The kidney and uremic toxin removal: glomerulus or tubule?
Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes.


Chrysin attenuates atopic dermatitis by suppressing inflammation of keratinocytes.
We previously reported the inhibitory effect of chrysin, a natural flavonoid plentifully contained in propolis, vegetables and fruits, on the mast cell-mediated allergic reaction. In this study, we evaluated the effect of chrysin on atopic dermatitis (AD) and defined underlying mechanisms of action. We used an AD model in BALB/c mice by the repeated local exposure of 2,4-dinitrochlorobenzene (DNCB) and house dust mite (Dermatophagoides farinae extract, DFE) to the ears. Repeated alternative treatment of DNCB/DFE caused AD-like skin lesions. Oral administration of chrysin diminished AD symptoms such as ear thickness and histopathological analysis, in addition to serum IgE and IgG2a levels. Chrysin decreased infiltration of mast cells, and reduced serum histamine level. Chrysin also suppressed AD by inhibiting the inflammatory responses of Th1, Th2, and Th17 cells in mouse lymph node and ear. Interestingly, chrysin significantly inhibited the production of cytokines, Th2 chemokines, CCL17 and CCL22 by the down-regulation of p38 MAPK, NF-κB, and STAT1 in tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT). Chrysin also inhibited TNF-α/IFN-γ-stimulated IL-33 expression in HaCaT cells and mouse primary keratinocytes. Taken together, the results indicate that chrysin suppressed AD symptoms, suggesting that chrysin might be a candidate for the treatment of AD and skin allergic diseases.


Design of molecular water oxidation catalysts with earth-abundant metal ions.
The four-electron oxidation of water (2H2O → O2 + 4H+ + 4e-) is considered the main bottleneck in artificial photosynthesis. In nature, this reaction is catalysed by a Mn4CaO5 cluster embedded in the oxygen-evolving complex of photosystem II. Ruthenium-based complexes have been successful artificial molecular catalysts for mimicking this reaction. However, for practical and large-scale applications in the future, molecular catalysts that contain earth-abundant first-row transition metal ions are preferred owing to their high natural abundance, low risk of depletion, and low costs. In this review, the frontier of water oxidation reactions mediated by first-row transition metal complexes is described. Special attention is paid towards the design of molecular structures of the catalysts and their reaction mechanisms, and these factors are expected to serve as guiding principles for creating efficient and robust molecular catalysts for water oxidation using ubiquitous elements.


Modulation of melanoma cell adhesion to basement membrane components by retinoic acid.
The effect of retinoic acid pretreatment on metastatic B16 melanoma cell adhesion in serum-free medium to tissue culture plastic precoated with fibronectin, laminin/nidogen, type I and type IV collagen was examined. Both control cells grown to subconfluence and cells treated with 10(-6) M-retinoic acid adhered and spread rapidly on fibronectin (greater than 75% following 1 h of incubation) but adhered poorly to type I collagen (less than 15%). Control cells adhered to laminin/nidogen (greater than 35%), type IV collagen (greater than 58%) and type IV collagen plus laminin/nidogen (greater than 80%), while retinoic acid-treated cells showed a reduced ability to attach and spread on these substrata, the number of adherent cells being reduced by 61% on laminin/nidogen, by 19% on type IV collagen, and by 41% on type IV collagen plus laminin/nidogen following 1 h of incubation. The minimum concentration of retinoic acid required to yield an effective reduction in adhesion was 10(-7) M for type IV collagen and 10(-10) M for laminin/nidogen. Melanoma cells harvested at low density showed a reduced adhesion to laminin/nidogen and type IV collagen compared to that of subconfluent control cultures, but also showed a reduced adhesion to fibronectin. The effect of retinoic acid on cell adhesion was not, however, due to reduced cell density, as the cells were seeded so that control and retinoic acid-treated cultures were of a similar density when harvested.


Rapid Quantum Squeezing by Jumping the Harmonic Oscillator Frequency.
Quantum sensing and quantum information processing use quantum advantages such as squeezed states that encode a quantity of interest with higher precision and generate quantum correlations to outperform classical methods. In harmonic oscillators, the rate of generating squeezing is set by a quantum speed limit. Therefore, the degree to which a quantum advantage can be used in practice is limited by the time needed to create the state relative to the rate of unavoidable decoherence. Alternatively, a sudden change of harmonic oscillator's frequency projects a ground state into a squeezed state which can circumvent the time constraint. Here, we create squeezed states of atomic motion by sudden changes of the harmonic oscillation frequency of atoms in an optical lattice. Building on this protocol, we demonstrate rapid quantum amplification of a displacement operator that could be used for detecting motion. Our results can speed up quantum gates and enable quantum sensing and quantum information processing in noisy environments.


Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach.
Two of the possible catalytic mechanisms for neurotransmitter oxidative deamination by monoamine oxidase B (MAO B), namely, polar nucleophilic and hydride transfer, were addressed in order to comprehend the nature of their rate-determining step. The Quantum Chemical Cluster Approach was used to obtain transition states of MAO B complexed with phenylethylamine (PEA), benzylamine (BA), and p-nitrobenzylamine (NBA). The choice of these amines relies on their importance to address MAO B catalytic mechanisms so as to help us to answer questions such as why BA is a better substrate than NBA or how para-substitution affects substrate's reactivity. Transition states were later validated by comparison with the experimental free energy barriers. From a theoretical point of view, and according to the our reported transition states, their calculated barriers and structural and orbital differences obtained by us among these compounds, we propose that good substrates such as BA and PEA might follow the hydride transfer pathway while poor substrates such as NBA prefer the polar nucleophilic mechanism, which might suggest that MAO B can act by both mechanisms. The low free energy barriers for BA and PEA reflect the preference that MAO B has for hydride transfer over the polar nucleophilic mechanism when catalyzing the oxidative deamination of neurotransmitters.


Prognostic impact of absolute peripheral blood NK cell count after four cycles of R-CHOP-like regimen treatment in patients with diffuse large B cell lymphoma.
As a subtype of lymphocyte, natural killer (NK) cell is the first line of defense that shows a strong function in tumor immunotherapy response and clinical outcomes. The current study aims to investigate the prognostic influence of peripheral blood absolute NK cell count after four cycles of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) treatment (NKCC4) in diffuse large B cell lymphoma (DLBCL) patients. A total of 261 DLBCL patients treated with R-CHOP from January 2018 to September 2022 were enrolled. The low NKCC4 was observed in patients who died during the study period compared with survival individuals. A NKCC4 < 135 cells/μl had a remarkable negative influence in overall survival and progression-free survival (PFS) compared to a NKCC4 ≥ 135 cells/μl (p < 0.0001 and p < 0.0004, respectively). In addition, the OS and PFS were synergistically lower in a NKCC4 < 135 cells/μl group among DLBCL patients with GCB type or high IPI. In conclusion, this study indicates NCKK4 as a valuable marker in clinical practice and provides an insight for combination treatment of R-CHOP to improve outcomes of DLBCL patients.


Chromosomal abnormalities and mental illness.
Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.


Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract.
Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE) is partly attributable to Peroxisome proliferator-activated receptors (PPARs) activation in the Human Umbilical Vein Endothelial Cells (HUVECs). Ethanol extract from PPE was prepared. HUVECs were treated in four groups (with PPE (10 μg/ml) alone, PPE with or without PPARγ (T0070907) and α (GW6471) antagonists, and control group). The possible effect of PPARs on angiogenic regulation was checked by Matrigel assay. The mRNA expression levels of vascular endothelial growth factor (VEGF) was detected by Quantitative reverse transcription-polymerase chain reaction (QRT-PCR). PPE significantly inhibited both tube formation (size, length, and junction of tubes) and VEGF mRNA expression (P<0.05). Our results showed that the anti-angiogenic effects of PPE were significantly reversed by both PPAR antagonists (P<0.05). There was no difference between PPE plus antagonists groups and the control group. In summary our results showed that the anti-angiogenic effects of PPE could be mediated in part through PPAR dependent pathway.


Growth of breast muscles in European and Japanese quail raised in meat production system: a morphological analysis.
Growth curves have been described in the quail but with no attention to the muscle composing of the breast. The description of the characteristics of growth curves to body weight and to breast muscle was the aim of this study. Morphological development of Musculus supracoracoideus and Musculus pectoralis in European and Japanese quail was assessed from the final incubation of to 35 days. Gompertz models were adjusted with maximum growth rates to body weight, breast weight, and Musculus pectoralis and supracoracoideus weight at 17.6; 22.2; 23.5, and 21.4 days. The European quail had a higher body and breast weight at maturity. Musculus supracoracoideus developed faster in both subspecies but with larger Musculus pectoralis. Both musculus had a greater number of fibers type IIA and largest fibers IIB, with quadratically increasing in fiber diameter with age in both subspecies and muscles. At 35 days, results of meat quality indicated similarity between genders and subspecies, with darker and redness breast meat in Japanese quail. In conclusion, breast weight gain was a result of type IIA and IIB fiber hypertrophy in both muscles and, despite the difference in size and aptitude, Japanese and European quail showed similar body and muscle growth patterns.


Enhanced thermoelectric performance of heavy-fermion compounds YbTM 2Zn20 (TM = Co, Rh, Ir) at low temperatures.
Thermoelectricity allows direct conversion between heat and electricity, providing alternatives for green energy technologies. Despite these advantages, for most materials the energy conversion efficiency is limited by the tendency for the electrical and thermal conductivity to be proportional to each other and the Seebeck coefficient to be small. Here we report counter examples, where the heavy fermion compounds YbTM 2Zn20 (TM = Co, Rh, Ir) exhibit enhanced thermoelectric performance including a large power factor (PF = 74 μW/cm-K2; TM = Ir) and a high figure of merit (ZT = 0.07; TM = Ir) at 35 K. The combination of the strongly hybridized electronic state originating from the Yb f-electrons and the novel structural features (large unit cell and possible soft phonon modes) leads to high power factors and small thermal conductivity values. This demonstrates that with further optimization these systems could provide a platform for the next generation of low temperature thermoelectric materials.


Intestinal fibroblasts regulate intestinal epithelial cell proliferation via hepatocyte growth factor.
Although the presence of subepithelial intestinal fibroblasts has been well recognized, the effects of fibroblasts on intestinal epithelial cell (IEC) growth are incompletely understood. In vitro studies were undertaken to evaluate the effects of fibroblasts on the proliferation of model IEC lines. IECs (Caco-2, T84, and IEC-6) were grown alone or in the presence of human intestinal (CCD-18), lung (CCD-37), or skin explant-derived fibroblasts. Cocultures were carried out directly on irradiated fibroblasts or by Transwell coculture technique with fibroblasts and epithelial cells separated by a porous filter. Cell proliferation was assessed by [3H]thymidine incorporation and cell counts. Hepatocyte growth factor (HGF) and c-met transcript expression in IECs and fibroblasts was examined by RT-PCR and Northern blotting; protein expression was evaluated by immunoblotting. Intestinal as well as lung and skin fibroblasts substantially stimulated proliferation of Caco-2, T84, and IEC-6 cells in both direct and Transwell cocultures. In addition, fibroblast-conditioned medium stimulated IEC proliferation, suggesting a paracrine mechanism. Anti-human HGF-neutralizing antibodies blocked the growth-promoting effects in both fibroblasts and fibroblast-conditioned medium. Recombinant human HGF dose dependently promoted IEC proliferation. HGF mRNA and protein expression was restricted to fibroblasts. High levels of c-met expression were found in Caco-2 and T84 cells; in contrast, expression in fibroblasts was weak. In summary, fibroblasts stimulate IEC proliferation through a paracrine mechanism mediated predominantly by HGF.


Two phases of actin polymerization display different dependencies on PI(3,4,5)P3 accumulation and have unique roles during chemotaxis.
The directional movement of cells in chemoattractant gradients requires sophisticated control of the actin cytoskeleton. Uniform exposure of Dictyostelium discoideum amoebae as well as mammalian leukocytes to chemoattractant triggers two phases of actin polymerization. In the initial rapid phase, motility stops and the cell rounds up. During the second slow phase, pseudopodia are extended from local regions of the cell perimeter. These responses are highly correlated with temporal and spatial accumulations of PI(3,4,5)P3/PI(3,4)P2 reflected by the translocation of specific PH domains to the membrane. The slower phase of PI accumulation and actin polymerization is more prominent in less differentiated, unpolarized cells, is selectively increased by disruption of PTEN, and is relatively more sensitive to perturbations of PI3K. Optimal levels of the second responses allow the cell to respond rapidly to switches in gradient direction by extending lateral pseudopods. Consequently, PI3K inhibitors impair chemotaxis in wild-type cells but partially restore polarity and chemotactic response in pten- cells. Surprisingly, the fast phase of PI(3,4,5)P3 accumulation and actin polymerization, which is relatively resistant to PI3K inhibition, can support inefficient but reasonably accurate chemotaxis.


Unusual intestinal obstruction due to idiopathic sclerosing encapsulating peritonitis: a report of two cases and a review.
Sclerosing encapsulating peritonitis (SEP) is a rare cause of intestinal obstruction that is characterized by a thick fibrotic membrane encasing the small intestine like a cocoon. Accurate preoperative diagnosis is often difficult. We present 2 cases of SEP that were diagnosed preoperatively by contrast-enhanced computed tomography scan. A 38-year-old man and a 56-year-old woman were admitted to Daegu Catholic University Medical Center because of recurrent intestinal obstruction. We performed exploratory laparotomy with doubt of the preoperative diagnosis of SEP. We confirmed the diagnosis of SEP on laparotomy and performed adhesiolysis. Both patients recovered successfully and had no signs of recurrence. A better awareness of SEP and its radiological features should lead to more correct preoperative diagnosis and result in more appropriate management, including surgery.


Survey of 150 strains belonging to the Mycobacterium terrae complex and description of Mycobacterium engbaekii sp. nov., Mycobacterium heraklionense sp. nov. and Mycobacterium longobardum sp. nov.
A thorough phenotypic and genotypic analysis of 150 strains belonging to the Mycobacterium terrae complex resulted in the identification of a number of previously unreported sequevars (sqvs) within the species known to belong to the complex. For the species Mycobacterium arupense, three sqvs were detected in the 16S rRNA gene, six sqvs in the hsp65 gene and 15 sqvs in the rpoB gene; in Mycobacterium senuense two sqvs were present in each of the three genetic regions; in Mycobacterium kumamotonense four, two and nine sqvs were found, respectively, and in M. terrae three, four and six sqvs were found, respectively. The inappropriate inclusion of Mycobacterium triviale within the M. terrae complex was confirmed. The limited utility of biochemical tests and of mycolic acid analyses for the differentiation of the members of M. terrae complex was also confirmed. The survey allowed the recognition of three previously undescribed species that were characterized by unique sequences in the 16S rRNA, hsp65 and rpoB genes. Mycobacterium engbaekii sp. nov. (proposed previously 40 years ago but never validly published) was characterized by pink photochromogenic pigmentation and rapid growth; phylogenetically it was related to Mycobacterium hiberniae. The type strain of this species, of which eight strains were investigated, is ATCC 27353(T) ( = DSM 45694(T)). A cluster of 24 strains was the basis for the description of Mycobacterium heraklionense sp. nov., which has an intermediate growth rate and is unpigmented; nitrate reductase activity is typically strong. Closely related to M. arupense with respect to the 16S rRNA gene, M. heraklionense sp. nov. could be clearly differentiated from the latter species in the other genetic regions investigated. The type strain is NCTC 13432(T) ( = LMG 24735(T) = CECT 7509(T)). Mycobacterium longobardum sp. nov., represented in the study by seven strains, was characterized by a unique phylogenetic location within the M. terrae complex, clearly divergent from any other species. The type strain is DSM 45394(T) ( = CCUG 58460(T)).


[Diagnosis, immunopathogenesis, clinical picture and treatment of uveitis in nephropathies].
Complex clinical and immunological studies in 39 patients with uveitis and a history of nephropathies disclosed a relationship between renal diseases and vascular tract of the eyes. Specific features in the clinical symptomatology and immunological disorders were detected. Anterior and generalized forms, bilateral involvement, Tyndall's symptom, combined vitreolenticular changes, often with the exudative hemorrhagic component, predominated in the clinical picture of uveitis in patients with nephropathies. Uveitis ran a protracted course resistant to therapy, with frequent relapses. The disease occurred mainly in women. Predominant disorders in immunopathogenesis were disorders in the complex formation system. Uveitis in patients with nephropathies should be treated with due consideration for the etiology of nephropathy, clinical course of uveitis, and immunological disorders. Diseases of the vascular tract associated with nephropathy are rare in the etiological structure of uveitis and retinovasculitis (3.24%).


The mechanism of action of aspirin.
The therapy of rheumatism began thousands of years ago with the use of decoctions or extracts of herbs or plants such as willow bark or leaves, most of which turned out to contain salicylates. Following the advent of synthetic salicylate, Felix Hoffman, working at the Bayer company in Germany, made the acetylated form of salicylic acid in 1897. This drug was named "Aspirin" and became the most widely used medicine of all time. In 1971, Vane discovered the mechanism by which aspirin exerts its anti-inflammatory, analgesic and antipyretic actions. He proved that aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) inhibit the activity of the enzyme now called cyclooxygenase (COX) which leads to the formation of prostaglandins (PGs) that cause inflammation, swelling, pain and fever. However, by inhibiting this key enzyme in PG synthesis, the aspirin-like drugs also prevented the production of physiologically important PGs which protect the stomach mucosa from damage by hydrochloric acid, maintain kidney function and aggregate platelets when required. This conclusion provided a unifying explanation for the therapeutic actions and shared side effects of the aspirin-like drugs. Twenty years later, with the discovery of a second COX gene, it became clear that there are two isoforms of the COX enzyme. The constitutive isoform, COX-1, supports the beneficial homeostatic functions, whereas the inducible isoform, COX-2, becomes upregulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis.


Do favorite movie stars influence adolescent smoking initiation?
We sought to determine whether adolescents whose favorite movie stars smoke on-screen are at increased risk of tobacco use. During interviews, adolescent never smokers taking part in the California Tobacco Survey nominated their favorite stars. We reviewed popular films released during 1994 through 1996 to determine whether stars smoked on-screen in at least 2 films. One third of never smokers nominated a star who smoked on-screen, which independently predicted later smoking risk (odds ratio [OR] = 1.36; 95% confidence interval [CI] = 1.02, 1.82). The effect was strong among girls (OR = 1.86; 95% CI = 1.26, 2.73). Among boys, there was no independent effect after control for receptivity to tobacco industry promotions. Public health efforts to reduce adolescent smoking must confront smoking in films as a tobacco marketing strategy.


CFPC's Certification Examination: An overview.
The certification examination of the College of Family Physicians of Canada is designed to assess the extent to which the College's educational objectives have been achieved. Since the first examination in 1969, more than 7000 physicians have received their certification. The authors describe the basic elements of this test and the process through which the Committee on Examinations designs and sets the examination. The authors comment on the role of the certification process in the education of family physicians in Canada.


Heterologous cross-expression of oxygenase and glycosyltransferase genes in streptomycetes, producing angucyclic antibiotics.
The heterologous expression of oxygenase genes urdM, ovmOIII, lanM2, IndZ5 and glycosyltransferase gene urdGT2 in different angucycline producers of genus Streptomyces has been carried out. The introduction of genes urdM, lanM2 and urdGT2 results in the accumulation of new glycosylated compounds in several strains under investigation. A number of processed recombinant strains display streptomycin sensitivity and decrease in total antibacterial activity. The obtained data is an evidence of changes in antibiotics production, resulting from post-polyketide synthase (post-PKS) tailoring gene expression across streptomycete strains. Our study demonstrates the potential of post-PKS tailoring genes for generation of novel bioactive metabolites.


The impact of fluctuating workloads on well-being and the mediating role of work-nonwork interference in this relationship.
Heavy workloads have been central to the discussion of well-being. However, fluctuations in workloads have received sparse attention, even though transient and routine levels of workloads may have independent effects on well-being. The article assesses this, particularly focusing on the effort-recovery model of the workload/well-being relationship in which work-nonwork interference mediates this relationship. Using data from a weekly diary study of freelance or portfolio workers, multilevel analyses showed that both routine and transient levels of work to nonwork interference mediated the job demands-calmness relationship. Work to nonwork interference also negatively mediated the hours worked-calmness relationship, but the direct relationship between hours worked and calmness was a positive one so the mediating effect reduced this positive effect. In the case of enthusiasm, which was a second measure of well-being, there were no mediating effects but both routine and nonroutine levels of job demands and transient levels of hours worked were related to it. The study highlights the value of introducing the temporal dimension into the study of the work-nonwork interface, and the diversity of relationships that occur across different dimensions of workload and well-being.


The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster.
The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role of secondary metabolite gene clusters and their metabolites in fungal biology.


Paneth Cell: the missing link between Obesity, MASH and Portal hypertension.
Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible but stages of liver disease before development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities which influences the pathophysiology of portal hypertension. This review provide evidence supporting that, Paneth cells[PC] in the intestinal epithelium which remained enigmatic for a century, is the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability which are the potential triggers of systemic inflammation. Thus it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.


Climatic, socio-economic, and health factors affecting human vulnerability to cholera in the Lake Victoria basin, East Africa.
Cholera epidemics have a recorded history in the eastern Africa region dating to 1836. Cholera is now endemic in the Lake Victoria basin, a region with one of the poorest and fastest growing populations in the world. Analyses of precipitation, temperatures, and hydrological characteristics of selected stations in the Lake Victoria basin show that cholera epidemics are closely associated with El Niño years. Similarly, sustained temperatures high above normal (T(max)) in two consecutive seasons, followed by a slight cooling in the second season, trigger an outbreak of a cholera epidemic. The health and socioeconomic systems that the lake basin communities rely upon are not robust enough to cope with cholera outbreaks, thus rendering them vulnerable to the impact of climate variability and change. Collectively, this report argues that communities living around the Lake Victoria basin are vulnerable to climate-induced cholera that is aggravated by the low socioeconomic status and lack of an adequate health care system. In assessing the communities' adaptive capacity, the report concludes that persistent levels of poverty have made these communities vulnerable to cholera epidemics.


Feedback inhibition of insulin gene expression by insulin.
To examine the possible involvement of insulin and glucose in regulation of pancreatic islet gene expression, hyperinsulinemic (insulin infusion 4.1 mU/kg per min) clamps were performed for 12 h in rats at two different levels of glycemia (either 3 or 8 mM). A control group received a saline infusion for 12 h. At the end of the 12-h study period, pancreatic RNA was extracted, proinsulin and amylin mRNAs were measured on total RNA, and glucokinase and glucose transporter (GLUT-2) mRNAs were measured on poly(A)+ RNA by dot blot analysis. In insulin-infused hypoglycemic rats, there was a 58% decrement in proinsulin mRNA (P less than 0.01) relative to levels in controls, with no change in amylin, glucokinase, or islet GLUT-2 mRNAs. In insulin-infused hyperglycemic rats, there was a comparable decrement (44%, P less than 0.01) in proinsulin mRNA and a smaller decrement in GLUT-2 mRNA (32%, P less than 0.05), with no change in amylin or glucokinase mRNAs relative to levels in control animals. These studies suggest that insulin has a negative feedback inhibitory effect on its own synthesis. The mechanism of inhibition is unknown. It could be a direct effect of insulin on its own transcription, or alternatively an indirect effect mediated by humoral or neural factors. Sustained hyperinsulinemia may lead to suppression of normal islet beta cells and may contribute to the ultimate hypoinsulinemia of noninsulin-dependent diabetes mellitus.


Comparison of three treatment approaches to decreasing cardiovascular disease risk in nondiabetic insulin-resistant dyslipidemic subjects.
The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese insulin-resistant nondiabetic subjects. Insulin sensitivity, fasting lipids and lipoproteins, and postprandial plasma glucose, insulin, free fatty acid, and triglycerides were measured before and after 3 months of treatment with FEN, RSG, or CRD. Weight decreased in the CRD group, but did not change significantly after treatment with either drug. Insulin sensitivity improved significantly in the CRD- and RSG-treated groups, but to a greater extent in those administered RSG, without a significant difference comparing FEN treatment with the CRD. Total cholesterol was significantly lower after FEN and CRD treatment. Fasting plasma triglycerides decreased significantly in the FEN- and CRD-treated groups, but postprandial concentrations decreased in only FEN-treated subjects. Significant decreases in postprandial glucose and insulin were seen in only the RSG- and CRD-treated groups. FEN administration improved dyslipidemia in these subjects without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients without improvement in dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated patients, and improvement in lipid metabolism not as great as with FEN. In conclusion, there did not appear to be 1 therapeutic intervention that effectively treated all metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.


Membranes of Saccharomyces cerevisiae.
A crude small particle pellet, obtained from postmitochondrial supernatant fractions of Saccharomyces cerevisiae, contains about half the ergosterol and phospholipid of crude cell homogenates. Most of the phospholipid of this pellet is in a "heavy" fraction which, with the aid of electron microscopy, shows membranous elements in addition to discrete particles. The "heavy" fraction, upon treatment with deoxycholate, can be freed of membranes, or, with ribonuclease treatment, ribosomes can be removed, leaving relatively clean membranes. The "heavy" fraction resembles the microsomes of animal cells, but contains considerably less lipids, including phospholipids, thus suggesting a less well-developed intracellular membrane system.


The genome of herpes simplex virus: structure, replication and evolution.
The objectives of this paper are to discuss the structure and genetic content of the genome of herpes simplex virus type 1 (HSV-1), the nature of virus DNA replicative processes, and aspects of the evolution of the virus DNA, in particular those bearing on DNA replication. We are in the late stages of determining the complete sequence of the DNA of HSV-1, which contains about 155,000 base pairs, and thus the treatment is primarily from a viewpoint of DNA sequence and organization. The genome possesses around 75 genes, generally densely arranged and without long range ordering. Introns are present in only a few genes. Protein coding sequences have been predicted, and the functions of the proteins are being pursued by various means, including use of existing genetic and biochemical data, computer based analyses, expression of isolated genes and use of oligopeptide antisera. Many proteins are known to be virion structural components, or to have regulatory roles, or to function in synthesis of virus DNA. Many, however, still lack an assigned function. Two classes of genetic entities necessary for virus DNA replication have been characterized: cis-acting sequences, which include origins of replication and packaging signals, and genes encoding proteins involved in replication. Aside from enzymes of nucleotide metabolism, the latter include DNA polymerase, DNA binding proteins, and five species detected by genetic assays, but of presently unknown functions. Complete genome sequences are now known for the related alphaherpesvirus varicella-zoster virus and for the very distinct gammaherpesvirus Epstein-Barr virus. Comparisons between the three sequences show various homologies, and also several types of divergence and rearrangement, and so allow models to be proposed for possible events in the evolution of present day herpesvirus genomes. Another aspect of genome evolution is seen in the wide range of overall base compositions found in present day herpesvirus DNAs. Finally, certain herpesvirus genes are homologous to non-herpesvirus genes, giving a glimpse of more remote relationships.


Hepatitis C virus: detection of intracellular virus particles by electron microscopy.
We previously demonstrated that a human T-cell line, HPBMa10-2 derived from HPBALL, was capable of supporting a productive infection of hepatitis C virus (HCV). We subsequently found Daudi cells, a human B-cell line, to be susceptible to HCV infection. Employing these cell lines infected with HCV as well as liver obtained during the acute phase of hepatitis C from a chimpanzee, we observed intracellular HCV particles by electron microscopy (EM). We detected viruslike particles with a diameter of approximately 50 nm in the cytoplasmic vesicles. In Daudi cells harvested 15 days after virus inoculation, the appearance of cytoplasmic tubular structures which we originally described for chimpanzee hepatocytes in association with HCV infection was noted. Immunoperoxidase EM using antibodies against HCV core and envelope demonstrated that the particles contained the viral antigens.


Sterilization of regenerated collagen sutures with beta-propiolactone.
Data are presented to show that beta-propiolactone when properly applied is a very effective agent for sterilization of regenerated collagen sutures. The chemical sterilization is accomplished with little or none of the loss in strength encountered with heat sterilization. The finished sterile suture is obtained without any harmful residue that might be detrimental to the patient.


The effect of mandatory post-call relief on sleep and wellness in ophthalmology residents.
Multiple duty hour reforms have been implemented to optimize resident wellness through increasing opportunities for sleep recovery, but few studies have recorded objectively measured sleep or shown direct sleep and wellness benefits from such interventions. This study seeks to determine whether mandatory post-call relief policies with a partial night float system improved resident sleep, activity, and burnout among ophthalmology residents taking home call. We conducted a two group cohort study of ophthalmology residents at the University Washington comparing post graduate year-2 (PGY-2) resident sleep, activity, and burnout between the optional post-call relief group from July 1, 2017 to June 30, 2019 to the mandatory post-call relief group from July 1, 2019 to June 30, 2021. Of twenty total residents participating in the survey portion, 18 residents participated in the sleep and activity tracking portion of the study, 9 in in the optional post-call relief cohort, and 9 in the mandatory post-call relief cohort. The mandatory post-call relief group recorded longer total sleep on call than the optional post-call relief group (p < 0.001). There was no difference in overnight sleep recorded on call (median 3.4 h), but residents recorded more time napping in the mandatory post-call relief cohort (p < 0.001). There was no significant difference between cohorts in amount of sleep while not on call. Residents in the mandatory post-call relief cohort recorded higher average daily steps, higher exercise time, and lower sedentary time than residents in the optional post-call relief cohort (p < 0.001). They also recorded lower median emotional exhaustion on the Maslach Burnout Inventory and lower stress in the Depression and Anxiety Stress Scale in the mandatory post-call relief cohort (p = 0.008). Implementation of mandatory post-call relief policies with a partial night-float system among PGY-2 residents was associated with more post-call naps with more overall physical activity, lower emotional exhaustion scores, and lower stress scores, despite no changes to overnight sleep on call or total sleep. Although sample size limits interpretation of data, implementation of mandatory post call relief could be considered to improve post-call sleep in programs with home call.


[Heterogeneity of purinergic P2 receptors at the level of the caudal artery of the rat and the saphenous vein of the dog].
Phentolamine (10(-5) M) and an inhibitor of the lipoxygenase pathway, nordihydroguaiaretic acid (N. D. G. A.; 8 10(-6) M) antagonized the ATP induced contraction but not antagonized the UTP induced contraction on both rat tail artery and dog saphenous vein. We conclude that the receptors to ATP are distinct from receptors to UTP and that the P2 purinoceptors are an heterogeneous group.


A quality evaluation of the clinical practice guidelines on breast cancer using the RIGHT checklist.
Breast cancer is the most frequent type of cancer in women. The methodological quality of clinical practice guidelines (CPGs) on breast cancer has been shown to be heterogeneous. The aim of our study was to evaluate the quality of breast cancer CPGs published in years 2018-2020, using the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist. We searched Medline (via PubMed), Chinese National Knowledge Infrastructure (CNKI), Wanfang and Chinese Biomedical Literature (CBM) as well as websites of guideline organizations for CPGs on breast cancer published between 2018 and 2020. We used the RIGHT checklist to evaluate the reporting quality of the included guidelines by assessing whether the CPGs adhered to each item of the checklist and calculated the proportions of appropriately reported RIGHT checklist items. We also presented the adherence reporting rates for each guideline and the mean rates for each of the seven domains of the RIGHT checklist. A total of 45 guidelines were included. Eighteen (40.0%) guidelines had an overall reporting rate below 50% and only three (6.7%) reported more than 80% of the items. The domains "Basic information" and "Background" had the highest reporting rates (75.9% and 62.5%, respectively). The mean reporting rates of the domains "Evidence", "Recommendation", "Review and quality assurance", "Funding and declaration and management of interests" and "Other information" were 42.7%, 53.0%, 33.3%, 45.0%, and 44.4%, respectively. The reporting quality varied among guidelines for breast cancer, showing the need for improvement in reporting the contents. Guideline developers should pay more attention to reporting the evidence, review and quality assurance, and funding and declaration and management of interests in future.


Breakpoint analysis of balanced chromosome rearrangements by next-generation paired-end sequencing.
Characterisation of breakpoints in disease-associated balanced chromosome rearrangements (DBCRs), which disrupt or inactivate specific genes, has facilitated the molecular elucidation of a wide variety of genetic disorders. However, conventional methods for mapping chromosome breakpoints, such as in situ hybridisation with fluorescent dye-labelled bacterial artificial chromosome clones (BAC-FISH), are laborious, time consuming and often with insufficient resolution to unequivocally identify the disrupted gene. By combining DNA array hybridisation with chromosome sorting, the efficiency of breakpoint mapping has dramatically improved. However, this can only be applied when the physical properties of the derivative chromosomes allow them to be flow sorted. To characterise the breakpoints in all types of balanced chromosome rearrangements more efficiently and more accurately, we performed massively parallel sequencing using Illumina 1G analyser and ABI SOLiD systems to generate short sequencing reads from both ends of DNA fragments. We applied this method to four different DBCRs, including two reciprocal translocations and two inversions. By identifying read pairs spanning the breakpoints, we were able to map the breakpoints to a region of a few hundred base pairs that could be confirmed by subsequent PCR amplification and Sanger sequencing of the junction fragments. Our results show the feasibility of paired-end sequencing of systematic breakpoint mapping and gene finding in patients with disease-associated chromosome rearrangements.


Bone marrow lesions and subchondral bone pathology of the knee.
Bone marrow lesions (BMLs) around the knee are a common magnetic resonance imaging (MRI) finding. However, despite the growing interest on BMLs in multiple pathological conditions, they remain controversial not only for the still unknown role in the etiopathological processes, but also in terms of clinical impact and treatment. The differential diagnosis includes a wide range of conditions: traumatic contusion and fractures, cyst formation and erosions, hematopoietic and infiltrated marrow, developmental chondroses, disuse and overuse, transient bone marrow oedema syndrome and, lastly, subchondral insufficiency fractures and true osteonecrosis. Regardless the heterogeneous spectrum of these pathologies, a key factor for patient management is the distinction between reversible and irreversible conditions. To this regard, MRI plays a major role, leading to the correct diagnosis based on recognizable typical patterns that have to be considered together with coexistent abnormalities, age, and clinical history. Several treatment options have been proposed, from conservative to surgical approaches. In this manuscript the main lesion patterns and their management have been analysed to provide the most updated evidence for the differential diagnosis and the most effective treatment.


[Effect of Actoflor preparations on survival of Escherichia coli M-17 and Salmonella enteritidis under starvation conditions in mixed cultures].
The viability of E. coli M-17 and S. enteritidis under starvation conditions in mono- and mixed cultures was studied. E. coli M-17 showed greater capacity for survival in mixed cultures than in monocultures, while for S. enteritidis the contrary was true. Preparations "Actoflor" enhanced the antagonistic activity of E. coli M-17, ensuring its absolute selective advantage under starvation conditions in mixed cultures. The role of E. coli M-17 low-molecular exometabolites is discussed; they are probably an important factor in the antagonistic activity of these microorganisms.


Maize inbreds exhibit high levels of copy number variation (CNV) and presence/absence variation (PAV) in genome content.
Following the domestication of maize over the past approximately 10,000 years, breeders have exploited the extensive genetic diversity of this species to mold its phenotype to meet human needs. The extent of structural variation, including copy number variation (CNV) and presence/absence variation (PAV), which are thought to contribute to the extraordinary phenotypic diversity and plasticity of this important crop, have not been elucidated. Whole-genome, array-based, comparative genomic hybridization (CGH) revealed a level of structural diversity between the inbred lines B73 and Mo17 that is unprecedented among higher eukaryotes. A detailed analysis of altered segments of DNA conservatively estimates that there are several hundred CNV sequences among the two genotypes, as well as several thousand PAV sequences that are present in B73 but not Mo17. Haplotype-specific PAVs contain hundreds of single-copy, expressed genes that may contribute to heterosis and to the extraordinary phenotypic diversity of this important crop.


Quantitative Analysis of NKX2-3 Expression in Human Colon: An Immunohistochemical Study.
In mice, Nkx2-3 homeodomain transcription factor defines the vascular specification of secondary and tertiary lymphoid tissues of the intestines. In human studies, polymorphisms in NKX2-3 have been identified as a susceptibility factor in inflammatory bowel diseases, whereas in mice, its absence is associated with protection against experimental colitis and enhanced intestinal epithelial proliferation. Here, we investigated the expression of NKX2-3 in normal, polyp, and adenocarcinoma human colon samples using immunohistochemistry and quantitative morphometry, correlating its expression with endothelial and mesenchymal stromal markers. Our results revealed that the expression of NKX2-3 is regionally confined to the lamina propria and lamina muscularis mucosae, and its production is restricted mostly to endothelial cells and smooth muscle cells with variable co-expression of CD34, alpha smooth muscle antigen (αSMA), and vascular adhesion protein-1 (VAP-1). The frequency of NKX2-3-positive cells and intensity of expression correlated inversely with aging. Furthermore, in most colorectal carcinoma samples, we observed a significant reduction of NKX2-3 expression. These findings indicate that the NKX2-3 transcription factor is produced by both endothelial and non-endothelial tissue constituents in the colon, and its expression changes during aging and in colorectal malignancies. (J Histochem Cytochem XX: XXX-XXX, XXXX).


Molecular chaperones as HSF1-specific transcriptional repressors.
The rapid yet transient transcriptional activation of heat shock genes is mediated by the reversible conversion of HSF1 from an inert negatively regulated monomer to a transcriptionally active DNA-binding trimer. During attenuation of the heat shock response, transcription of heat shock genes returns to basal levels and HSF1 reverts to an inert monomer. These events coincide with elevated levels of Hsp70 and other heat shock proteins (molecular chaperones). Here, we show that the molecular chaperone Hsp70 and the cochaperone Hdj1 interact directly with the transactivation domain of HSF1 and repress heat shock gene transcription. Overexpression of either chaperone represses the transcriptional activity of a transfected GAL4-HSF1 activation domain fusion protein and endogenous HSF1. As neither the activation of HSF1 DNA binding nor inducible phosphorylation of HSF1 was affected, the primary autoregulatory role of Hsp70 is to negatively regulate HSF1 transcriptional activity. These results reveal that the repression of heat shock gene transcription, which occurs during attenuation, is due to the association of Hsp70 with the HSF1 transactivation domain, thus providing a plausible explanation for the role of molecular chaperones in at least one key step in the autoregulation of the heat shock response.


Rare non-epithelial ovarian neoplasms: Pathology, genetics and treatment.
Rare non-epithelial ovarian neoplasms have posed management challenges for many years. Their rarity means that most specialist practitioners will see one such case every several years, and most generalists may never see a case. The first step in management is to establish the correct diagnosis and this may necessitate specialist pathology review. Here, we review recent developments in the pathology, genetics and treatment of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and sex cord-stromal tumours. Pathologically, these tumours often display morphological overlap with other neoplasms; for example, SCCOHT overlaps with many other "small round blue cell" tumours. Specific immunohistochemical stains, while useful, may not always be definitive. The discovery of somatic mutations in FOXL2 (adult granulosa cell tumours) and germline and somatic mutations in DICER1 (Sertoli-Leydig cell tumours) and SMARCA4 (SCCOHT) has demonstrated the value of molecular investigation as an adjunct to traditional histopathological approaches. In addition, the presence of germline mutations in a significant proportion of some of these neoplasms points to the need for genetic counselling and testing, offering the prospect of prevention and early diagnosis. Treatment of these rare tumours, as a group, should be on the basis of sound oncological principles, given that level 1 evidence will almost always be lacking. The rationale for experimental therapies must be clearly established. In view of the complex issues involved in the management of these conditions, expert opinion in pathology, genetics and treatment may be essential to offer the patient and her family the best chance of a good outcome.


Analysis of maize brittle-1 alleles and a defective Suppressor-mutator-induced mutable allele.
A mutant allele of the maize brittle-1 (bt1) locus, brittle-1-mutable (bt1-m), was shown genetically and molecularly to result from the insertion of a defective Suppressor-mutator (dSpm) transposable element. An Spm-hybridizing restriction enzyme fragment, which cosegregates with the bt1-m allele and is absent from wild-type revertants of bt1-m, was identified and cloned. Non-Spm portions of it were used as probes to identify wild-type (Bt1) cDNAs in an endosperm library. The 4.3-kb bt1-m genomic clone contains a 3.3-kb dSpm, which is inserted in an exon and is composed of Spm termini flanking non-Spm sequences. RNA gel blot analyses, using a cloned Bt1 cDNA probe, indicated that Bt1 mRNA is present in the endosperm of developing kernels and is absent from embryo or leaf tissues. Several transcripts are produced by bt1-m. The deduced translation product from a 1.7-kb Bt1 cDNA clone has an apparent plastid transit peptide at its amino terminus and sequence similarity to several mitochondrial inner-envelope translocator proteins, suggesting a possible role in amyloplast membrane transport.


The Role of CO-RADS Scoring System in the Diagnosis of COVID-19 Infection and its Correlation with Clinical Signs.
Computed tomography (CT) evaluation systematics has become necessary to eliminate the difference of opinion among radiologists in evaluating COVID-19 CT findings. The objectives of this study were to evaluate the efficiency of CO-RADS scoring system in our patients with COVID-19 as well as to examine its correlation with clinical and laboratory findings. The CO-RADS category of all patients included in the study was determined by a radiologist who did not know the rtRT-PCR test result of the patients, according to the Covid-19 reporting and data system of Mathias Prokop et al. Results: A total of 1338 patients were included. CT findings were positive in 66.3%, with a mean CO-RADS score of 3,4 ± 1,7. 444 (33.1%) of the patients were in the CO-RADS 1-2, 894 (66.9%) were in the CO-RADS 3-5 group. There were positive correlations between CO-RADS score and age, CMI, hypertension, diabetes mellitus, chronic pulmonary diseases presence of symptoms, symptom duration, presence of cough, shortness of breath, malaise, CRP, and LDH, while CORADS score was negatively correlated with lymphocyte count. The results of the ROC analysis suggested that those with age ≥40 years, symptom duration >2 days, CMI score >1 and/or comorbid conditions were more likely to have a CO-RADS score of 3-5. The CO-RADS classification system is a CT findings assessment system that can be used to diagnose COVID-19 in patients with symptoms of cough, shortness of breath, myalgia and fatigue for more than two days.


Administrative and claims records as sources of health care cost data.
Many economic studies of disease require cost data at the person level to identify diagnosed cases and to capture the type and timing of specific services. One source of cost data is claims and other administrative records associated with health insurance programs and health care providers. To describe and compare strengths and limitations of various administrative and claims databases. Data sources included claims and enrollment records from Medicare, Medicaid, and private insurers; Veterans' Health Administration records; state hospital discharge datasets; Healthcare Cost and Utilization Project hospital databases; managed care plan data systems; and provider cost reports. Claims provide information on payments, whereas cost reports yield resource costs incurred to produce services. Administrative data may be significantly augmented by linkage to disease registries and surveys. Administrative data are often available for large, enrolled populations, have detailed information on individual service use, and can be aggregated by service type, episode, and patient. Service use and costs can often be tracked longitudinally. Because they are not collected for research purposes, administrative data can be difficult to access and use. Limitations include generalizability, complexity, coverage and benefit restrictions, and lack of coverage continuity. Linked datasets permit identification of incident cases of disease, and analyses of health care costs by stage at diagnosis, phase of care, comorbidity status, income, and insurance status. Administrative data are an essential source of information for studies of the financial burden of disease. Cost estimates can vary substantially by specific measures (payments, charges, cost to charge ratios) and across data sources.


Maternal Labor Force Participation During the Child's First Year and Later Separation Anxiety Symptoms.
Separation anxiety symptoms are frequent among preschool-aged children, but it is also a possible gateway for diagnosis of separation anxiety disorder. Early maternal employment after childbirth can increase the risk for the development of separation anxiety symptoms. From an economic perspective, however, securing employment is one effective strategy to ensure child well-being. This study investigated how mothers' participation in the labor force (vs. maternal leave) and the financial state of families when the child was 5 months old was prospectively associated with separation anxiety symptoms. This study is based on 1,295 Canadian families with children assessed longitudinally from 17 months to age 6 on their levels of separation anxiety. Separation anxiety was measured during face-to-face interviews with the mothers. Maternal labor force participation, financial status, and risk factors were measured at 5 months. Results adjusted for propensity scores and for sample weight revealed that children of working mothers, despite having sufficient income (n = 245, 18.9%), were at higher risk of separation anxiety during early childhood. In contrast, maternity leave was most beneficial for children's separation anxiety, whether they were in a family with sufficient income (n = 950, 73.4%) or temporary low income (n = 100, 7.7%). Children of mothers in maternity leave were at risk of heightened separation anxiety only if they experienced chronic economic hardship. Therefore, maternity leave uptake could help prevent the development of separation anxiety. Providing families with opportunity to care for the baby as their main occupation during this sensitive developmental period could help improve children's mental health.


A Quality Improvement Project to Improve the Pathway and Outcomes for Patients with Necrotising Fasciitis.
Necrotising fasciitis (NF) is a life-threatening illness that requires a multidisciplinary approach between surgeons in multiple specialties, intensivists, and microbiologists. Serial debridements and change of dressings are required prior to reconstruction. The aim of this study was to review the workload and streamline services in a tertiary centre for regional and internal referrals by formalizing an NF pathway agreed upon by all multidisciplinary team stakeholders and securing adequate resources for these complex patients. Retrospective data was collected on all patients with NF referred to the plastic surgery department between January 2017 and September 2018. Referrals were categorized as either regional (debridement had already taken place at another hospital) or internal (conducted on patients admitted through the emergency department). A total of 41 patients (17 regional and 24 internal referrals) with a median age of 63 years (range, 28 to 85 years) were included in the study. Overall mortality rate was found to be 27%, median length of stay (LOS) amongst internal referrals was 25 days (range, 11 to 94 days), and median intensive care unit LOS was 8 days (range, 0 to 64 days). A total of 121 operations were conducted by 4 surgical specialties with a median time per procedure of 145 minutes (range, 50 to 605). 11 patients underwent reconstruction with split thickness graft and the median number of days between initial debridement to grafting was 13 (range, 2 to 38 days). Patients with NF require complex care and treatment. By characterizing and defining the workload involved in treating these patients, it may be possible to improve advanced planning and allocate resources accordingly to ensure that the centre runs as smoothly as possible without interruption to the acute trauma service.


No ambiguity: Chemosensory-based ayurvedic classification of medicinal plants can be fingerprinted using E-tongue coupled with multivariate statistical analysis.
Background: Ayurveda, the indigenous medical system of India, has chemosensory property (rasa) as one of its major pharmacological metric. Medicinal plants have been classified in Ayurveda under six rasas/tastes-sweet, sour, saline, pungent, bitter and astringent. This study has explored for the first time, the use of Electronic tongue for studies of rasa-based classification of medicinal plants. Methods: Seventy-eight medicinal plants, belonging to five taste categories (sweet, sour, pungent, bitter, astringent) were studied along with the reference taste standards (citric acid, hydrochloric acid, caffeine, quinine, L-alanine, glycine, β-glucose, sucrose, D-galactose, cellobiose, arabinose, maltose, mannose, lactose, xylose). The studies were carried out with the potentiometry-based Electronic tongue and the data was analysed using Principle Component Analysis, Discriminant Function Analysis, Taste Discrimination Analysis and Soft Independent Modeling of Class Analogy. Results: Chemosensory similarities were observed between taste standards and the plant samples-citric acid with sour group plants, sweet category plants with sucrose, glycine, β-glucose and D-galactose. The multivariate analyses could discriminate the sweet and sour, sweet and bitter, sweet and pungent, sour and pungent plant groups. Chemosensory category of plant (classified as unknown) could also be identified. Conclusion: This preliminary study has indicated the possibility of fingerprinting the chemosensory-based ayurvedic classification of medicinal plants using E-tongue coupled with multivariate statistical analysis.


Bacterial volatiles promote growth in Arabidopsis.
Several chemical changes in soil are associated with plant growth-promoting rhizobacteria (PGPR). Some bacterial strains directly regulate plant physiology by mimicking synthesis of plant hormones, whereas others increase mineral and nitrogen availability in the soil as a way to augment growth. Identification of bacterial chemical messengers that trigger growth promotion has been limited in part by the understanding of how plants respond to external stimuli. With an increasing appreciation of how volatile organic compounds signal plants and serve in plant defense, investigations into the role of volatile components in plant-bacterial systems now can follow. Here, we present chemical and plant-growth data showing that some PGPR release a blend of volatile components that promote growth of Arabidopsis thaliana. In particular, the volatile components 2,3-butanediol and acetoin were released exclusively from two bacterial strains that trigger the greatest level of growth promotion. Furthermore, pharmacological applications of 2,3-butanediol enhanced plant growth whereas bacterial mutants blocked in 2,3-butanediol and acetoin synthesis were devoid in this growth-promotion capacity. The demonstration that PGPR strains release different volatile blends and that plant growth is stimulated by differences in these volatile blends establishes an additional function for volatile organic compounds as signaling molecules mediating plant-microbe interactions.


Isolated Dimers Versus Solid-State Dimers of N-Heteropolycycles: Matrix-Isolation Spectroscopy in Concert with Quantum Chemistry.
In this work, matrix-isolation spectroscopy and quantum-chemical calculations are used together to analyse the structure and properties of weakly bound dimers of the two isomers benzo[a]acridine and benzo[c]acridine. Our measured experimental electronic absorbance spectra agree with simulated spectra calculated for the equilibrium structures of the dimers in gas-phase, but in contrast, disagree with the simulated spectra calculated for the structures obtained by optimising the experimental solid-state structures. This highlights the sensitivity of the electronic excitations with respect to the dimer structures. The comparison between the solid-state and gas-phase dimers shows how far the intermolecular interactions could change the geometric and electronic structure in a disordered bulk material or at device interfaces, imposing consequences for exciton and charge mobility and other material properties.


Supportive Mental Health Self-Monitoring among Smartphone Users with Psychological Distress: Protocol for a Fully Mobile Randomized Controlled Trial.
Mobile health (mHealth) could be widely used in the population to improve access to psychological treatment. In this paper, we describe the development of a mHealth intervention on the basis of supportive self-monitoring and describe the protocol for a randomized controlled trial to evaluate its effectiveness among smartphone users with psychological distress. Based on power analysis, a representative quota sample of N = 186 smartphone users will be recruited, with an over-sampling of persons with moderate to high distress. Over a 4-week period, the intervention will be compared to a self-monitoring without intervention group and a passive control group. Telephone interviews will be conducted at baseline, post-intervention (4 weeks), and 12-week follow-up to assess study outcomes. The primary outcome will be improvement of mental health. Secondary outcomes will include well-being, intentions toward help-seeking and help-seeking behavior, user activation, attitudes toward mental-health services, perceived stigmatization, smartphone app quality, user satisfaction, engagement, and adherence with the intervention. Additionally, data from the user's daily life as collected during self-monitoring will be used to investigate risk and protective factors of mental health in real-world settings. Therefore, this study will allow us to demonstrate the effectiveness of a smartphone application as a widely accessible and low-cost intervention to improve mental health on a population level. It also allows to identify new assessment approaches in the field of psychiatric epidemiology.


Mission-Based Filters in the Electronic Residency Application Service: Saving Time and Promoting Diversity.
Holistic review promotes diversity, but widespread implementation remains limited. We aimed to develop a practical approach to incorporate holistic review principles in screening applicants in the Electronic Residency Application Service (ERAS) and to assess the impact on diversity. Three residency programs (internal medicine [IM], pediatrics, and surgery) at McGovern Medical School developed filters to identify applicants with experiences/attributes aligned with the institutional mission. These filters were retroactively applied to each program's 2019-2020 applicant pool using built-in ERAS capabilities to group applicants by user-defined features. We compared the demographics of applicants reviewed during the cycle with those identified retrospectively through experiences/attributes filters. The IM, pediatrics, and surgery programs received 3527, 1341, and 1313 applications, respectively, in 2019-2020. Retrospective use of experiences/attributes filters, without scores, narrowed the IM applicant pool for review to 1301 compared to 1323 applicants reviewed during actual recruitment, while the pediatrics filters identified 514 applicants compared to 384 at baseline. The surgery filters resulted in 582 applicants, but data were missing for baseline comparison. Compared to the baseline screening approach utilizing scores, mission-based filters increased the proportions of underrepresented in medicine applicants selected for review in IM (54.8% [95% CI 52.1-57.5] vs 22.7% [20.4-24.9], P < .0001) and pediatrics (63.2% [95% CI 59.1-67.4] vs 25.3% [20.9-29.6], P < .0001). Program directors can leverage existing ERAS features to conduct application screening in alignment with holistic review principles. Widespread implementation could have important repercussions for enhancing physician workforce diversity.


Clinical Milestones Preceding the Diagnosis of Multiple System Atrophy and Progressive Supranuclear Palsy: A Retrospective Cohort Study.
Multiple System Atrophy (MSA) and progressive supranuclear palsy (PSP) are rapidly progressive forms of degenerative Parkinsonism. The difficulties of diagnosing MSA and PSP in their early stages may lead to delayed referral to appropriate specialists and distress to patients, as well as delaying symptomatic treatment and participation in clinical trials. This work aimed to describe the symptoms that patients with MSA and PSP developed and plot their emergence relative to final diagnosis using a median onset in months. Forty-seven patients from the United Kingdom with MSA or PSP diagnosed by a movement disorder specialist were interviewed with carers or relatives to establish milestone onset. This was corroborated using clinical notes and letters. In the MSA cohort (n = 23), autonomic symptoms (median 5.5 months before diagnosis) and falls (median 1 month before diagnosis) were the two clinical milestones which occurred before diagnosis. In the PSP cohort (n = 24), falling was the only milestone which occurred before diagnosis (median of 18.5 months). This Study Shows That Psp Patients Experience Falling More Than A Year And A Half An Average Before Receiving A Diagnosis And Although Msa Patients Also Tended To Fall, This Was Much Closer To The Time Of Diagnosis. Further Work With Larger Cohorts May Illustrate Whether These Preliminary Findings Can Be Generalised To Guide Diagnosis And Management.


Advancement Flap Using Excess Skin for Upper Eyelid Full-Thickness Defects.
Reconstruction of upper eyelid defects should aim for a moveable lid with perfect corneal protection and good aesthetic quality. Numerous procedures to reconstruct large upper eyelid defects have been reported, but these methods require 2-stage procedures. A new method for reconstructing full-thickness upper eyelid defects after tumor excision in a single stage was presented in this study. The preferred technique uses excess skin as an advancement flap together with an ear cartilage graft for the lining. Reconstruction was performed with an advancement flap using excess skin and ear cartilage for full-thickness defects after upper eyelid tumor excision. The rectangular flap was outlined on the excess skin of the upper eyelid. After tumor resection of the full-thickness defect, the ear cartilage was sutured to the remaining tarsus. The residual levator aponeurosis and posterior lamellar were connected to the transplanted ear cartilage. The outer layer was reconstructed with an advancement rectangular flap. The authors performed this technique for 4 patients, aged 62 to 88 years, for upper eyelid reconstruction. Good functional and aesthetic results were achieved for all patients. Our method involves a single-stage reconstruction, which is simpler and less invasive than other techniques.


Preclinical Cushing's syndrome resulting from black adrenal adenoma. A case report.
A 59-year-old Japanese woman, admitted for the treatment of diabetes mellitus and hypertension, was incidentally discovered to have a solid mass of 1.4 cm in diameter by CT scan with the attenuation value of 38 Hounsfield units, relatively higher for ordinary adrenal adenomas. Magnetic resonance imaging revealed no reduction of signal intensity on opposite-phase image on T1-weighted sequence. Adrenal scintigraphy imaging with 131I-adosterol did not show any uptake of the isotope in the area corresponding to both adrenals. Although she had no characteristic feature of overt Cushing's syndrome, her serum cortisol level was not suppressed after an overnight dexamethasone administration. She was diagnosed as having preclinical Cushing's syndrome. Left adrenalectomy was performed, revealing the well-circumscribed black tumor, mainly consisted of compact cell, in which cytoplasm was filled with numerous granules pigmented with dark to golden brown colors on hematoxylin-eosin staining. These findings suggested that her incidentaloma was a black adrenal adenoma. Production of steroid hormones was confirmed by immunohistochemical analysis of steroidogenic enzymes and by measurement of the tissue contents of hormones, whose levels were comparable with those in adenomas of overt Cushing's syndrome. This is the first case report of preclinical Cushing's syndrome resulting from black adrenal adenoma.


Single-center nonrandomized clinical trial to assess the safety and efficacy of irreversible electroporation (IRE) ablation of liver tumors in humans: Short to mid-term results.
A single-center nonrandomized clinical trial was performed to assess the safety and efficacy of IRE ablation of liver tumors in humans. 38 malignant liver tumors on 30 patients were treated with IRE between September 2011 and September 2014. Treatment was with curative intent, and the diagnoses were colorectal cancer with liver metastases (CRLM) (n = 23), hepatocellular carcinoma (HCC) (n = 8) and other metastasis (n = 7). Patients were selected when surgery, radiofrequency ablation (RFA) or microwave ablation (MWA) was not an option, and when they met inclusion criteria (tumor size < 3 cm, 1-2 tumors). Patients were followed-up at 1 and 6 months with a contrast-enhanced computed tomography (CE-CT), and contrast-enhanced ultrasound (CE-US) at 3 months. Ablation success was defined as no evidence of residual tumor in the ablated area as confirmed by CE-CT and CE-US. At 3 months ablation success was 78.9%, and 65.8% at 6 months. There was no statistically significant difference between tumor volume (<5 cm3 vs >5 cm3, p = 0.518), and between diagnosis (CRLM vs HCC, p = 0.084) in terms of local recurrence. Complications were classified according to the standardized grading system of Society of Interventional Radiology (SIR). A minor complication occurred in six patients (20%), one patient (3.3%) suffered from a major complication (bile duct dilatation and stricture of the portal vein and bile duct). No mortalities occurred at 30 days. IRE appears to be a safe treatment modality for a selected group of patients with liver tumors and offers high local tumor control at 3 and 6 months.


An NAC transcription factor orchestrates multiple features of cell wall development in Medicago truncatula.
To identify genes controlling secondary cell wall biosynthesis in the model legume Medicago truncatula, we screened a Tnt1 retrotransposon insertion mutant population for plants with altered patterns of lignin autofluorescence. From more than 9000 R1 plants screened, four independent lines were identified with a total lack of lignin in the interfascicular region. The mutants also showed loss of lignin in phloem fibers, reduced lignin in vascular elements, failure in anther dehiscence and absence of phenolic autofluorescence in stomatal guard cell walls. Microarray and PCR analyses confirmed that the mutations were caused by the insertion of Tnt1 in a gene annotated as encoding a NAM (no apical meristem)-like protein (here designated Medicago truncatula NAC SECONDARY WALL THICKENING PROMOTING FACTOR 1, MtNST1). MtNST1 is the only family member in Medicago, but has three homologs (AtNST1-AtNST3) in Arabidopsis thaliana, which function in different combinations to control cell wall composition in stems and anthers. Loss of MtNST1 function resulted in reduced lignin content, associated with reduced expression of most lignin biosynthetic genes, and a smaller reduction in cell wall polysaccharide content, associated with reduced expression of putative cellulose and hemicellulose biosynthetic genes. Acid pre-treatment and cellulase digestion released significantly more sugars from cell walls of nst1 mutants compared with the wild type. We discuss the implications of these findings for the development of alfalfa (Medicago sativa) as a dedicated bioenergy crop.


Seaweed Dietary Fiber Sodium Alginate Suppresses the Migration of Colonic Inflammatory Monocytes and Diet-Induced Metabolic Syndrome via the Gut Microbiota.
Metabolic syndrome (MetS) is a multifactorial chronic metabolic disorder that affects approximately one billion people worldwide. Recent studies have evaluated whether targeting the gut microbiota can prevent MetS. This study aimed to assess the ability of dietary fiber to control MetS by modulating gut microbiota composition. Sodium alginate (SA) is a seaweed-derived dietary fiber that suppresses high-fat diet (HFD)-induced MetS via an effect on the gut microbiota. We observed that SA supplementation significantly decreased body weight gain, cholesterol levels, and fat weight, while improving glucose tolerance in HFD-fed mice. SA changed the gut microbiota composition and significantly increased the abundance of Bacteroides. Antibiotic treatment completely abolished the suppressive effects of SA on MetS. Mechanistically, SA decreased the number of colonic inflammatory monocytes, which promote MetS development, in a gut microbiota-dependent manner. The abundance of Bacteroides was negatively correlated with that of inflammatory monocytes and positively correlated with the levels of several gut metabolites. The present study revealed a novel food function of SA in preventing HFD-induced MetS through its action on gut microbiota.


[Outpatient and inpatient neurological rehabilitation--a follow-up comparison].
Since the mid-90s outpatient rehabilitation has been developed by public health insurance companies and pension funds. Outpatient rehabilitation is defined as comprehensive multidisciplinary and medically supervised service which in neurological rehabilitation mostly follows inpatient rehabilitation. In the present paper partial results of a larger study (by Schoenle and Leyhe, 2000) are reported with respect to the follow-up of the effects of outpatient versus inpatient rehabilitation 6 month after termination of the treatment. Major results are the endurance of the effects over the observed time interval and the equivalent effectiveness of the two forms of rehabilitation. Distinct effects were observed for the two patient groups (more progress in the body related functional disturbances for inpatients versus cognitively related progress for the outpatients). The results reflect intrinsic features of neurological rehabilitation and the current organizational status of neurological rehabilitation in Germany.


Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis.
Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.


Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer.
Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21WAF1 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.


Commissioning vocational rehabilitation after stroke: Can the Cinderella services get to the ball? A qualitative study.
To understand the barriers and enablers to commissioning vocational rehabilitation (VR) after stroke. Interviews with health and social care commissioners responsible for stroke services across three counties were conducted to explore their views on the barriers and enablers to commissioning VR. Transcripts were subjected to thematic analysis, and validity checked with members of the research team. The findings indicate that health commissioners have had to focus on demand-led and expensive acute stroke services, leaving little resource for community services. Though the benefits of VR to patient health are acknowledged, any cost savings would not be realized within the health budget. Social care commissioners, in times of budget restriction, focus on the most vulnerable, aiming to maintain independence and reduce care home admission. In the absence of evidence, there is a perception that the need for VR after stroke is relatively minor. Factors which might facilitate commissioning of a VR service include adapting the service to align with commissioners' requirements, making VR a targeted outcome of community stroke services, utilizing emerging opportunities for joint health and social care commissioning such as Health and Wellbeing Boards, and closer working with researchers to improve the evidence-base.


[Analysis of the implementation of a mobile pre-hospital treatment system in five Brazilian state capitals].
The article presents a description and analysis of the implementation of a pre-hospital treatment system (SAMU) as part of the research project Diagnostic Analysis of the Implementation of a National Policy for the Reduction of Violence and Accidents. Implementation and organization of the SAMU service, together with the related materials, human resources, and equipment, was studied in five Brazilian State capitals with high morbidity and mortality rates from external causes: Curitiba (Paraná), Recife (Pernambuco), Brasília (Federal District), Rio de Janeiro, and Manaus (Amazonas). The study involved four phases, each developing exploratory and analytical cycles, combined with fieldwork, triangulating quantitative and qualitative data. Implementation of the pre-hospital treatment system is now a key health sector asset. Further necessary steps include: comprehensive legislation covering vehicles, personnel, and equipment; closer networking between mobile units and healthcare facilities; focus on information generated in this sub-system, thus facilitating planning; and maintaining and upgrading high qualifications for SAMU crews. The service is officially establishing, standardizing, and regulating a sub-system that is crucial for saving lives.


Abnormal expression levels of BMP15/Smad1 are associated with granulosa cell apoptosis in patients with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects reproductive dysfunction and metabolism in women of childbearing age. An increasing number of studies have suggested that the bone morphogenetic protein 15 (BMP15) signalling pathway serves an important role in the pathogenesis of PCOS; however, the full mechanism remains unknown. The present study revealed that intrinsic follicular dysplasia may be associated with regulation disorders of ovarian granulosa cell apoptosis. Compared with the control group, body mass index, luteinising hormone and testosterone levels were significantly increased (P<0.05). The percentage of S phase cells was significantly higher, cells in G2/M phase cells was significantly lower, and cells undergoing apoptosis was significantly higher in the PCOS group compared with the control group (P<0.05). The expression levels of B‑cell lymphoma 2 was significantly decreased in granulosa cells of PCOS group, whereas the expression of caspase‑3 was higher than the control group (P<0.05). The rate of apoptosis of granulosa cells was measured by a terminal deoxynucleotide transferase dUTP nick‑end labelling assay. The relative mRNA expression levels of BMP receptor 2 and SMAD1 were significantly decreased in granulosa cells in the PCOS group compared with the control (P<0.05). In addition, the expression of BMP15 in follicular fluid and Smad1 in granulosa cells was significantly decreased in the PCOS group compared with the control (P<0.05). The data suggested that the BMP15/Smad1 signalling pathway may be involved in granulosa cell apoptosis, and may be a target for clinical treatment for PCOS.


Reduced allorecognition of adenovirus-2 infected cells.
The early region 3 of adenovirus 2 encodes the membrane glycoprotein E19. This protein specifically binds class I transplantation antigens of a variety of species. Concomitant with this interaction the intracellular transport of newly synthesized class I heavy chains is abrogated. At late stages of the virus infection this leads to a notable decrease in the cell surface expression of class I antigens. We have studied how infection with adenovirus 2 influences target cell recognition by alloreactive cytolytic T lymphocytes. We found that the E19 protein-induced reduction of the HLA-B7 cell surface expression led to a greatly reduced lysis of the infected cells. These findings support our hypothesis that the E19 protein has evolved to facilitate the in vivo replication of the virus by reducing the expression of HLA class I antigens.


Regenerative potential of dental pulp.
The regenerative potential of dental pulp, particularly in mature teeth, has been considered extremely limited. However, our improved understanding of pulpal inflammation and repair and improved dental materials and technologies make vital pulp therapy a viable alternative to root canal treatment. This article explores our knowledge in this regard and the future potential of saving or even regenerating the pulp as a routine dental procedure.


An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro.
Cancer stem-like properties of various types of cancer, including pancreatic cancer, one of the most aggressive types, correlate with metastasis, invasion, and therapeutic resistance. More importantly, chemoresistance in cancer stem-like cells (CSLCs) is a critical problem for eradication of pancreatic cancer. Several cell surface markers, such as CD44 and epithelial cell adhesion molecule (EpCAM), are molecular targets on CSLCs of pancreatic carcinoma. In this study, we investigated whether catumaxomab, a clinical-grade bi-specific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant pancreatic CSLCs in vitro. Firstly, we established a CSLC line (MU-PK1) from human pancreatic carcinoma cells derived from a patient with chemoresistant and disseminated pancreatic cancer. These CSLCs were almost completely resistant to gemcitabine-mediated cytotoxicity up to a concentration of 10 μg/ml. The cells expressed high levels of CSLC markers (CD44 and EpCAM) and had significantly higher capacities for sphere formation, invasion, and aldehyde dehydrogenase-1 expression, which are associated with cancer stemness properties. We found that pre-treatment with catumaxomab and subsequent addition of interleukin-2/OKT3 activated autologous T-cells eliminated CSLCs during a short incubation period. Moreover, when MU-PK1 cells were cultured under hypoxic conditions, the CSLCs became more aggressive. However, the combination of cytokine-activated killer T-cells with catumaxomab successfully lysed almost all these cells. In conclusion, catumaxomab combined with activated T-cells may be a potent therapeutic modality to eradicate chemoresistant pancreatic CSLCs.


A Quality Improvement Project to Gain Insight Into What Helps Cancer Patients Cope During Outpatient Radiation Therapy Treatments.
Psychosocial support in cancer care has not been researched or published to the degree of physical support. This type of support includes the mental, emotional, social, and spiritual needs of patients and loved ones. This quality improvement project provides insight for those seeking understanding of what exactly helps cancer patients cope during outpatient radiation therapy treatments. The purpose of this project was to learn what practices benefit patient's coping during outpatient external radiation therapy treatments in order to increase attention given to psychosocial support of future cancer patients receiving outpatient external radiation therapy treatments. Insight from this project was used to create a resource handout for Novant Health Cancer Institute to help increase awareness, discussion, and attention to supporting outpatient radiation therapy patients emotionally and spiritually.


Scanning the genome for gene SNPs related to climate adaptation and estimating selection at the molecular level in boreal black spruce.
Outlier detection methods were used to scan the genome of the boreal conifer black spruce (Picea mariana [Mill.] B.S.P.) for gene single-nucleotide polymorphisms (SNPs) potentially involved in adaptations to temperature and precipitation variations. The scan involved 583 SNPs from 313 genes potentially playing adaptive roles. Differentiation estimates among population groups defined following variation in temperature and precipitation were moderately high for adaptive quantitative characters such as the timing of budset or tree height (Q(ST) = 0.189-0.314). Average differentiation estimates for gene SNPs were null, with F(ST) values of 0.005 and 0.006, respectively, among temperature and precipitation population groups. Using two detection approaches, a total of 26 SNPs from 25 genes distributed among 11 of the 12 linkage groups of black spruce were detected as outliers with F(ST) as high as 0.078. Nearly half of the outlier SNPs were located in exons and half of those were nonsynonymous. The functional annotations of genes carrying outlier SNPs and regression analyses between the frequencies of these SNPs and climatic variables supported their implication in adaptive processes. Several genes carrying outlier SNPs belonged to gene families previously found to harbour outlier SNPs in a reproductively isolated but largely sympatric congeneric species, suggesting differential subfunctionalization of gene duplicates. Selection coefficient estimates (S) were moderate but well above the magnitude of drift (>>1/N(e)), indicating that the signature of natural selection could be detected at the nucleotide level despite the recent establishment of these populations during the Holocene.


A light writable microfluidic "flash memory": optically addressed actuator array with latched operation for microfluidic applications.
This paper presents a novel optically addressed microactuator array (microfluidic "flash memory") with latched operation. Analogous to the address-data bus mediated memory address protocol in electronics, the microactuator array consists of individual phase-change based actuators addressed by localized heating through focused light patterns (address bus), which can be provided by a modified projector or high power laser pointer. A common pressure manifold (data bus) for the entire array is used to generate large deflections of the phase change actuators in the molten phase. The use of phase change material as the working media enables latched operation of the actuator array. After the initial light "writing" during which the phase is temporarily changed to molten, the actuated status is self-maintained by the solid phase of the actuator without power and pressure inputs. The microfluidic flash memory can be re-configured by a new light illumination pattern and common pressure signal. The proposed approach can achieve actuation of arbitrary units in a large-scale array without the need for complex external equipment such as solenoid valves and electrical modules, which leads to significantly simplified system implementation and compact system size. The proposed work therefore provides a flexible, energy-efficient, and low cost multiplexing solution for microfluidic applications based on physical displacements. As an example, the use of the latched microactuator array as "normally closed" or "normally open" microvalves is demonstrated. The phase-change wax is fully encapsulated and thus immune from contamination issues in fluidic environments.