The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans.
Fungi and many other eukaryotes use specialized mitogen-activated protein kinases (MAPK) of the Hog1/p38 family to transduce environmental stress signals. In Aspergillus nidulans, the MAPK SakA and the transcription factor AtfA are components of a central multiple stress-signaling pathway that also regulates development. Here we characterize SrkA, a putative MAPK-activated protein kinase, as a novel component of this pathway. ΔsrkA and ΔsakA mutants share a derepressed sexual development phenotype. However, ΔsrkA mutants are not sensitive to oxidative stress, and in fact, srkA inactivation partially suppresses the sensitivity of ΔsakA mutant conidia to H2O2, tert-butyl-hydroperoxide (t-BOOH), and menadione. In the absence of stress, SrkA shows physical interaction with nonphosphorylated SakA in the cytosol. We show that H2O2 induces a drastic change in mitochondrial morphology consistent with a fission process and the relocalization of SrkA to nuclei and mitochondria, depending on the presence of SakA. SakA-SrkA nuclear interaction is also observed during normal asexual development in dormant spores. Using SakA and SrkA S-tag pulldown and purification studies coupled to mass spectrometry, we found that SakA interacts with SrkA, the stress MAPK MpkC, the PPT1-type phosphatase AN6892, and other proteins involved in cell cycle regulation, DNA damage response, mRNA stability and protein synthesis, mitochondrial function, and other stress-related responses. We propose that oxidative stress induces DNA damage and mitochondrial fission and that SakA and SrkA mediate cell cycle arrest and regulate mitochondrial function during stress. Our results provide new insights into the mechanisms by which SakA and SrkA regulate the remodelling of cell physiology during oxidative stress and development.


Influences from Long-Term Crop Rotation, Soil Tillage, and Fertility on the Severity of Rice Grain Smuts.
False smut (Ustilaginoidea virens) and kernel smut (Neovossia horrida) are diseases of rice (Oryza sativa) that reduce both grain yield and quality. Susceptible rice cultivars are in widespread use on production acreage in the United States, and the effects from crop management practices on smut control are poorly understood. We studied the long-term effects of crop rotation, soil tillage, and fertility level on rice smut severity. The highest levels of false smut observed in this study were on cultivars grown in rotation with soybean, on traditionally tilled soils, with high fertilizer treatments. The highest levels of kernel smut were observed in a rice-soybean rotation with winter wheat grown between summer crops. These rotations are commonly used in rice-growing regions of the southern United States. Using combinations of crop rotation, soil tillage, and fertility rate, several alternative crop-management practices were identified that provided effective control of smuts in susceptible rice cultivars. The most effective method for controlling both false smut and kernel smut was in 3-year rotations of rice, soybean, and corn. Regardless of rotation order or tillage and fertility treatments within the rotations, rotating out of rice for 2 years was the most effective approach for smut control.


Contrasting mode of evolution at a coat color locus in wild and domestic pigs.
Despite having only begun approximately 10,000 years ago, the process of domestication has resulted in a degree of phenotypic variation within individual species normally associated with much deeper evolutionary time scales. Though many variable traits found in domestic animals are the result of relatively recent human-mediated selection, uncertainty remains as to whether the modern ubiquity of long-standing variable traits such as coat color results from selection or drift, and whether the underlying alleles were present in the wild ancestor or appeared after domestication began. Here, through an investigation of sequence diversity at the porcine melanocortin receptor 1 (MC1R) locus, we provide evidence that wild and domestic pig (Sus scrofa) haplotypes from China and Europe are the result of strikingly different selection pressures, and that coat color variation is the result of intentional selection for alleles that appeared after the advent of domestication. Asian and European wild boar (evolutionarily distinct subspecies) differed only by synonymous substitutions, demonstrating that camouflage coat color is maintained by purifying selection. In domestic pigs, however, each of nine unique mutations altered the amino acid sequence thus generating coat color diversity. Most domestic MC1R alleles differed by more than one mutation from the wild-type, implying a long history of strong positive selection for coat color variants, during which time humans have cherry-picked rare mutations that would be quickly eliminated in wild contexts. This pattern demonstrates that coat color phenotypes result from direct human selection and not via a simple relaxation of natural selective pressures.


Angle-multiplexed hologram storage in LiNbO(3):Tb, Fe.
We have performed hologram multiplexing with a cw laser at lambda=532 nm in a near-stoichiometric LiNbO(3) :Tb, Fe crystal that exhibits a visible absorption band induced by UV light. When 50 plane-wave holograms were angle multiplexed from the UV preexposed state, the recording sensitivity gradually decreased, owing to bleaching of the induced absorption. However, a conventional recording schedule of multiplexing many holograms of equal diffraction efficiency can be used in this photochromic material. The gradual decrease in recording sensitivity throughout multiplexing can be compensated for by the increased erasure-time constants of later-written holograms. An M/# of 1.73 was obtained in a crystal of 3.3-mm thickness.


An Algorithm for Optimizing Rotational Control of Globodera rostochiensis on Potato Crops in Bolivia.
The outline area of new cysts of Globodera rostochiensis was measured by image analysis. A linear regression of this value against egg content provided a basis for adjusting the egg number for cyst size. This adjusted egg content provides an estimate of the relative fullness of a cyst with eggs. This value showed an exponential decline in eggs over 3.5 years since the last potato crop. It corresponds to an average loss in the dormant egg population of 32.8 +/- 5.6%/year for 26 fields at Toralapa, Bolivia. This value compared well with a mean decline of 40 +/- 4%/year for 42 fields after measuring viable eggs/100 g soil on two occasions one year apart. The new approach allows declines to be estimated at one time point. The decline in lipid content of the dormant, unhatched second-stage juveniles (J2) was 17 +/- 6% per annum as measured by image analysis after Oil red O staining. This may be sufficient to compromise infectivity after 3 to 4 years of dormancy. A standard model was modified to consider the effect of both lipid depletion during dormancy and choice of susceptible potato on the population dynamics of G. rostochiensis under rotational control. It is concluded that a few cultivars may impose lower populations on G. rostochiensis in 3 to 4-year rotations than the majority used in Bolivia.


Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.
Heme oxygenase is a heme-oxidizing enzyme which generates biliverdin and carbon monoxide (CO). The present study was designed to elucidate whether CO endogenously produced by this enzyme serves as an active vasorelaxant in the hepatic microcirculation. Microvasculature of the isolated perfused rat liver was visualized by dual-color digital microfluorography to alternately monitor sinusoidal lining and fat-storing Ito cells. In the control liver, the CO flux in the venous effluent ranged at 0.7 nmol/min per gram of liver. Administration of a heme oxygenase inhibitor zinc protoporphyrin IX (1 microM) eliminated the baseline CO generation, and the vascular resistance exhibited a 30% elevation concurrent with discrete patterns of constriction in sinusoids and reduction of the sinusoidal perfusion velocity. The major sites of the constriction corresponded to local sinusoidal segments colocalized with Ito cell which were identified by imaging their vitamin A autofluorescence. The increase in the vascular resistance and sinusoidal constriction were attenuated significantly by adding CO (1 microM) or a cGMP analogue 8-bromo-cGMP (1 microM) in the perfusate. From these findings, we propose that CO can function as an endogenous modulator of hepatic sinusoidal perfusion through a relaxing mechanism involving Ito cells.


Genetics of mouse behavior: interactions with laboratory environment.
Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.


A BMP pathway regulates cell fate allocation along the sea urchin animal-vegetal embryonic axis.
To examine whether a BMP signaling pathway functions in specification of cell fates in sea urchin embryos, we have cloned sea urchin BMP2/4, analyzed its expression in time and space in developing embryos and assayed the developmental consequences of changing its concentration through mRNA injection experiments. These studies show that BMP4 mRNAs accumulate transiently during blastula stages, beginning around the 200-cell stage, 14 hours postfertilization. Soon after the hatching blastula stage, BMP2/4 transcripts can be detected in presumptive ectoderm, where they are enriched on the oral side. Injection of BMP2/4 mRNA at the one-cell stage causes a dose-dependent suppression of commitment of cells to vegetal fates and ectoderm differentiates almost exclusively as a squamous epithelial tissue. In contrast, NOGGIN, an antagonist of BMP2/4, enhances differentiation of endoderm, a vegetal tissue, and promotes differentiation of cells characteristic of the ciliated band, which contains neurogenic ectoderm. These findings support a model in which the balance of BMP2/4 signals produced by animal cell progeny and opposing vegetalizing signals sent during cleavage stages regulate the position of the ectoderm/ endoderm boundary. In addition, BMP2/4 levels influence the decision within ectoderm between epidermal and nonepidermal differentiation.


Active thermal fine laser tuning in a broad spectral range and optical properties of cholesteric liquid crystal.
In this study, we achieved active fine laser tuning in a broad spectral range with dye-doped cholesteric liquid crystal wedge-type cells through temperature control. The spatial pitch gradient of each position of the wedge cell at room temperature was almost maintained after developing a temperature gradient. To achieve the maximum tuning range, the chiral dopant concentration, thickness, thickness gradient, and temperature gradient on the wedge cell should be matched properly. In order to understand the laser tuning mechanism for temperature change, we studied the temperature dependence of optical properties of the photonic bandgap of cholesteric liquid crystals. In our cholesteric liquid crystal samples, when temperature was increased, photonic bandgaps were shifted toward blue, while the width of the photonic bandgap was decreased, regardless of whether the helicity was left-handed or right-handed. This is mainly due to the combination of decreased refractive indices, higher molecular anisotropy of chiral molecules, and increased chiral molecular solubility. We envisage that this kind of study will prove useful in the development of practical active tunable CLC laser devices.


Multiple antibody targets on herpes B glycoproteins B and D identified by screening sera of infected rhesus macaques with peptide microarrays.
Herpes B virus (or Herpesvirus simiae or Macacine herpesvirus 1) is endemic in many populations of macaques, both in the wild and in captivity. The virus elicits only mild clinical symptoms (if any) in monkeys, but can be transmitted by various routes, most commonly via bites, to humans where it causes viral encephalitis with a high mortality rate. Hence, herpes B constitutes a considerable occupational hazard for animal caretakers, veterinarians and laboratory personnel. Efforts are therefore being made to reduce the risk of zoonotic infection and to improve prognosis after accidental exposure. Among the measures envisaged are serological surveillance of monkey colonies and specific diagnosis of herpes B zoonosis against a background of antibodies recognizing the closely related human herpes simplex virus (HSV). 422 pentadecapeptides covering, in an overlapping fashion, the entire amino acid sequences of herpes B proteins gB and gD were synthesized and immobilized on glass slides. Antibodies present in monkey sera that bind to subsets of the peptide collection were detected by microserological techniques. With 42 different rhesus macaque sera, 114 individual responses to 18 different antibody target regions (ATRs) were recorded, 17 of which had not been described earlier. This finding may pave the way for a peptide-based, herpes B specific serological diagnostic test.


Rational approach, technique and selection criteria treating lumbar disk herniations by oxygen-ozone therapy.
Radicular lumbar back pain is an important public health problem not yet benefiting from a unequivocal treatment approach. Medical and physical therapies represent the first solution; however, when these fail, the second therapeutic step is still controversial and mini-invasive treatments may play an important role. In these cases oxygen-ozone therapy has been proved to be a very safe and effective option that is widely used with different modalities. This paper, by reviewing oxygen-ozone therapy literature data, aims to describe the rationale of oxygen-ozone therapy for the treatment of lumbar disk herniations, propose an effective procedural technique and clarify patient selection criteria; furthermore, complications and follow-up management are also considered.


Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors.
Alpha/beta interferon (IFN) and gamma IFN exert widely overlapping biological effects. Still, mice with individually inactivated alpha/beta or gamma receptors exhibit variably severely reduced resistance to infection and altered immune responses. To investigate to what extent the two IFN systems are functionally redundant, we generated mice with a combined receptor defect (AG129 mice). Like mice with individual mutations, AG129 mice had no apparent anomalies, confirming that in the mouse the IFN system is not essential for normal development. These mice showed an additive phenotype with respect to antiviral defense and exhibited an increased susceptibility to lymphocytic choriomeningitis virus (LCMV) and notably vaccinia virus infection. Because of unlimited replication and subsequent rapid exhaustion of cytotoxic T lymphocyte (CTL) precursors, these mice were unable to mount a CTL response to LCMV. CD8(+)-mediated immunopathology was absent in LCMV-infected mice, and virus persisted. Vaccinia virus replicated much faster in AG129 mice, and a 10(4)-fold lower dose of vaccinia virus was sufficient to prime these mice. With the normal priming dose of 10(6) PFU, cytopathic effects and overwhelming infection possibly causing partial exhaustion of CTL interfered with the anti-vaccinia virus response. Even though global antiviral immunoglobulin G (IgG) titers were within normal ranges, the IgG subclass distribution was heavily biased toward IgG1.


Association of Uveal Melanoma Metastatic Rate With Stochastic Mutation Rate and Type of Mutation.
It is necessary to understand the mechanisms of metastasis of uveal melanoma to advise patients and develop treatments for this tumor. To examine the stochastic properties of primary uveal melanoma including the mutation rate as a function of tumor size and metastatic rate relative to the type of mutation. We computed the mutation rate in different sized uveal melanomas using previously published large data sets. Tumor volume was estimated using the spherical cap method. We also calculated the metastatic rate using an updated data set of patients with uveal melanoma with known mutations in BAP1, SF3B1, and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group. Data were analyzed from 2 studies, one taking place from August 25, 1970, to August 27, 2008, and the other taking place between 1993 and 2013. Data were analyzed between 2016 and 2017. Mutation rates and metastic rates. Based on the 5-year metastatic rates, mutation rates ranged from 1.09 × 10-8 to 7.86 × 10-7 per cell division, using our calculation algorithm. A higher mutation rate was found for tumors with smaller thicknesses. EIF1AX mutations were not exclusive of other mutations because 2 cases with EIF1AX mutations and metastasis also had BAP1 mutations. None of the tumors with only an EIF1AX mutation metastasized. After plotting the yearly metastatic rate vs time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations. We observed a higher mutation rate for smaller tumors, which may be explained by a greater number of cell divisions occurring during the expansion phase of smaller uveal melanomas. Regarding time to clinically detected metastases, the first 2 peaks appear to be associated with BAP1-mutated tumors and the late peak to SF3B1-mutated tumors.


Ovarian cancer and hormone replacement therapy in the Million Women Study.
Ovarian cancer is the fourth most common cancer in women in the UK, with about 6700 developing the malignancy and 4600 dying from it every year. However, there is limited information about the risk of ovarian cancer associated with the use of hormone replacement therapy (HRT). 948,576 postmenopausal women from the UK Million Women Study who did not have previous cancer or bilateral oophorectomy were followed-up for an average of 5.3 years for incident ovarian cancer and 6.9 years for death. Information on HRT use was obtained at recruitment and updated where possible. Relative risks for ovarian cancer were calculated, stratified by age and hysterectomy status, and adjusted by area of residence, socioeconomic group, time since menopause, parity, body-mass index, alcohol consumption, and use of oral contraceptives. When they last reported HRT use, 287,143 women (30%) were current users and 186 751 (20%) were past users. During follow-up, 2273 incident ovarian cancers and 1591 deaths from the malignancy were recorded. Current users were significantly more likely to develop and die from ovarian cancer than never users (relative risk 1.20 [95% CI 1.09-1.32; p=0.0002] for incident disease and 1.23 [1.09-1.38; p=0.0006] for death). For current users of HRT, incidence of ovarian cancer increased with increasing duration of use, but did not differ significantly by type of preparation used, its constituents, or mode of administration. Risks associated with HRT varied significantly according to tumour histology (p<0.0001), and in women with epithelial tumours the relative risk for current versus never use of HRT was greater for serous than for mucinous, endometroid, or clear cell tumours (1.53 [1.31-1.79], 0.72 [0.52-1.00], 1.05 [0.77-1.43], or 0.77 [0.48-1.23], respectively). Past users of HRT were not at an increased risk of ovarian cancer (0.98 [0.88-1.11] and 0.97 [0.84-1.11], respectively, for incident and fatal disease). Over 5 years, the standardised incidence rates for ovarian cancer in current and never users of HRT were 2.6 (2.4-2.9) and 2.2 (2.1-2.3) per 1000, respectively-ie, one extra ovarian cancer in roughly 2500 users; death rates were 1.6 (1.4-1.8) and 1.3 (1.2-1.4) per 1000, respectively-ie, one extra ovarian cancer death in roughly 3300 users. Women who use HRT are at an increased risk of both incident and fatal ovarian cancer. Since 1991, use of HRT has resulted in some 1300 additional ovarian cancers and 1000 additional deaths from the malignancy in the UK.


Nanocrystalline silver dressings in wound management: a review.
This paper describes the properties of nanocrystalline silver products (Acticoat) and their applications and examines available evidence supporting their use in wound management. Acticoat utilizes nanotechnology to release nanocrystalline silver crystals. Acticoat releases 30 times less silver cations than silversulfadiazine cream or 0.5% silver nitrate solution but more of the silver released (by Acticoat). Silver-impregnated slow-release dressings release minute concentrations of silver which are quickly bound up by the chloride in the wound exudate. While extrapolations from in vitro and animal studies are cautious, evidence from these studies suggests Acticoat is: effective against most common strains of wound pathogens; can be used as a protective covering over skin grafts; has a broader antibiotic spectrum activity; and is toxic to keratinocytes and fibroblasts. Animal studies suggest a role for nanocrystalline silver in altering wound inflammatory events and facilitation of the early phase of wound healing. Quality human clinical trials into nanocrystalline silver are few. However, evidence suggests using Acticoat in wound management is cost effective, reduces wound infection, decreases the frequency of dressing changes and pain levels, decreases matrix metalloproteinase activity, wound exudate and bioburden levels, and promotes wound healing in chronic wounds. Although there is no in vivo evidence to suggest nanocrystalline silver is toxic to human keratinocytes and fibroblasts, there is in vitro evidence to suggest so; thus these dressings should be used cautiously over epithelializing and proliferating wounds. Future clinical research, preferably randomized controlled trials into nanocrystalline silver technology, may provide clinicians a better understanding of its applications in wound management.


CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients.
Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation. A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12. Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36). We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.


A computational functional genomics based self-limiting self-concentration mechanism of cell specialization as a biological role of jumping genes.
Specialization is ubiquitous in biological systems and its manifold mechanisms are active research topics. Although clearly adaptive, the way in which specialization of cells is realized remains incompletely understood as it requires the reshaping of a cell's genome to favor particular biological processes in the competition on a cell's functional capacity. Here, a self-specialization mechanism is identified as a possible biological role of jumping genes, in particular LINE-1 retrotransposition. The mechanism is self-limiting and consistent with its evolutionary preservation despite its likely gene-breaking effects. The scenario we studied was the need for a cell to process a longer exposition to an extraordinary situation, for example continuous exposure to the nociceptive input or the intake of addictive drugs. Both situations may evolve toward chronification. The mechanism involves competition within a gene set in which a subset of genes cooperating in particular biological processes. The subset carries a piece of information, consisting of the LINE-1 sequence, about the destruction of their functional competitor genes which are not involved in that process. During gene transcription, an active copy of LINE-1 is co-transcribed. At a certain low probability, a subsequently transcribed and thus actually exposed gene can be rendered nonfunctional by LINE-1 retrotransposition in a relevant gene part. As retrotransposition needs time it is unlikely that LINE-1 retrotranspose into its own carrier gene. This reshapes the cell genome toward self-specializing of those biological processes that are carried out with a high number of LINE-1 containing genes. Self-termination of the mechanism is achieved by allowing LINE-1 to also occasionally jump into the coding region of itself, thus destroying the information about competitor destruction by successively decreasing the number of LINE-1 until the mechanism ceases. Employing a computational functional genomics approach, we demonstrate the biological plausibility in functional genomic datasets of potentially chronifying situations and interpret our results in relation to a biological mechanism of self-specialization of complex systems in response to a persistent challenge as met in chronifying traits.


Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.


Modulation of colon cancer by nutmeg.
Colon cancer is the most common cancer and the third leading cause of cancer mortality in humans. Using mass spectrometry-based metabolomics, the current study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with an increase in the expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, which exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apc(min/+) mice. Nutmeg-treated Apc(min/+) mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible, in part, for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link among gut microbial metabolism, inflammation, and metabolic disorders and suggest that modulation of gut microbiota and lipid metabolism using dietary intervention or drugs may be effective in colon cancer chemoprevention strategies.


Promoting analysis of real-world data: Prospects for preventive cardiology in Japan.
According to the statistics for 2018 in Japan, cardiovascular disease and cerebrovascular disease were the most common causes of death (cardiovascular disease with 208,210, cerebrovascular disease with 108,165), and these two diseases account for 23.2% of all deaths. Stroke, especially cerebral hemorrhage, was the main cause of death in Japan after World War II. Along with improved management of hypertension, the mortality rate from cerebral hemorrhage reached a high of 266.7 per 100,000 men in 1960 and 213.9 per 100,000 women in 1951, then decreased to 15.9 per 100,000 men and 6.9 per 100,000 women in 2013. However, mortality from lifestyle-related diseases such as metabolic syndrome and ischemic heart disease has been on the rise since 1990 due to the westernization of diet, urban lifestyles, and lack of exercise habits. Moreover, since aging is the greatest risk factor for heart failure, the number of patients with heart failure in Japan will inevitably increase in the future. A large amount of evidence has demonstrated that prevention and proper management of risk factors can reduce the future incidence of cardiovascular disease. Specific health checkups (metabolic syndrome checkups) have been carried out in Japan since 2008. Big data on physical examinations are valuable real-world data that can be utilized for clinical research. As the importance of preventive cardiology increases in the future, we should analyze the real-world data from health checkups in Japan in detail and disseminate these results to clinical practice, which will contribute to development of preventive cardiology and the promotion of public health.


Preoperative breast MRI and surgical outcomes in elderly women with invasive ductal and lobular carcinoma: a population-based study.
Existing evidence suggests that preoperative breast magnetic resonance imaging (MRI) might not improve surgical outcomes in the general breast cancer population. To determine if patients differentially benefit from breast MRI, we examined surgical outcomes-initial mastectomy, reoperation, and final mastectomy rates-among patients grouped by histologic type. We identified women diagnosed with early-stage breast cancer from 2004 to 2007 in the SEER-Medicare dataset. We classified patients as having invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), mixed ductal/lobular carcinoma (IDLC) or other histologic type. Medicare claims were used to identify breast MRI and definitive surgeries during the initial surgical treatment episode. We used propensity score methods to account for the differential likelihood of exposure to MRI. Of the 20,332 patients who met our inclusion criteria for this study, 12.2 % had a preoperative breast MRI. Patients with ILC as compared to other histologic groups were most likely to receive MRI [OR 2.32; 95 % CI (2.02-2.67)]. In the propensity score-adjusted analyses, breast MRI was associated with an increased likelihood of an initial mastectomy for all patients and among all histologic subgroups. Among patients with ILC, having a breast MRI was associated with lower odds of a reoperation [OR 0.59; 95 % CI (0.40-0.86)], and an equal likelihood of a final mastectomy compared to similar patients without a breast MRI. Overall and among patients with IDC and IDLC, breast MRI was not significantly associated with a likelihood of a reoperation but was associated with greater odds of a final mastectomy. Our study provides evidence in support of the targeted use of preoperative breast MRI among patients with ILC to improve surgical planning; it does not provide evidence for the routine use of breast MRI among all newly diagnosed breast cancer patients or among patients with IDC.


Perceptions of HIV and Safe Male Circumcision in High HIV Prevalence Fishing Communities on Lake Victoria, Uganda.
In 2010, the Uganda Ministry of Health introduced its Safe Male Circumcision (SMC) strategy for HIV prevention with the goal of providing 4.2 million voluntary medical male circumcisions by 2015. Fishing communities, where HIV prevalence is approximately 3-5 times higher than the national average, have been identified as a key population needing targeted HIV prevention services by the National HIV Prevention Strategy. This study aimed to understand perceptions of HIV and identify potential barriers and facilitators to SMC in fishing communities along Lake Victoria. We conducted 8 focus group discussions, stratified by sex and age, with 67 purposefully sampled participants in 4 communities in Kalangala District, Uganda. There was universal knowledge of the availability of SMC services, but males reported high uptake in the community while females indicated that it is low. Improved hygiene, disease prevention, and improved sexual performance and desirability were reported facilitators. Barriers included a perceived increase in SMC recipients' physiological libido, post-surgical abstinence, lost income during convalescence, and lengthier recovery due to occupational hazards. Both males and females reported concerns about spousal fidelity during post-SMC abstinence. Reported misconceptions and community-held cultural beliefs include fear that foreskins are sold after their removal, the belief that a SMC recipient's first sexual partner after the procedure should not be his spouse, and the belief that vaginal fluids aid circumcision wound healing. Previous outreach efforts have effectively reached these remote communities, where availability and health benefits of SMC are widely understood. However, community-specific intervention strategies are needed to address the barriers identified in this study. We recommend the development of targeted counseling, outreach, and communication strategies to address barriers, misconceptions, and community-held beliefs. Interventions should also incorporate female partners into the SMC decision-making process and develop compensation strategies to address lost income during SMC recovery.


Efficacy of denileukin diftitox in subcutaneous panniculitis-like T-cell lymphoma.
Subcutaneous panniculitis-like lymphomas (SPTCLs) are a heterogeneous group of diseases characterized by pleomorphic lymphocytes infiltrating the subcutis in a lobular panniculitis-like pattern. Characterization of SPTCL based on T-cell phenotype has prognostic significance in that most patients with the alpha/beta T-cell phenotype of SPTCL demonstrate clinically indolent behavior, whereas those with gamma/delta variant typically manifest more aggressive disease. In the past, traditional therapies have included single-agent or systemic multi-agent chemotherapy with or without radiation therapy, immunosuppressive therapies, or, in refractory patients, bone marrow transplantation. We describe complete clinical regression of disease and a median response duration of > 6 months in 2 patients with SPTCL treated with corticosteroids and denileukin diftitox. Furthermore, the addition of bexarotene to denileukin diftitox restored a clinical response in 1 of the patients after disease progression, suggesting the activity of this combination in patients with SPTCL.


Insulin-Like Peptide 3 (INSL3) Serum Concentration During Human Male Fetal Life.
Context: Insulin-like peptide 3 (INSL3), a protein hormone produced by Leydig cells, may play a crucial role in testicular descent as male INSL3 knockout mice have bilateral cryptorchidism. Previous studies have measured human fetal INSL3 levels in amniotic fluid only. Objective: To measure INSL3 serum levels and mRNA in fetal umbilical cord blood and fetal testes, respectively. Design: INSL3 concentrations were assayed on 50 μl of serum from male human fetal umbilical cord blood by a non-commercial highly sensitive and specific radioimmunoassay. For secondary confirmation, quantitative real-time PCR was used to measure INSL3 relative mRNA expression in 7 age-matched human fetal testes. Setting: UT Southwestern Medical Center, Dallas, TX and Medical University of South Carolina, Charleston, SC. Patients or other Participants: Twelve human male umbilical cord blood samples and 7 human male testes were obtained from fetuses 14-21 weeks gestation. Male sex was verified by leukocyte genomic DNA SRY PCR. Interventions: None. Main Outcome Measures: Human male fetal INSL3 cord blood serum concentrations and testicular relative mRNA expression. Results: INSL3 serum concentrations during human male gestational weeks 15-20 were 2-4 times higher than published prepubertal male levels and were 5-100 times higher than previous reports of INSL3 concentrations obtained from amniotic fluid. Testicular fetal INSL3 mRNA relative expression was low from weeks 14-16, rose significantly weeks 17 and 18, and returned to low levels at week 21. Conclusions: These findings further support the role of INSL3 in human testicular descent and could prove relevant in uncovering the pathophysiology of cryptorchidism.


Improved scanning laser fundus imaging using polarimetry.
We present a polarimetric technique to improve fundus images that notably simplifies and extends a previous procedure [Opt. Lett.27, 830 (2002)]. A generator of varying polarization states was incorporated into the illumination path of a confocal scanning laser ophthalmoscope. A series of four images, corresponding to independent incoming polarization states, were recorded. From these images, the spatially resolved elements of the top row of the Mueller matrix were computed. From these elements, images with the highest and lowest quality (according to different image quality metrics) were constructed, some of which provided improved visualization of fundus structures of clinical importance (vessels and optic nerve head). The metric values were better for these constructed images than for the initially recorded images and better than averaged images. Entropy is the metric that is most sensitive to differences in the image quality. Improved visualization of features could aid in the detection, localization, and tracking of ocular disease and may be applicable in other biomedical imaging.


Is mammalian chromosomal evolution driven by regions of genome fragility?
A fundamental question in comparative genomics concerns the identification of mechanisms that underpin chromosomal change. In an attempt to shed light on the dynamics of mammalian genome evolution, we analyzed the distribution of syntenic blocks, evolutionary breakpoint regions, and evolutionary breakpoints taken from public databases available for seven eutherian species (mouse, rat, cattle, dog, pig, cat, and horse) and the chicken, and examined these for correspondence with human fragile sites and tandem repeats. Our results confirm previous investigations that showed the presence of chromosomal regions in the human genome that have been repeatedly used as illustrated by a high breakpoint accumulation in certain chromosomes and chromosomal bands. We show, however, that there is a striking correspondence between fragile site location, the positions of evolutionary breakpoints, and the distribution of tandem repeats throughout the human genome, which similarly reflect a non-uniform pattern of occurrence. These observations provide further evidence that certain chromosomal regions in the human genome have been repeatedly used in the evolutionary process. As a consequence, the genome is a composite of fragile regions prone to reorganization that have been conserved in different lineages, and genomic tracts that do not exhibit the same levels of evolutionary plasticity.


Reliability of estimating the room volume from a single room impulse response.
The methods investigated for the room volume estimation are based on geometrical acoustics, eigenmode, and diffuse field models and no data other than the room impulse response are available. The measurements include several receiver positions in a total of 12 rooms of vastly different sizes and acoustic characteristics. The limitations in identifying the pivotal specular reflections of the geometrical acoustics model in measured room impulse responses are examined both theoretically and experimentally. The eigenmode method uses the theoretical expression for the Schroeder frequency and the difficulty of accurately estimating this frequency from the varying statistics of the room transfer function is highlighted. Reliable results are only obtained with the diffuse field model and a part of the observed variance in the experimental results is explained by theoretical expressions for the standard deviation of the reverberant sound pressure and the reverberation time. The limitations due to source and receiver directivity are discussed and a simple volume estimation method based on an approximate relationship with the reverberation time is also presented.


Comparative physiology and architecture associated with the mammalian urine concentrating mechanism: role of inner medullary water and urea transport pathways in the rodent medulla.
Comparative studies of renal structure and function have potential to provide insights into the urine-concentrating mechanism of the mammalian kidney. This review focuses on the tubular transport pathways for water and urea that play key roles in fluid and solute movements between various compartments of the rodent renal inner medulla. Information on aquaporin water channel and urea transporter expression has increased our understanding of functional segmentation of medullary thin limbs of Henle's loops, collecting ducts, and vasa recta. A more complete understanding of membrane transporters and medullary architecture has identified new and potentially significant interactions between these structures and the interstitium. These interactions are now being introduced into our concept of how the inner medullary urine-concentrating mechanism works. A variety of regulatory pathways lead directly or indirectly to variable patterns of fluid and solute movements among the interstitial and tissue compartments. Animals with the ability to produce highly concentrated urine, such as desert species, are considered to exemplify tubular structure and function that optimize urine concentration. These species may provide unique insights into the urine-concentrating process.(1)


Assessing the fidelity of ancient DNA sequences amplified from nuclear genes.
To date, the field of ancient DNA has relied almost exclusively on mitochondrial DNA (mtDNA) sequences. However, a number of recent studies have reported the successful recovery of ancient nuclear DNA (nuDNA) sequences, thereby allowing the characterization of genetic loci directly involved in phenotypic traits of extinct taxa. It is well documented that postmortem damage in ancient mtDNA can lead to the generation of artifactual sequences. However, as yet no one has thoroughly investigated the damage spectrum in ancient nuDNA. By comparing clone sequences from 23 fossil specimens, recovered from environments ranging from permafrost to desert, we demonstrate the presence of miscoding lesion damage in both the mtDNA and nuDNA, resulting in insertion of erroneous bases during amplification. Interestingly, no significant differences in the frequency of miscoding lesion damage are recorded between mtDNA and nuDNA despite great differences in cellular copy numbers. For both mtDNA and nuDNA, we find significant positive correlations between total sequence heterogeneity and the rates of type 1 transitions (adenine --> guanine and thymine --> cytosine) and type 2 transitions (cytosine --> thymine and guanine --> adenine), respectively. Type 2 transitions are by far the most dominant and increase relative to those of type 1 with damage load. The results suggest that the deamination of cytosine (and 5-methyl cytosine) to uracil (and thymine) is the main cause of miscoding lesions in both ancient mtDNA and nuDNA sequences. We argue that the problems presented by postmortem damage, as well as problems with contamination from exogenous sources of conserved nuclear genes, allelic variation, and the reliance on single nucleotide polymorphisms, call for great caution in studies relying on ancient nuDNA sequences.


Silk fibroin-keratin based 3D scaffolds as a dermal substitute for skin tissue engineering.
Development of highly vascular dermal tissue-engineered skin substitutes with appropriate mechanical properties and cellular cues is in need for significant advancement in the field of dermal reconstruction. Limitations have been imposed on natural biomaterials despite their superb biocompatibility hence, studies in biomaterial blending have been ongoing. Herein, we investigated blends of silk fibroin and human hair-derived keratin as wound-healing substrates that promote enhanced fibroblast cell adhesion and proliferation. Three-dimensional (3D) blended scaffolds were fabricated by freeze-drying, and their physico-chemical, mechanical and degradable properties were extensively characterized. Cytocompatibility tests observing cell adhesion and cell proliferation have shown significant enhancements in blended scaffolds. Also, its structural composition with high porosity (>85%) and interconnected pores in the range of 100-120 microns further confirms the superiority of the complex compared to its counterparts. FTIR studies identified the enhanced stability within its structure and were followed-up with sequential experiments to demonstrate improved thermal, degradation, and mechanical properties. Furthermore, immunohistochemical staining revealed greater expression of collagen type I in the cultured cells, indicating functional fibroblast proliferation and, hence, the exciting potential of this construct for dermal applications. Taken together, this study demonstrates the promising attributes from blended biomaterials and specifically present silk fibroin and human hair keratin blended scaffolds as a promising dermal substitute for skin tissue engineering.


Investigation of metal-polyelectrolyte complex toxicity.
Water-soluble binary and ternary copper complexes of polyelectrolytes were synthesized, and the toxicity of these complexes was tested in mouse fibroblast cell line (L929) in vitro. Both the binary and ternary complexes were prepared at the ratio of 0.4 mole copper(II) ions per monomer of acrylic acid and 0.5 mole copper(II) ions per monomer of methyl vinyl ether maleic anhydride, furthermore at the ratio of 1 and 2 mole bovine serum albumin per mole of polyacrylic acid and poly(methyl vinyl ether-co-maleic anhydride), respectively. Compared to binary copper(II)-polyelectrolyte complexes, these ternary complexes have been determined to be of least toxicity.


Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae.
Pneumococcal surface protein A (PspA) has been shown previously to elicit antibodies protective against pneumococcal infection and to be necessary for full pneumococcal virulence in mice. The protein was originally defined by the two mouse monoclonal antibodies Xi64 and Xi126, which together recognized PspA on 14% of pneumococcal isolates. Some PspA molecules reacted with both antibodies, but most reacted with only one or the other. In the present study we demonstrated that PspA is produced by all pneumococci, confirming our hypothesis that there are variants of PspA which are not detected by Xi64 and Xi126. We produced a rabbit antiserum and five additional monoclonal antibodies specific for PspA for these studies. The rabbit antiserum reacted with each of 95 pneumococcal isolated tested, comprising 16 capsular serotypes. One or more of the seven monoclonal anti-PspA antibodies reacted with 95% (53 of 57) of pneumococcal isolates tested. The specificity of the monoclonal and polyclonal antibodies to PspA was confirmed in two ways: (i) by detection of molecules on wild-type pneumococci that are identical in molecular weight to those detected in Western blots (immunoblots) with Xi64 and Xi126 and (ii) by the use of mutants of Streptococcus pneumoniae that fail to produce PspA or that produce a truncated form of PspA. By using the seven monoclonal antibodies, we observed 31 PspA types among the 57 isolates. When the 53 strains reactive with the monoclonal antibodies were analyzed by capsular type as well as by serologic type and molecular weight of PspA, we observed 50 different clonotypes of pneumococci.


The transcription factor B cell-specific activator protein (BSAP) enhances both IL-4- and CD40-mediated activation of the human epsilon germline promoter.
Induction of isotype switching to a particular C(H) gene correlates with the transcriptional activation of the same gene in germline configuration. Induction of correctly spliced germline transcripts is necessary to target a switch region for recombination and switching. Different cytokines activate transcription at different germline promoters. Because binding sites for the B cell-specific transcription factor BSAP are located upstream of several switch regions in the Ig locus, BSAP might play a role in isotype switching by regulating germline transcription. We investigated whether BSAP plays a role in the transcriptional regulation of the epsilon germline promoter in human B cells. We identified human EBV-negative B cell lines that express epsilon germline transcripts upon stimulation with IL-4. Electrophoretic mobility shift assay analysis showed that the human epsilon germline promoter binds BSAP. BSAP activity was expressed constitutively and was not affected by stimulation with IL-4 and/or anti-CD40 mAb. Reporter assays with constructs containing a luciferase gene driven by the epsilon germline promoter, with or without mutations in the BSAP binding site, showed that BSAP plays a role in both IL-4-dependent induction and CD40-mediated up-regulation of human epsilon germline transcription. Furthermore, epsilon germline promoter activity was abrogated in REH cells that express a BSAP polypeptide truncated in the trans-activation domain. Among the transcription factors that regulate epsilon germline expression, BSAP is unique, in that it is B cell-specific and is at the merging point of two signaling pathways that are distinct but both critical for the induction of IgE switching.


The Mechanics of Human Achievement.
Countless studies have addressed why some individuals achieve more than others. Nevertheless, the psychology of achievement lacks a unifying conceptual framework for synthesizing these empirical insights. We propose organizing achievement-related traits by two possible mechanisms of action: Traits that determine the rate at which an individual learns a skill are talent variables and can be distinguished conceptually from traits that determine the effort an individual puts forth. This approach takes inspiration from Newtonian mechanics: achievement is akin to distance traveled, effort to time, skill to speed, and talent to acceleration. A novel prediction from this model is that individual differences in effort (but not talent) influence achievement (but not skill) more substantially over longer (rather than shorter) time intervals. Conceptualizing skill as the multiplicative product of talent and effort, and achievement as the multiplicative product of skill and effort, advances similar, but less formal, propositions by several important earlier thinkers.


Topical application of 5-aminolevulinic acid hexyl ester and 5-aminolevulinic acid to normal nude mouse skin: differences in protoporphyrin IX fluorescence kinetics and the role of the stratum corneum.
An important limitation of topical 5-aminolevulinic acid (ALA)-based photodetection and photodynamic therapy is that the amount of the fluorescing and photosensitizing product protoporphyrin IX (PpIX) formed is limited. The reason for this is probably the limited diffusion of ALA through the stratum corneum. A solution to this problem might be found in the use of ALA derivatives, as these compounds are more lipophilic and therefore might have better penetration properties than ALA itself. Previous studies have shown that ALA hexyl ester (ALAHE) is more successful than ALA for photodetection of early (pre)malignant lesions in the bladder. However, ALA pentyl ester slightly increased the in vivo PpIX fluorescence in early (pre)malignant lesions in hairless mouse skin compared to ALA. The increased PpIX fluorescence is located in the stratum corneum and not in the dysplastic epidermal layer. In the present study, ALA- and ALAHE-induced PpIX fluorescence kinetics are compared in the normal nude mouse skin, of which the permeability properties differ from the bladder. Application times and ALA(HE) concentrations were varied, the effect of a penetration enhancer and the effect of tape stripping the skin before or after application were investigated. Only during application for 24 h, did ALAHE induce slightly more PpIX fluorescence than ALA. After application times ranging from 1 to 60 min, ALA-induced PpIX fluorescence was higher than ALAHE-induced PpIX fluorescence. ALA also induced higher PpIX production than ALAHE after 10 min of application with concentrations ranging from 0.5 to 40%. The results of experiments with the penetration enhancer and tape stripping indicated that the stratum corneum acts a barrier against ALA and ALAHE. Use of penetration enhancer or tape stripping enhanced the PpIX production more in the case of ALAHE application than in the case of ALA application. This, together with the results from the different application times and concentrations indicates that ALAHE diffuses more slowly across the stratum corneum than ALA.


Completeness and Reliability of the Republic of South Africa National Tuberculosis (TB) Surveillance System.
Accurate surveillance data are paramount to effective TB control. The Republic of South Africa's National TB Control Program (NTP) has conducted TB surveillance since 1995 and adopted the Electronic TB Register (ETR) in 2005. This evaluation aimed to determine the completeness and reliability of data in the Republic of South Africa's TB Surveillance System. Three of nine provinces, three subdistricts per province, and 54 health facilities were selected by stratified random sampling. At each facility, 30 (or all if <30) patients diagnosed in Quarter 1 2009 were randomly selected for review. Patient information was evaluated across two paper and four electronic sources. Completeness of program indicators between paper and electronic sources was compared with chi-square tests. The kappa statistic was used to evaluate agreement of values. Over one-third (33.7 %) of all persons with presumptive TB recorded as smear positive in the TB Suspect Register did not have any records documenting notification, treatment, or management for TB disease. Of 1339 persons with a record as a TB patient at the facility, 1077 (80 %) were recorded in all data sources. Over 98 % of records contained complete age and sex data. Completeness varied for HIV status (53-86 %; p < 0.001) and DOT during the intensive phase of treatment (17-54 %; p < 0.001). Agreement for sex was excellent across sources (kappa 0.94); moderate for patient type (0.78), treatment regimen (0.79), treatment outcome (0.71); and poor for HIV status (0.33). The current evaluation revealed that one-third of persons diagnosed with TB disease may not have been notified of their disease or initiated on treatment ('initial defaulters'). The ETR is not capturing all TB patients. Further, among patients with a TB record, completeness and reliability of information in the TB Surveillance System is inconsistent across data sources. Actions are urgently needed to ensure that all diagnosed patients are treated and managed and improve the integrity of surveillance information.


Intestinal Transport Characteristics and Metabolism of C-Glucosyl Dihydrochalcone, Aspalathin.
Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (Papp) typical of poorly absorbed compounds (1.73 × 10-6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10-6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the Papp value to 2.9 × 10-7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.


Geographical variations in elderly disability in Taiwan.
Inequality in health has long been a topic of discussion. The purpose of this research was to provide estimates of the proportions of elderly who had difficulties in activities of daily living in each of the 23 administrative areas of Taiwan, and to assess if there was geographical disparity in disability across areas. A nationally representative sample of 303,545 subjects was selected for interview. Among the subjects selected for interview, 239,861 completed the survey, a completion rate of about 80%. For the purpose of this research, only those aged 65 years or older were included (N = 114,873) in the analyses. Non-standardized and standardized prevalences of disability were presented for each of the 23 administrative areas in Taiwan, and geographical distribution of elderly disability was plotted. Results show that significant difference in disability prevalence exists among administrative districts, even after adjusting for age and sex structure of the population. Moreover, the extent of gender disparity also varied from one area to another. The western region, in general, had lower disability prevalence than the eastern region. Findings imply that since disability prevalence varied significantly across administrative areas, funding for long-term care should not be allocated based on the number of elderly population in an administrative area. Areas with high prevalence should identify reasons for their high prevalence rates and implement proper interventions.


Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats.
Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy. alpha-Lipoic acid, a thiol antioxidant, has been shown to have beneficial effects on polyneuropathy and on the parameters of oxidative stress in various tissues, including nerve, kidney, and retina. The purpose of this study was to examine the effect of alpha-lipoic acid on retinal capillary cell apoptosis and the development of pathology in diabetes. Retina was used from streptozotocin-induced diabetic rats receiving diets supplemented with or without alpha-lipoic acid (400 mg/kg) for 11 months of diabetes. Capillary cell apoptosis (by terminal transferase-mediated dUTP nick-end labeling) and formation of acellular capillaries were investigated in the trypsin-digested retinal microvessels. The effect of alpha-lipoic acid administration on retinal 8-hydroxy-2'deoxyguanosine (8-OHdG) and nitrotyrosine levels was determined by enzyme-linked immunosorbent assay. alpha-Lipoic acid administration for the entire duration of diabetes inhibited capillary cell apoptosis and the number of acellular capillaries in the retina, despite similar severity of hyperglycemia in the two diabetic groups (with and without alpha-lipoic acid). Retinal 8-OHdG and nitrotyrosine levels were increased by over twofold and 70%, respectively, in diabetes, and alpha-lipoic acid administration inhibited these increases. Our results demonstrate that the long-term administration of alpha-lipoic acid has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine in the retina. alpha-Lipoic acid supplementation represents an achievable adjunct therapy to help prevent vision loss in diabetic patients.


Use of newer prognostic indices for patients with myelodysplastic syndromes in the low and intermediate-1 risk categories: a population-based study.
We aimed to compare the ability of recently developed prognostic indices for myelodysplastic syndromes to identify patients with poor prognoses within the lower-risk (low and intermediate-1) categories defined by the International Prognosis Scoring System (IPSS). We included patients with de-novo myelodysplastic syndromes diagnosed between Nov 29, 1972, and Dec 15, 2011, who had low or intermediate-1 IPSS scores and were in the Spanish Registry of Myelodysplastic Syndromes. We reclassified these patients with the new prognostic indices (revised IPSS [IPSS-R], revised WHO-based Prognostic Scoring System [WPSS-R], Lower Risk Scoring System [LRSS], and the Grupo Español de Síndromes Mielodisplásicos [Spanish Group of Myelodysplastic Syndromes; GESMD]) and calculated the overall survival of the different risk groups within each prognostic index to identify the groups of patients with overall poor prognoses (defined as an expected overall survival <30 months). We calculated overall survival with the Kaplan-Meier method. We identified 2373 patients. None of the prognostic indices could be used to identify a population with poor prognoses (median overall survival <30 months) for the patients with low IPSS scores (1290 individuals). In the group with intermediate-1 scores (1083 individuals), between 17% and 47% of patients were identified as having poor prognoses with the new prognostic indices. The LRSS had the best model fit with the lowest value in the Akaike information criteria test, whereas the IPSS-R identified the largest proportion of patients with poor prognoses (47%). Patients with intermediate-1 scores who were classified as having poor prognoses by one or more prognostic index (646 [60%] individuals) had worse median overall survival (33·1 months, 95% CI 28·4-37·9) than did patients who were classified as having low risk by all prognostic indices (63·7 months, 49·5-78·0], HR 1·9, 95% CI 1·6-2·3, p<0·0001) INTERPRETATION: Recently proposed prognostic indices for myelodysplastic syndromes can be used to improve identification of patients with poor prognoses in the group of patients with intermediate-1 IPSS scores, who could potentially benefit from a high-risk treatment approach. None.


Occurrence of imagery and its link with early memories in agoraphobia.
Recent cognitive models suggest that mental imagery can help us understand the maintenance of anxiety disorders (e.g., de Silva, 1986; Hackmann, Surawy, & Clark, 1998). However, imagery is relatively unexplored within agoraphobia. Such images are also thought to be useful in uncovering memories that occurred around the onset of a disorder (Hackmann, Clark, & McManus, 2000). A total of 20 patients with agoraphobia and 20 matched controls took part in this investigation. Participants described any recurrent images they experienced in agoraphobic situations, and also any associated memories. All patients with agoraphobia (but no control participants) reported having distinct recurrent images in "agoraphobic situations". Most images involved several sensory modalities and in the majority of cases appeared to be linked with unpleasant memories of events experienced many years previously. While these exploratory findings require replication, potential treatment implications are discussed.


Predictors for Development of Excessive Daytime Sleepiness in Women: A Population-Based 10-Year Follow-Up.
To analyze predictors of excessive daytime sleepiness (EDS) and to analyze how changes within risk factors over time predict incident EDS in women. Population-based prospective study. General population of the City of Uppsala, Sweden. From a random, general population sample of 7,051 women from the Sleep and HEalth in women ("SHE") cohort, 4,322 women without EDS at baseline were followed up after 10 y. N/A. At baseline and follow-up, women answered a questionnaire on sleeping habits, somatic disease, obesity, insomnia, anxiety and depression, lifestyle, and social factors. The risk of incident EDS was analyzed from changes over time in risk factors using logistic regression modeling. Of the women, EDS developed in 7.9%. Incident: insomnia (adjusted odds ratio = 5.01; 95% confidence interval 3.63-6.92), anxiety and/or depression (3.34; 2.22-5.02), somatic disease (1.73; 1.17-2.55), obesity (1.91; 1.14-2.57), snoring (1.91; 1.17-3.10) and smoking (4.31; 1.95-9.54) were all independent risk factors for the development of EDS. In addition, persistent: insomnia (4.44; 2.97-6.65) and anxiety and/or depression (4.91; 3.17-7.62) increased the risk of developing EDS. Apart from incident: snoring and obesity, similar results were obtained when only including women without somatic disease in the analyses. Insomnia, anxiety and/or depression, and smoking were the most important factors for predicting incident excessive daytime sleepiness (EDS) and, in addition, somatic disease, obesity, and snoring predicted EDS. It is important not only to treat these conditions but also to inform women of the importance of a healthy lifestyle in order to prevent and reduce EDS in women.


Uncovering the behaviour of road accidents in urban areas.
Different patterns in the incidence of road accidents are revealed when considering areas with increased levels of urbanization. To understand these patterns, road accident data from England and Wales is explored. In particular, the data are used to (i) generate time series for comparison of the incidence of road accidents in urban as opposed to rural areas, (ii) analyse the relationship between the number of road accidents and the population size of a set of urban areas, and (iii) model the likelihood of suffering an accident in an urban area and its dependence with population size. It is observed that minor and serious accidents are more frequent in urban areas, whereas fatal accidents are more likely in rural areas. It is also shown that, generally, the number of accidents in an urban area depends on population size superlinearly, with this superlinear behaviour becoming stronger for lower degrees of severity. Finally, given an accident in an urban area, the probability that the accident is fatal or serious decreases with population size and the probability that it is minor, increases sublinearly. These findings promote the question as to why such behaviours exist, the answer to which will lead to more sustainable urban policies.


Novel heteroaromatic organofluorine inhibitors of fructose-1,6-bisphosphatase.
A broad group of compounds including substituted pyrazoles, pyrroles, indoles, and carbazoles were screened to identify potential inhibitor lead compounds of fructose-1,6-bisphosphatase (FBPase). Best inhibitors are (1H-indol-1-yl)(4-(trifluoromethyl)phenyl)methanone, ethyl 3-(3,5-dimethyl-1H-pyrrol-2-yl)-4,4,4-trifluoro-3-hydroxybutanoate, 3,5-diphenyl-1-(3-(trifluoromethyl) phenyl)-1H-pyrazole, and ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-methyl-1H-indol-3-yl)propanoate. The IC50 values (3.1, 4.8, 6.1, and 11.9 microM) were comparable to that of AMP, the natural inhibitor of murine FBPase (IC50 of 4.0 microM). Docking programs were utilized to interpret the experiments.


Real-time PCR targeting a 529-bp repeat element for diagnosis of toxoplasmosis.
Sensitive and rapid detection of infection with Toxoplasma gondii in transplanted immunocompromised patients is crucial for a good prognosis. Two DNA fragments are used currently for detecting T. gondii infection by PCR, i.e., the B1 gene and a 529-bp repeat element that exists in 200-300 copies/genome. This study investigated whether targeting the 529-bp repeat element gives better sensitivity and accuracy than can be obtained when targeting the B1 gene (35 copies) when concentrations of T. gondii DNA are low. The results demonstrated that detection of the 529-bp repeat element increased diagnostic sensitivity and accuracy. Addition of an internal amplification control did not affect the PCR performance and was useful in order to monitor PCR inhibition by non-specific DNA in the LightCycler instrument. The real-time PCR was used successfully in a clinical context to monitor parasitaemia in the blood of a transplant recipient suffering from toxoplasmosis.


Transport of free fatty acid and triglyceride in anhepatic rats.
Without a liver the fractional plasma removal of free fatty acid is one third and chylomicron triglyceride one half of that in the intact rat. The intestine of the anhepatic rat converted enteral fatty acid to plasma triglyceride but was unable to do the same for plasma free fatty acid. This decrease in plasma free fatty acid removal and the inability to recycle the acid as triglyceride were, in part, responsible for the conversion of large fractions of plasma triglyceride flux to the plasma free acid in hepatectomized rats. Increased intravascular triglyceride lipolysis resulting from high circulating lipoprotein lipase concentrations and reduced plasma triglyceride removal were other factors shifting the partition of anhepatic plasma fatty-acid transport from the ester to the free. After the anhepatic plasma clearance of either free fatty acid or triglyceride, relatively more of both compounds was recovered in the lipid of actively metabolizing (heart and muscle) as opposed to storage (adipose) tissue when compared with controls. Sequential evaluations of the recovery of plasma free fatty acid and triglyceride in tissues of anhepatic rats demonstrated accumulation or storage solely in adipose tissue and only when the plasma fatty acid was in triglyceride. This observation and the large conversion of anhepatic circulating triglyceride to the free acid may, in part, explain the lack of an increase in adipose lipid with reduced hepatic mass. The data help explain the preferential use of a lipid fuel in liver disease and the difficulties in obtaining carbon storage in this condition.


Factors and Outcome of Renal Osteodystrophy-Associated Initial Fragility Fracture in End-Stage Renal Disease Patients.
Renal osteodystrophy has caused increased risk of fragility fracture in end-stage renal disease (ESRD) patients. However, risk factors and outcome of ESRD patients with fragility fracture remain uncharacterized. We aimed to assess these parameters in ESRD patients. This retrospective case-control study analyzed 354 ESRD patients (initial fragility fracture [FF] group, n = 59; control group, n = 295). Pre-dialysis blood hemoglobin, serum albumin, lipid, calcium, phosphorus, alkaline phosphatase (ALP), and intact parathyroid hormone (iPTH) were collected. All procedures performed involving human participants were in accordance with the ethical standards of the institutional committee of The First Affiliated Hospital of Chongqing Medical University (IRB approval number 216-82), and informed consent was obtained from all participants. There were higher prevalence rates of primary hypertension and diabetes, higher serum ALP, corrected calcium, and lower serum total cholesterol, low-density lipoprotein, lipoprotein-α, and iPTH in the FF group. Fractures were more likely to occur in the higher level of corrected calcium as well as in the lower iPTH group. High corrected calcium (p = 0.010, OR = 11.308, 95% CI: 1.770-72.242) and serum ALP (p = 0.000, OR = 1.007, 95% CI: 1.004-1.011) were independent risk factors of fragility fracture. The incidence of all-cause mortality and cardiovascular (CV) events in ESRD patients with fragility fracture was higher than in those without fracture. Patients with hypertension, diabetes, excessive suppression of PTH, and poor nutritional status are more prone to fractures. Serum corrected calcium and ALP were independent risk factors of fragility fracture. Patients with initial fragility fracture had more CV events and higher mortality.


Two speeds of increasing milk feeds for very preterm or very low-birthweight infants: the SIFT RCT.
Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. The setting was 55 UK neonatal units, from May 2013 to June 2015. The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. Current Controlled Trials ISRCTN76463425. This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information.


Bioequivalence and Bioavailability Clinical Trials: A Status Report from the National Institutes of Health ClinicalTrials.gov Registry.
Drug development is an expensive process that is marked by a high-failure rate. For this reason early stage bioequivalence and pharmacokinetic studies are essential in determining the fate of new drug products. In this study, we sought to systematically assess the current trends of ongoing and recently completed bioequivalence and bioavailability trials that have been registered within a national clinical trials registry. All bioequivalence and bioavailability studies registered in the United States ClinicalTrials.gov registry from late-2007 through 2011 were identified. Over this period, more than 2300 interventional bioequivalence and bioavailability trials were registered. As of 2013, the vast majority of studies (86%) have been completed, 10% are actively recruiting participants, and the remainder are engaged in data analysis (4%). When compared to completed trials, ongoing trials are in later phases of clinical development, recruiting larger numbers of participants, and more likely to recruit women and children (P<0.001 for all). These data suggest that the quality of bioequivalence and bioavailability studies has improved rapidly, even over the last five years. However, further work is needed to sustain - and accelerate - these improvements in the design of bioequivalence and bioavailability studies to ensure that safe and efficacious medicines swiftly reach healthcare providers and their patients.


Temporal control over cellular targeting through hybridization of folate-targeted dendrimers and PEG-PLA nanoparticles.
Polymeric nanoparticles (NPs) and dendrimers are two major classes of nanomaterials that have demonstrated great potential for targeted drug delivery. However, their targeting efficacy has not yet met clinical needs, largely because of a lack of control over their targeting kinetics, which often results in rapid clearance and off-target drug delivery. To address this issue, we have designed a novel hybrid NP (nanohybrid) platform that allows targeting kinetics to be effectively controlled through hybridization of targeted dendrimers with polymeric NPs. Folate (FA)-targeted generation 4 poly(amidoamine) dendrimers were encapsulated into poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs using a double emulsion method, forming nanohybrids with a uniform size (~100 nm in diameter) at high encapsulation efficiencies (69-85%). Targeted dendrimers encapsulated within the NPs selectively interacted with FA receptor (FR)-overexpressing KB cells upon release in a temporally controlled manner. The targeting kinetics of the nanohybrids were modulated using three different molecular weights (MW) of the PLA block (23, 30, and 45 kDa). The release rates of the dendrimers from the nanohybrids were inversely proportional to the MW of the PLA block, which dictated their binding and internalization kinetics with KB cells. Our results provide evidence that selective cellular interactions can be kinetically controlled by the nanohybrid design, which can potentially enhance targeting efficacy of nanocarriers.


Antiangiogenic Steroids in Human Cancer Therapy.
Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers. This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation. Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non-small cell lung and breast cancers. Clinical trials with squalamine alone or combined with standard chemotherapies or other biologic therapies, including antiangiogenic agents, should be considered for selected cancer patients, and further study of the mechanism of action and bioactivity of squalamine is warranted.


On the coronary and cardiotonic action of crataemon.
Crataemon contains the purified flavonoid mixture of Crataegus monogyna. Flowmetric studies of dog coronary blood flow show that it increases after intravenous application of 2 mg/kg crataemon. This increase is statistically significant and lasts about 30 min, with no significant changes in the heart rate and ECG. In experiments on cats it has been found that only the high crataemon doses have a bradycardic effect. Influence on the blood pressure is insignificant and brief. The minute cardiac volume and the cardiac index increase after all doses tested. The work of the left ventricle is also increased, which is considered to be favourable under conditions of operative shock. The general peripheral resistance is much less inhibited, most active being the highest dose tested.


Structural basis for a complex I mutation that blocks pathological ROS production.
Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia-reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the "deactive" state, usually formed only after prolonged inactivity. Despite its tendency to adopt the "deactive" state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.


Ruminant metabolic systems biology: reconstruction and integration of transcriptome dynamics underlying functional responses of tissues to nutrition and physiological state.
High-throughput 'omics' data analysis via bioinformatics is one key component of the systems biology approach. The systems approach is particularly well-suited for the study of the interactions between nutrition and physiological state with tissue metabolism and functions during key life stages of organisms such as the transition from pregnancy to lactation in mammals, ie, the peripartal period. In modern dairy cows with an unprecedented genetic potential for milk synthesis, the nature of the physiologic and metabolic adaptations during the peripartal period is multifaceted and involves key tissues such as liver, adipose, and mammary. In order to understand such adaptation, we have reviewed several works performed in our and other labs. In addition, we have used a novel bioinformatics approach, Dynamic Impact Approach (DIA), in combination with partly previously published data to help interpret longitudinal biological adaptations of bovine liver, adipose, and mammary tissue to lactation using transcriptomics datasets. Use of DIA with transcriptomic data from those tissues during normal physiological adaptations and in animals fed different levels of energy prepartum allowed visualization and integration of most-impacted metabolic pathways around the time of parturition. The DIA is a suitable tool for applying the integrative systems biology approach. The ultimate goal is to visualize the complexity of the systems at study and uncover key molecular players involved in the tissue's adaptations to physiological state or nutrition.


Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response.
Patients with leukemia who receive a T cell-depleted allogeneic stem cell graft followed by postponed donor lymphocyte infusion (DLI) can experience graft-versus-leukemia (GVL) reactivity, with a lower risk of graft-versus-host disease (GVHD). Here, we have investigated the magnitude, diversity, and specificity of alloreactive CD8 T cells in patients who developed GVL reactivity after DLI in the absence or presence of GVHD. We observed a lower magnitude and diversity of CD8 T cells for minor histocompatibility antigens (MiHAs) in patients with selective GVL reactivity without GVHD. Furthermore, we demonstrated that MiHA-specific T cell clones from patients with selective GVL reactivity showed lower reactivity against nonhematopoietic cells, even when pretreated with inflammatory cytokines. Expression analysis of MiHA-encoding genes showed that similar types of antigens were recognized in both patient groups, but in patients who developed GVHD, T cell reactivity was skewed to target broadly expressed MiHAs. As an inflammatory environment can render nonhematopoietic cells susceptible to T cell recognition, prevention of such circumstances favors induction of selective GVL reactivity without development of GVHD.


Low diversity of t haplotypes in the eastern form of the house mouse, Mus musculus L.
In previous studies, 13 different recessive embryonic lethal genes have been associated with t haplotypes in the wild mice of the species Mus domesticus. In this communication we have analyzed five populations of Mus musculus for the presence and identity of t haplotypes. The populations occupy geographically distant regions in the Soviet Union: Altai Mountains, western and eastern Siberia, Azerbaijan and Turkmenistan. No t haplotypes were found in mice from eastern Siberia. In the remaining four populations, t haplotypes occurred with frequencies ranging from 0.07 to 0.21. All the t haplotypes extracted from these populations and analyzed by the genetic complementation test were shown to carry the same lethal gene tcl-w73. In one population (that of western Siberia), another lethal gene (tcl-w5) was found to be present on the same chromosome as tcl-w73. This situation is in striking contrast to that found in the populations of the western form of the house mouse, M. domesticus. In the latter species, tcl-w73 has not been found at all and the different populations are characterized by the presence of several different lethal genes. The low diversity of t haplotypes in M. musculus is consistent with lower genetic variability of other traits and indicates a different origin and speciation mode compared to M. domesticus. Serological typing for H-2 antigenic determinants suggests that most, if not all, of the newly described t haplotypes might have arisen by recombination of tw73 from M. musculus with t haplotypes from M. domesticus either in the hybrid zone between the two species or in regions where the two species mixed accidentally.


The effectiveness of community-based animal health workers, for the poor, for communities and for public safety.
The development of community animal health (CAH) is an invaluable tool for addressing a series of challenges, particularly for the policy-maker, whose prime concern is public welfare. This paper examines three of the major challenges which confront governments, particularly the governments of less-developed countries, namely, the collapse of government services, the crucial issue of poverty reduction and the misuse of animal drugs. Although CAH is a potentially powerful tool for approaching all of these problems, the authors argue that CAH can only be fully exploited on a macroscopic level by developing strong institutions to support and regulate such community initiatives. In some countries, developing such institutions depends upon accepting the more fundamental and controversial principle of legalising non-professional animal health service providers who work within the private sector. In Section 1, the authors outline the three principal challenges which face governments, particularly in developing countries, and to which CAH offers a potential solution. Sections 2 to 4 investigate the evidence relating to each of these challenges in turn. Section 5 briefly draws on the lessons that have been generated by field experiences over the years, to propose how governments may develop CAH systems to their best advantage.


Segmental concatenation of individual signatures and context cues in banded mongoose (Mungos mungo) close calls.
All animals are anatomically constrained in the number of discrete call types they can produce. Recent studies suggest that by combining existing calls into meaningful sequences, animals can increase the information content of their vocal repertoire despite these constraints. Additionally, signalers can use vocal signatures or cues correlated to other individual traits or contexts to increase the information encoded in their vocalizations. However, encoding multiple vocal signatures or cues using the same components of vocalizations usually reduces the signals' reliability. Segregation of information could effectively circumvent this trade-off. In this study we investigate how banded mongooses (Mungos mungo) encode multiple vocal signatures or cues in their frequently emitted graded single syllable close calls. The data for this study were collected on a wild, but habituated, population of banded mongooses. Using behavioral observations and acoustical analysis we found that close calls contain two acoustically different segments. The first being stable and individually distinct, and the second being graded and correlating with the current behavior of the individual, whether it is digging, searching or moving. This provides evidence of Marler's hypothesis on temporal segregation of information within a single syllable call type. Additionally, our work represents an example of an identity cue integrated as a discrete segment within a single call that is independent from context. This likely functions to avoid ambiguity between individuals or receivers having to keep track of several context-specific identity cues. Our study provides the first evidence of segmental concatenation of information within a single syllable in non-human vocalizations. By reviewing descriptions of call structures in the literature, we suggest a general application of this mechanism. Our study indicates that temporal segregation and segmental concatenation of vocal signatures or cues is likely a common, but so far neglected, dimension of information coding in animal vocal communication. We argue that temporal segregation of vocal signatures and cues evolves in species where communication of multiple unambiguous signals is crucial, but is limited by the number of call types produced.


An investigation on systematic history and distribution areas of tarek (Alburnus tarichi (Güldenstädt, 1814)).
This study aimed to determine the distribution area of tarek (Alburnus tarichi (Güldenstädt, 1814)) and to define how it must be called according to the scientific name by evaluating its previous studies made by various systematisers and their reports on its distribution, and by comparing literature knowledge. The taxonomic characteristics of the collected samples were evaluated and several measurements and counts were taken on the samples; analfin origin 0-4 scales behind dorsal fin-base; 72-91 lateral line scales; 21-29 gill rakers; 7½-10 branched dorsal-fin rays and 10-12½ branched anal-fin rays. Body and caudal peduncle was moderately compressed. Body was covered by overlapping scales. Tarek has five different populations in the Basin. They are Van, Erçek, Nazik and Aygır Lakes and Koçköprü Dam Lake populations. The main living area of the tarek population is Lake Van; however, between May and June, mature individuals of tarek enter to tributaries of Van Lake. Some of them are Karasu, Bendimahi, Deliçay, Zilan, Karmuç, Sapur, Yanıkçay, Gevaş, Engil, Kurubaş and Akköprü Streams. At the end of study, it was concluded that tarek should be called as Alburnus tarichi (Güldenstädt, 1814) and it is an endemic fish species distributed only in Van Lake Basin.


Association of Vitamin D Deficiency and Thyroid Function in Postmenopausal Women.
Pupose: Although there are reports of vitamin D (VitD) insufficiency in immune-mediated hypothyroidism, an association between VitD and thyroid-stimulating hormone (TSH) levels has yet to be shown. We aim to examine VitD and TSH levels among postmenopausal women, as both conditions are more prevalent in elderly women. Methods: The clinic records of postmenopausal women during their routine maintenance visits were reviewed. All patients were examined for the symptoms related to thyroid function and osteoporosis. Participants were divided into three subgroups according to their TSH levels (below <0.5 mIU/L, 0.51-4.0 mIU/L and >4.0 mIU/L). Patient characteristics and VitD levels were compared between these subgroups. Multivariate linear regression model was constructed using serum VitD and serum TSH as the dependent variables to identify factors independently associated with these laboratory values. Results: Two-hundred and nighty nine postmenopausal women were included. Average age was 62.2±7.5 years old. VitD was insufficient (10-30 ng/mL) in 12.0% and deficient (<10 ng/mL) in 60.9% of the participants. In 11.3%, TSH was low and in 7.6% of women, TSH was high, while the remaining 80.1%, had normal TSH levels. Subjects with low TSH had significantly higher VitD concentrations (34.2±29.1 ng/mL) compared to the other two groups (P-value: 0.039). In multivariate regression analysis, TSH was not a contributing factor, as age was the only significant predictor of VitD levels. Meanwhile, no predictor (including age and VitD) was identified for TSH levels in linear regression analysis. Conclusion: Age was the only independent predictor of serum VitD in this study population. Though suppressed TSH was associated with higher VitD levels, the association was not linear between TSH and VitD in postmenopausal women.