed in the context of the development of adequate methods of pest control.


Speed of pattern appearance in reaction-diffusion models: implications in the pattern formation of limb bud mesenchyme cells.
It has been postulated that fibroblast growth factor (FGF) treatment of cultured limb bud mesenchyme cells reinforces the lateral inhibitory effect, but the cells also show accelerated pattern appearance. In the present study, we analyze how a small change in a specific parameter affects the speed of pattern appearance in a Turing reaction-diffusion system using linear stability analysis. It is shown that the sign of the change in appearance speed is qualitatively decided if the system is under the diffusion-driven instability condition, and this is confirmed by numerical simulations. Numerical simulations also show that a small change in parameter value induced easily detectable differences in the appearance speed of patterns. Analysis of the Gierer-Meinhardt model revealed that a change in a single parameter can explain two effects of FGF on limb mesenchyme cells-reinforcement of lateral inhibition and earlier appearance of pattern. These qualitative properties and easy detectability make this feature a promising tool to elucidate the underlying mechanisms of biological pattern formation where the quantitative parameters are difficult to obtain.


Obstructive Sleep Apnea and Vascular Diseases.
Obstructive sleep apnea (OSA) affects a large proportion of adults, and is as an independent risk factor for cerebrovascular and cardiovascular disease. The repetitive airway obstruction that characterizes OSA results in intermittent hypoxia, intrathoracic pressure swings, and sleep fragmentation, which in turn lead to sympathetic activation, oxidative stress, inflammation, and endothelial dysfunction. This review outlines the associations between OSA and vascular diseases and describes basic mechanisms that may be responsible for this association, in both the micro- and macrocirculation. It also reports on interventional studies that aim to ameliorate OSA and thereby reduce vascular disease burden. © 2016 American Physiological Society. Compr Physiol 6:1519-1528, 2016.


Selective suppression of rat hepatic microsomal activity during chronic cyclosporine nephrotoxicity.
Cyclosporine is an immunosuppressant that undergoes extensive hepatic biotransformation to hydroxylated and demethylated metabolites. At present, the CYP3A gene family is thought to be the primary enzyme system responsible for cyclosporine metabolism. The effect of chronic cyclosporine therapy on the suppression of drug metabolism was studied in male and female rats maintained on a low-salt diet. After 28 days of subcutaneous cyclosporine dosing 15 mg/kg, cyclosporine-treated rats had significant renal dysfunction as compared with gender-matched control rats. Creatinine clearance in male cyclosporine-treated rats was reduced by 47% (P < .01) as compared with male controls. Female rats demonstrated a 38% (P < .01) decrease in creatinine clearance as a result of chronic cyclosporine therapy. Despite similar nephrotoxicity, female rats had whole blood cyclosporine levels 48% (P < .01) less than male rats. Immunoblot analysis of hepatic microsomal proteins indicated that chronic cyclosporine treatment decreased the protein levels of P450 3A2 in male rats. This loss was paralleled by reduced production of 6 beta-hydroxytestosterone, the primary product of P450 3A activity, by hepatic microsomes from cyclosporine-treated male rats by 76% (P < .001). In addition, cyclosporine treatment of male rats also reduced the formation of 2 alpha-hydroxytestosterone and 16 alpha-hydroxytestosterone by 81% (P < .01) and 84% (P < .001), respectively. At the end of the study period, steroid 5 alpha-reductase activity in control male rats was only 4% (P < .001) of female counter-parts; however, cyclosporine treatment increased steroid 5 alpha-reductase activity in male rats to 79% (P < .001) of female values. These alterations in testosterone metabolism are consistent with the suppression of the predominately male-associated P450 3A2, P450 2C11 and P450 2C13 isoforms. Levels of 6 alpha-hydroxytestosterone and 7 alpha-hydroxytestosterone were not statistically different between rat groups. Taken together, the steady-state blood levels and metabolism studies suggest that, after chronic cyclosporine treatment, isoforms other than those from the CYP3A family or unidentified members of the CYP3A family are likely responsible for cyclosporine metabolism.


Osseodensification - A novel approach in implant dentistry.
Primary stability in dental implants is an essential factor for achieving successful osseointegration. Surgical procedure and bone quality are among the most common factors that affect primary stability. It is also crucial to achieve high-insertion torque which is important for obtaining primary stability. Maintaining sufficient bone bulk and density is essential to achieve necessary bone-to-implant contact for obtaining a biomechanically stable implant. A new concept for osteotomy called osseodensification (OD) has been at the forefront of changes in surgical site preparation in implantology. This relatively new concept with universally compatible drills has been proposed to help in better osteotomy preparation, bone densification, and indirect sinus lift and also achieve bone expansion at different sites of varying bone densities. This procedure has also shown improvement in achieving better implant primary stability and better osteotomy than conventional implant drills. A systematic review was undertaken to analyze if OD procedure had any advantages over conventional osteotomy on bone density and primary stability. An electronic database search was conducted in PubMed using keywords such as "OD," "implant primary stability," "implant bone density," and "implant osteotomy." A total of 195 articles were collected and subjected to screening using inclusion and exclusion criteria. A literature review was done, following which it was seen that the use of versah drills for bone OD resulted in undersized osteotomy compared to conventional drills. It also resulted in improved bone density and increase in percentage bone volume and bone-to-implant contact, thereby improving implant stability.


Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome.
Numerous mechanisms have been proposed to explain the thrombotic/proinflammatory tendency of antiphospholipid syndrome (APS) patients. Prothrombotic monocyte activation by antiphospholipid antibodies involves numerous proteins and intracellular pathways. The anti-inflammatory, anticoagulant and immunoregulatory effects of statins have been aimed as a therapeutic tool in APS patients. This study delineates the global effects of fluvastatin on the prothrombotic tendency of monocytes from APS patients. Forty-two APS patients with thrombosis and 35 healthy donors were included in the study. APS patients received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start, at the end and 2 months after the end of treatment. After 1 month of treatment, monocytes showed a significant inhibition of tissue factor, protein activator receptors 1 and 2, vascular endothelial growth factor and Flt1 expression that was related to the inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B/Rel DNA-binding activity. Proteomic analysis showed proteins involved in thrombotic development (annexin II, RhoA and protein disulphide isomerase) with altered expression after fluvastatin administration. In-vitro studies indicated that the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by fluvastatin might inhibit protein prenylation and MAPK activation. The data from this study support the belief that fluvastatin has multiple profound effects in monocyte activity, which might contribute to thrombosis prevention in APS patients.


All hands on DEK.
In this issue of the JCI, Capitano et al. demonstrate that the secreted form of the DNA-binding chromatin factor DEK regulates hematopoiesis. It is known that DEK can be secreted by macrophages and other cells, but no function has been attached to secreted DEK. Capitano et al. showed that extracellular DEK activates signaling through the CXCL2 receptor, which in turn enhances the proliferation of hematopoietic stem cells and decreases hematopoietic progenitor cell numbers both in vivo and in vitro. These results offer the opportunity to expand transplantable stem cells to improve outcomes in patients undergoing bone marrow transplant.


Can zinc enhance response interferon therapy for patients with HCV-related liver disease?
Patients with liver disease may be at risk of zinc depletion. Zinc supplementation has been shown to contribute to inhibition of liver fibrosis and improvement in hepatic encephalopathy. However, little is known about the anti-inflammatory effect of zinc on hepatitis C virus (HCV)-related chronic liver disease. The standard of care for chronic HCV has improved markedly since the approval of interferon (IFN) therapy more than a decade ago. Over the past 20 years, IFN therapy has improved to more effectively eliminate the virus, progressing from single IFN therapy to combination therapy with ribavirin (RBV) and finally to pegylated IFN (PEG-IFN) therapy. However, even combined therapy with PEG-IFN and RBV for 48 wk is unable to eliminate the virus in some 40% of hepatitis C cases, particularly those with genotype 1b and high viral load. Treatment options for patients who have relapsed or are refractory to treatment with PEG-IFN and RBV therefore need to be critically assessed. This paper overviews the relationship between chronic liver disease and zinc metabolism.


Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and prevents oxidative stress in uremic rats.
Chronic renal failure causes left ventricular hypertrophy, but the molecular mechanisms involved remain unknown. We, therefore, investigated whether the mineralocorticoid receptor is implicated in the cardiac hypertrophy observed in uremic rats and whether mineralocorticoid receptor blockade could be protective in chronic renal failure. Experimental groups were: control rats, uremic rats (NPX) with 5/6 nephrectomy (5 weeks), and NPX rats fed with spironolactone for 5 weeks. Systolic blood pressure was increased in both NPX rats and NPX rats fed with spironolactone for 5 weeks. Echocardiography revealed concentric left ventricular hypertrophy in uremia, which was attenuated by spironolactone. Enlarged cardiomyocyte size was observed in both left and right ventricles of NPX rats, an effect that was prevented by spironolactone. Mineralocorticoid receptor antagonism attenuated the increase of ventricular brain natriuretic peptide mRNA levels induced by nephrectomy. Left ventricular gene expressions of aldosterone synthase, mineralocorticoid receptor, and hydroxysteroid dehydrogenase type 2 were the same in the 3 groups, whereas gene expression of the glucocorticoid receptor was significantly diminished in chronic renal failure rats. No significant differences in cardiac aldosterone were observed between control rats and NPX rats, although NPX rats fed with spironolactone for 5 weeks showed increased plasma aldosterone levels. However, a significant increase in serum and glucocorticoid-inducible kinase-1 mRNA expression and protein was present in the NPX group; spironolactone treatment significantly reduced serum and glucocorticoid-inducible kinase-1 mRNA and protein in the left ventricle. Uremic rats exhibited a significant increase of superoxide production and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits expression (NOX-2, NOX-4, and p47(phox)) in the left ventricle, which was prevented by the mineralocorticoid receptor antagonist. Our findings provide evidence of the beneficial effects of spironolactone in cardiac hypertrophy and cardiac oxidative stress in chronic renal failure.


Hyperbolic damped-wave models for transient light-pulse propagation in scattering media.
Transient optical transport in highly scattering media such as tissues is usually modeled as a diffusion process in which the energy flux is assumed proportional to the fluence (intensity averaged over all solid angles) gradients. Such models exhibit an infinite speed of propagation of the optical signal, and finite transmission values are predicted even at times smaller than those associated with the propagation of light. If the hyperbolic, or wave, nature of the complete transient radiative transfer equation is retained, the resulting models do not exhibit such drawbacks. Additionally, the hyperbolic equations converge to the solution at a faster rate, which makes them very attractive for numerical applications in time-resolved optical tomography.


Identification of Clb2 residues required for Swe1 regulation of Clb2-Cdc28 in Saccharomyces cerevisiae.
Wee1 kinases regulate the cell cycle through inhibitory phosphorylation of cyclin-dependent kinases (CDKs). Eukaryotic cells express multiple CDKs, each having a kinase subunit (Cdk) and a regulatory "cyclin" subunit that function at different stages of the cell cycle to regulate distinct processes. The cyclin imparts specificity to CDK-substrate interactions and also determines whether a particular CDK is subject to Wee1 regulation. Saccharomyces Wee1 (Swe1) inhibits Cdc28 (Cdk1) associated with the mitotic cyclin, Clb2, but not with the G(1) (Cln1, -2, and -3) or the S-phase (Clb5 and -6) cyclins. Here, we show that this specificity depends on two amino acids associated with a conserved "hydrophobic patch" (HP) motif on the cyclin surface, which mediates specificity of CDK-substrate interactions. Mutation of Clb2 residues N260 and K270 largely abrogates Clb2-Cdc28 regulation by Swe1, and reciprocal mutation of the corresponding residues in Clb5 can subject Clb5-Cdc28 to regulation by Swe1. Swe1 phosphorylation by Clb2-Cdc28, which is thought to activate Swe1 kinase, depends on N260 and K270, suggesting that specific regulation of Clb2-Cdc28 by Swe1 derives from the specific ability of Clb2 to target Swe1 for activating phosphorylation. The stable association of Swe1 with Clb2-Cdc28 also depends on these residues, suggesting that Swe1 may competitively inhibit Clb2-Cdc28 interactions with substrates, in addition to its well-known function as a regulator of CDK activity through tyrosine phosphorylation.


Expression of p63 in papillary thyroid carcinoma and in Hashimoto's thyroiditis: a pathobiologic link?
p63 proteins are p53 homologs that are postulated to regulate squamous stem cell commitment. An immunohistochemical survey of p63 expression in normal thyroid and in reactive, neoplastic, and inflammatory thyroid disorders was performed. Sections from routinely fixed and processed archival thyroidectomy specimens were pretreated with citric acid, pH 6.0, for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as a chromagen, and then were counterstained with hematoxylin. The results showed that p63 expression was negative in normal thyroid tissue, nodular goiters, and oncocytic follicular adenomas. Positivity was rare and weak in follicular adenomas. p63-positive foci were commonly found in Hashimoto's thyroiditis (1 or more foci in 78.8% of cases), but rare in Graves' disease. Twenty-seven of 33 papillary thyroid carcinomas (81.8%) displayed p63-positive foci. Staining was uncommon in follicular carcinomas and rare in medullary carcinomas. One case of insular carcinoma was p63-positive. All squamoid structures were p63-positive; p63-positive structures morphologically consistent with solid cell nests were also identified. Based on the results of this study, we conclude that p63 is commonly expressed in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Given the debated association of papillary thyroid carcinoma with Hashimoto's thyroiditis, it is possible that p63 expression may be a potential pathobiologic link between the two disorders. The finding of p63 in benign squamoid nests supports a possible interrelationship between these structures and both Hashimoto's thyroiditis and papillary carcinoma. The high percentage of papillary carcinomas with p63-positive foci appears to distinguish papillary carcinoma from other neoplasms originating in the thyroid.


Effect of purified allicin, the major ingredient of freshly crushed garlic, on cancer cell proliferation.
The diverse health benefit effects of garlic include its anticancer activity. However, very little is known about such activity of isolated garlic compounds, among which allicin (the major ingredient of crushed garlic) has been the least studied. The aim of this work was to determine whether pure allicin exhibits the antiproliferative effect reported for garlic in in vitro models. Allicin, but not its precursor alliin, inhibited proliferation of human mammary (MCF-7), endometrial (Ishikawa), and colon (HT-29) cancer cells (50% inhibitory concentration = 10-25 microM). Two of three tested primary lines of human fibroblasts displayed a similar response to allicin (50% inhibitory concentration = 16-40 microM), whereas the third line was almost unaffected by this compound. The pure allicin and water extract of garlic powder with equivalent allicin concentrations displayed a similar potency, suggesting that allicin is responsible for the antiproliferative effect of the extract. The growth inhibition was accompanied by accumulation of cells in the G0/G1 and G2/M phases of the cell cycle (MCF-7 cells) and not by a significant increase in cell death. Allicin caused a transient drop in the intracellular glutathione (GSH) level, the magnitude and kinetics of which significantly varied depending on cell type. The extent of the decrease in GSH levels correlated well (r = 0.75) with the growth inhibitory activity of allicin. On the basis of these findings, we suggest that allicin plays a major role in the antiproliferative effect of water-soluble garlic preparations and that this effect may be attributed to the ability of allicin to transiently deplete the intracellular GSH level.


Building k-connected neighborhood graphs for isometric data embedding.
Isometric data embedding using geodesic distance requires the construction of a connected neighborhood graph so that the geodesic distance between every pair of data points can be estimated. This paper proposes an approach for constructing k-connected neighborhood graphs. The approach works by applying a greedy algorithm to add each edge, in a nondecreasing order of edge length, to a neighborhood graph if end vertices of the edge are not yet k-connected on the graph. The k-connectedness between vertices is tested using a network flow technique by assigning every vertex a unit flow capacity. This approach is applicable to a wide range of data. Experiments show that it gives better estimation of geodesic distances than other approaches, especially when the data are undersampled or nonuniformly distributed.