Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219.
GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219. A cell line resistant to 9-(2-Phosphonylmethoxyethyl)-N(6)-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the deamination of cPrPMEDAP metabolite to PMEG. Mutations affecting the activity of ADAL confer resistance to both GS-9219 and its metabolite cPrPMEDAP.


Carbon and nitrogen assimilation in deep subseafloor microbial cells.
Remarkable numbers of microbial cells have been observed in global shallow to deep subseafloor sediments. Accumulating evidence indicates that deep and ancient sediments harbor living microbial life, where the flux of nutrients and energy are extremely low. However, their physiology and energy requirements remain largely unknown. We used stable isotope tracer incubation and nanometer-scale secondary ion MS to investigate the dynamics of carbon and nitrogen assimilation activities in individual microbial cells from 219-m-deep lower Pleistocene (460,000 y old) sediments from the northwestern Pacific off the Shimokita Peninsula of Japan. Sediment samples were incubated in vitro with (13)C- and/or (15)N-labeled glucose, pyruvate, acetate, bicarbonate, methane, ammonium, and amino acids. Significant incorporation of (13)C and/or (15)N and growth occurred in response to glucose, pyruvate, and amino acids (∼76% of total cells), whereas acetate and bicarbonate were incorporated without fostering growth. Among those substrates, a maximum substrate assimilation rate was observed at 67 × 10(-18) mol/cell per d with bicarbonate. Neither carbon assimilation nor growth was evident in response to methane. The atomic ratios between nitrogen incorporated from ammonium and the total cellular nitrogen consistently exceeded the ratios of carbon, suggesting that subseafloor microbes preferentially require nitrogen assimilation for the recovery in vitro. Our results showed that the most deeply buried subseafloor sedimentary microbes maintain potentials for metabolic activities and that growth is generally limited by energy but not by the availability of C and N compounds.


Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis.
The effects of the human immunodeficiency virus (HIV) on tuberculosis management was investigated in 227 patients initially treated with a regimen containing streptomycin, isoniazid, and thiacetazone (STH). 93 of these 227 were HIV-seropositive. 60 patients, of whom 18 were HIV-seropositive, received a regimen consisting of streptomycin, isoniazid, rifampicin, and pyrazinamide (SHRZ) in the initial phase, and thiacetazone and isoniazid (TH) in the continuation phase. Cutaneous hypersensitivity reactions occurred in 22 of 111 (20%) HIV-seropositive patients, and in 2 of 176 (1%) HIV-seronegative patients (RR = 18, 95% CI 4.4-76, p less than 10(-7]. During the first 8 weeks of treatment 18 reactions occurred among the 93 HIV-seropositive patients on STH, whereas no reaction occurred in 17 HIV-seropositive patients during the initial phase of SHRZ/TH (p = 0.04). None of the 18 HIV-seropositive patients with cutaneous reactions who were subsequently challenged with isoniazid reacted, nor did any of the 10 tested with streptomycin, but 6 of the 7 challenged with thiacetazone reacted. 3 patients (all HIV-positive and with toxic epidermal necrolysis) died as a result of the cutaneous reaction. These results have major implications for tuberculosis control programmes in Africa.


[Microsurgical and endovascular treatment of residual and recurrent cerebral aneurysms].
Cerebral aneurysms are characterized by high risk of adverse outcome due to severe intracranial hemorrhages and their consequences. Aneurysm remnants after incomplete exclusion can cause hemorrhage. Filling of these fragments immediately after surgery is usually defined as residual aneurysms. Recurrent aneurysms develop in the area of excluded aneurysm in long-term period after surgery. The authors analyze foreign and national literature data on the diagnosis and management of residual and recurrent aneurysms. Risk factors, the most common classifications, diagnostic methods and surgical treatment are presented.


Colour-coded duplex ultrasonography in selection of patients for transluminal angioplasty.
Transluminal angioplasty can be used to relieve symptomatic lower extremity arterial disease with minimal morbidity. This prospective study compares the accuracy of colour-coded duplex ultrasonography with intra-arterial digital subtraction angiography in selection of femoro-popliteal lesions for angioplasty. Isolated, short (< 6 cm) and haemodynamically significant stenosis (> 50% reduction in diameter) were considered for angioplasty. Colour-duplex selection and exclusion was in agreement with angiography in 68 out of 86 lower limbs (79%). The sensitivity, specificity, positive and negative predictive value of colour duplex compared with angiography yielded values of 60.9, 87.5, 60.9 and 85.7%, respectively. The discrepancy between colour duplex and digital subtraction angiography can be partly explained by the tendency of duplex to underestimate the severity and length of disease. It is concluded that colour-coded duplex can be used as a screening tool for lower extremity arterial disease to select appropriate lesions for endovascular procedures. The accuracy of duplex in the present study was not perfect and the decision for further intervention should be based on clinical grounds.


Bioanalytical equivalents and relative potencies for predicting the biological effects of mixtures.
Bioanalytical equivalents (BEQs) of mixtures and environmental samples are widely used to reflect the potential threat of pollutants in the environment and can be obtained by bioassays or using chemical analysis combined with relative potencies (REPs). In this study, the relationships between bioassay-detected BEQs (Bio-BEQs) and chemically analyzed BEQs (Chem-BEQs) were studied. BEQs and REPs are correlated with effect level and the concentration-response curves of the reference standard and sample. Thus, effect level (e.g., EC10, EC25 and EC50) should be addressed for the BEQ values obtained from bioassays or chemical analyses. The previous prerequisites for REPs application (i.e., curves that are parallel and have the same maximum response) are redundant, and the use of REPs for the calculation of BEQs or in risk assessment should instead be based on the same effect level. For a complex mixture with many components, all active components can be regarded as dilutions of a standard compound for inducing a specific effect. Relative toxicity estimates based on EC50 ignore the contribution of weak-active components with maximum response below EC50 of the reference standard, especially in complex mixtures or environmental samples. REPs based on an effect level EC10 that can be clearly discriminated from background response are recommended for BEQ calculation. As an example, the aryl hydrocarbon receptor (AhR)-mediated activity of US EPA priority polycyclic aromatic hydrocarbons (PAHs) in RTL-W1 cells was used to assess the reliability of REPs for mixture toxicity prediction based on the effect level EC10.


Complications from a testicular prosthesis in a stallion.
A testicular prosthesis was removed from the scrotum of a 3-year-old Quarter Horse stallion. The prosthesis had been placed in the left side of the scrotum 10 months earlier, after an unsuccessful attempt to reposition the retained left testis. Because of a persistent draining fistula on the scrotum, first noted 5 months after placement of the prosthesis, surgery was performed to remove the prosthesis. At surgery, the left testis was found in a fibrous mass surrounding the prosthesis. The left testis had descended after placement of the prosthesis, and its involvement in the fibrous tissue surrounding the infected prosthesis necessitated its removal. Had the prosthesis not been placed, descent of the left testis probably would have resulted in an essentially normal stallion.


Molecular-targeted agents combination therapy for cancer: developments and potentials.
Although chemotherapy has advanced into the era of targeted drugs, the antitumor efficacies of current therapies are limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity and cell signal complexity. As shutdown of a single target does not necessarily eradicate the cancer, the use of combinations of molecular-targeted agents (MATs) has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. In this article, the clinical and preclinical studies that are underway in an attempt to improve the anticancer efficacy of chemotherapies through combination strategies are summarized. Studies of combining cytotoxic agents with MATs, coinhibiting two or more targets in a single pathway or coinhibiting parallel or compensatory pathways as well as specific combinations will be introduced, and the antitumor potentials of each combination strategy will be evaluated.


An Open-Label, Prospective, Pilot Study of Hypertonic Saline for Hidradenitis Suppurativa.
Hidradenitis suppurativa (HS) fistulas are likely to persist without surgical intervention. Hypertonic saline (HTS), a venous sclerosant, disrupts the endothelial lining leading to occlusion and fibrosis when used for venous insufficiency. To evaluate the efficacy and tolerability of HTS sclerotherapy for HS fistulas. This Institutional review board-approved, nonrandomized, clinical trial included adult patients with a diagnosis of HS and at least one confirmed HS fistula who underwent HTS injections into their fistulas every two weeks followed by a 4-week follow-up period. The study was performed from 2016 to 2019 at two academic outpatient dermatology clinics in Boston, MA. Primary outcomes were physician-assessed improvement of HS fistula characteristics between final and baseline visits and physician-assessed HS improvement during course of study. Overall, 21 patients participated. Physician-assessed overall HS improvement was significant between Visits 2 and 3 (p = .036). Drainage (p = .035), erythema (p = .008), and swelling (p = .025) demonstrated statistically significant improvement from baseline to final visit. Dermatology life quality index scores significantly improved from baseline to Visit 2 (p = .0005), Visit 3 (p = .0008), and final visit (p = .011). Numeric rating scale stinging scores increased with sclerosant volume. This study demonstrated physician-reported and patient-reported improvement in fistulas following serial HTS injections. HTS injections were well tolerated.


Respiratory indices by gas analysis and fat metabolism by indirect calorimetry in normal subjects and triathletes.
The effects of exercise on different indices reflecting the metabolism have been of interest for a long time, and a relationship between anaerobic indices and maximal oxygen uptake has been established. The inter-relationship between different respiratory indices during an exercise test remains to be studied in order to understand differences between individuals. Therefore, the aim of this study was to determine three respiratory indices and investigate their inter-relationship in individuals with highly variable working capacity. A second aim was to investigate the fat metabolism at the VO(2) corresponding to the respiratory compensation point (Pq) in the different subjects using indirect calorimetry. Sixty control subjects (20 female) and 18 triathletes (six female) performed an exercise test with gas analysis. Three respiratory indices, derivative crossing (Dx), point of crossing (Px) and respiratory compensation point (Pq), were calculated using a computerized method. Fat metabolism at Pq was calculated using indirect calorimetry. Two different sequences of the respiratory indices were found: Dx<Px<Pq and Dx<Pq<Px. In subjects whom Px occurred before Pq, no fat metabolism was seen at Pq, whilst in subjects with Pq occurring before Px, a combined aerobic fat metabolism and anaerobic carbohydrate metabolism was found at Pq. This study has shown two different sequences of the respiratory indices Dx, Px and Pq in subjects of varying working capacity. The individual differences in the order of occurrence of Px and Pq during the exercise test are most likely caused by different abilities to metabolize fat at high workloads.


Metabolic Profiling of Developing Pear Fruits Reveals Dynamic Variation in Primary and Secondary Metabolites, Including Plant Hormones.
Metabolites in the fruits of edible plants include sweet sugars, visually appealing pigments, various products with human nutritional value, and biologically active plant hormones. Although quantities of these metabolites vary during fruit development and ripening because of cell division and enlargement, there are few reports describing the actual dynamics of these changes. Therefore, we applied multiple metabolomic techniques to identify the changes in metabolite levels during the development and ripening of pear fruits (Pyrus communis L. 'La France'). We quantified and classified over 250 metabolites into six groups depending on their specific patterns of variation during development and ripening. Approximately half the total number of metabolites, including histidine and malate, accumulated transiently around the blooming period, during which cells are actively dividing, and then decreased either rapidly or slowly. Furthermore, the amounts of sulfur-containing amino acids also increased in pear fruits around 3-4 months after the blooming period, when fruit cells are enlarging, but virtually disappeared from ripened fruits. Some metabolites, including the plant hormone abscisic acid, accumulated particularly in the receptacle prior to blooming and/or fruit ripening. Our results show several patterns of variation in metabolite levels in developing and ripening pear fruits, and provide fundamental metabolomic data that is useful for understanding pear fruit physiology and enhancing the nutritional traits of new cultivars.


Sympathetic, parasympathetic and enteric regulation of the gastrointestinal vasculature in rainbow trout (Oncorhynchus mykiss) under normal and postprandial conditions.
The control of the gastrointestinal hyperemia that occurs after feeding in most animals is of fundamental importance for the subsequent absorption, metabolism and redistribution of nutrients. Yet, in fish, it has received little attention and the nature of it is far from clear. We sought to investigate the importance of extrinsic and intrinsic innervation of the gastrointestinal tract in the regulation of gastrointestinal blood flow in rainbow trout (Oncorhynchus mykiss). The contribution of the extrinsic innervation, i.e. by the sympathetic and the parasympathetic nervous system, was examined by comparing the response to the injection of a predigested nutrient diet into the proximal intestine of untreated fish with the response in fish in which the splanchnic and vagal innervation of the gut had been removed. We also injected the predigested nutrient diet into anaesthetized fish treated with tetrodotoxin that would block the intrinsic innervation of the gut (i.e. enteric nervous system). Our results confirm the notion that the sympathetic portion of the extrinsic innervation maintains the basal vascular tone, but neither the splanchnic nor the vagal innervation is fundamental to the postprandial hyperemia. However, the tetrodotoxin treatment completely abolished the postprandial hyperemia, indicating the importance of the enteric nervous system. In conclusion, it seems as though the enteric nervous system is essential to the regulation of the postprandial hyperemia, and that the extrinsic innervation is involved mainly in the regulation of gastrointestinal blood flow under normal conditions and in response to central coordination with other organs.


Tumor Associated Macrophages in Kidney Cancer.
Tumor associated macrophages (TAMs) are an important element of tumor stroma. They originate from blood monocytes attracted by chemokines and cytokines produced by tumor cells and, being instructed by tumor microenvironment, develop into potent tumor-supporting cell population. TAMs were demonstrated to directly stimulate tumor cell proliferation and to promote angiogenesis. Further TAMs provide for efficient immune escape by producing immunosuppressive cytokines and facilitate tumor dissemination by producing extracellular matrix remodeling enzymes. In renal cell carcinoma (RCC), numerous studies were performed for elucidation of the role of TAM in tumor progression. Using pan-macrophages marker CD68 and type 2 macrophage (M2) markers CD163 and CD206, it was demonstrated that increased density of TAMs is associated with poor survival of patients. Although most of the studies are focused on M2 population in RCC, several markers rather typical for type 1 macrophages (M1) were also characterized. Macrophages isolated from RCC tumors were shown to produce proinflammatory cytokines TNFα, IL-1β, IL-6, and CCL2. It can be concluded that RCC is an excellent example of a tumor with hybrid phenotype of TAMs that share both M1 and M2 properties. Moreover, TAMs seem to be an attractive therapeutic target as well. Further investigations are needed for identification of RCC-specific TAM markers with high predictive capacity and/or suitable for therapeutic targeting.


Glycoprotein Biosynthesis in Chlamydomonas: I. IN VITRO INCORPORATION OF GALACTOSE FROM UDP-[C]GALACTOSE INTO MEMBRANE-BOUND PROTEIN.
A crude membrane fraction from Chlamydomonas reinhardii was found to catalyze d-galactose transfer from UDP-galactose to endogenous proteins. Highest incorporation rates were achieved by incubation at 25 degrees C and pH 7.5 in the presence of 10 millimolar Fe(2+). Hydrolytic studies on the labeled polymer revealed that radioactivity was attached to protein via an alkali-stable and acid-labile linkage. Identification of galactose as the only labeled sugar in the acid hydrolysate and results of a tentative estimation of the molecular weight of the charged alkaline degradation product indicate that monomeric galactose units are transferred to form an O-glycosidic bond with peptidyl hydroxyproline. No indications were found for a similar linkage to serine which, in contrast to the hydroxyproline-O-glycoside linkage, is acid-stable but is cleaved by beta-elimination. Chromatography of the sodium dodecyl sulfate-solubilized polymer on Sepharose-6B demonstrated that galactosyl residues are mainly associated with proteins which are of considerably higher molecular weight than are the majority of sodium dodecyl sulfate-denatured membrane proteins in this fraction.


Dynamic cross-waveguide optical switching with a nonlinear photonic band-gap structure.
We present a numerical study of a two dimensional all- optical switching device which consists of two crossed waveguides and a nonlinear photonic band{gap structure in the center. The switching mechanism is based on a dynamic shift of the photonic band edge by means of a strong pump pulse and is modeled on the basis of a two dimensional finite volume time domain method. With our arrangement we find a pronounced optical switching effect in which due to the cross-waveguide geometry the overlay of the probe beam by a pump pulse is significantly reduced.


[Reduction in hypoxia-derived neuroinflammation and dysfunctional glutamate transporters by minocycline may restore hypoxia-injured cognition of neonatal rat].
The aim of the present study was to investigate the effects of minocycline on cognitive functions in neonatal rat after hypoxia exposure and the underlying mechanism. A model of hypoxic brain damage (HBD) was developed by exposing postnatal 1 day (P1) rats to systemic hypoxia. The rats were intraperitoneally injected with normal saline (Hy group) or minocycline (Hy + M group) 2 h after hypoxia exposure. Some other P1 rats that were not subjected to systemic hypoxia were used as normal control (NG group). The Y-maze test was used to evaluate learning and memory ability on postnatal day 30. Inflammatory mediators (Iba-1, IL-1β, TNF-α and TGF-β1), glutamate transporters (EAAT1 and EAAT2), total Tau and phosphorylated Tau (phosphorylation sites: Tyr18, Thr205, Thr231, Ser396 and Ser404) protein expressions in the hippocampus were detected by Western blot 7 d after hypoxic exposure. The results showed that hypoxia induced learning and memory impairments of the neonatal rats, and minocycline administration could reverse the effects of hypoxia. The protein expression levels of Iba-1, IL-1β, TNF-α, EAAT2 and Tau phosphorylated at T231 were increased, but the total Tau expression was decreased in the hippocampus of the rats from Hy group 7 d after hypoxia exposure. In the hypoxia-treated rats, minocycline down-regulated Iba-1, IL-1β, TNF-α and EAAT2 protein expressions significantly, but did not affect total Tau and phosphorylated Tau protein expressions. Our results suggest that minocycline can prevent cognitive deficits of rats with hypoxia exposure, and the underlying mechanism may involve the inhibition of neuroinflammation and dysfunctional glutamate transporters but not the regulation of the Tau hyperphosphorylation.


The process of awakening: a PET study of regional brain activity patterns mediating the re-establishment of alertness and consciousness.
Awakening from sleep entails rapid re-establishment of consciousness followed by the relatively slow (20-30 min later) re-establishment of alertness--a temporal dissociation that facilitates specification of the physiological underpinnings of each of these facets of the awakening process. H(2)(15)O PET was used to assess changes in regional cerebral blood flow (rCBF) upon awakening from stage 2 sleep. Cerebral blood flow (CBF) was most rapidly re-established in centrencephalic regions (e.g. brainstem and thalamus), suggesting that the reactivation of these regions underlies the re-establishment of conscious awareness. Across the ensuing 15 min of wakefulness, further increases in CBF were evident primarily in anterior cortical regions, suggesting that the dissipation of sleep inertia effects (post-awakening performance and alertness deficits) is effected by reactivation of these regions. Concomitant shifts in correlation patterns of regional brain activity across the post-awakening period [in particular, a waning negative correlation between prefrontal cortex and mesencephalic reticular formation (RF) activity, and a waxing positive correlation between prefrontal cortex and ventromedial caudate nucleus (CAUD) activity] suggest that the post-awakening reversal of sleep inertia effects may be mediated by more than mere reactivation--it may also involve the functional reorganization of brain activity. Conversely, stable post-awakening correlations--such as those found between the anterior cingulate cortex (ACC) and most other brain regions--may denote the pattern of functional connectivity that underlies consciousness itself.


A procedure for the purification of thioredoxin-m from leaves of the C4 plant Zea mays.
A simple four-step procedure for the purification of thioredoxin-m from Zea mays leaves is described. The procedure provides pure protein with recoveries of 20-25%. This thioredoxin mediates in the regulation of NADP-malate dehydrogenase involved in photosynthesis in C4 plants.


[Role of angiotensin II type 1 receptor in activation of nuclear factor-kappaB and activator protein-1 in lung of mice with acute lung injury].
To explore the role of angiotensin II type 1 (AT1) receptor in activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in lung of mice with LPS-induced acute lung injury (ALI). Eighty-eight BABL/c mice were divided into control group (n = 8), LPS group (n = 40), and LPS + AT1 receptor antagonist ZD7155 group (n = 40) according to the random number table. Puncture of trachea was done in all mice. Mice in LPS + ZD7155 group were intraperitoneally injected with 10 mg/kg ZD7155. Mice in LPS and control groups were intraperitoneally injected with normal saline in the same volume as that of ZD7155. Thirty minutes later, 1 mg/mL LPS was dripped into trachea of mice in LPS and LPS + ZD7155 groups (2 mg/kg). Normal saline in the same volume as that of LPS was dripped into trachea of mice in control group. Lung tissue samples of mice in LPS and LPS + ZD7155 groups were harvested at post dripping hour (PDH) 1, 3, 6, 12, and 24. Lung tissue sample of mice in control group was harvested at PDH 24. Expression of AT1 receptor was determined with Western blot. AP-1 and NF-kappaB activity in lung tissue was detected with electrophoretic mobility shift assay. Data were processed with one-way analysis of variance. The relative expression amount of AT1 receptor protein in lung tissue of mice in LPS group at each time point was increased obviously as compared with that of mice in control group (0.69 +/- 0.28, F = 9.356, with P values all below 0.01), and it peaked at PDH 6 (3.44 +/- 0.90), while that of mice in LPS + ZD7155 group was less than that in LPS group at each time point (F = 9.356, with P values all below 0.01). NF-kappaB activity in mice lung was markedly increased in LPS group at each time point as compared with mice in control group (5.47 +/- 0.08, F = 26.443, with P values all below 0.05), and its peak value in LPS group was found at PDH 3 (52.33 +/- 3.25). While NF-kappaB activity in mice of LPS + ZD7155 group was obviously lower than that in LPS group at each time point (F = 26.443, with P values all below 0.05). AP-1 activity in lung was enhanced significantly in LPS group at each time point as compared with that in control group (2.5 +/- 0.4, F = 34.685, with P values all below 0.05), and the activity peaked at PDH 6 (73.3 +/- 9.5) in LPS group. The activity was obviously weaker in mice in LPS + ZD7155 group as compared with that in LPS group at each time point (F = 34.685, with P values all below 0.05). AT1 receptor contributes to LPS-induced ALI through activating NF-kappaB and AP-1 in lung tissue.


Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators.
The tumor necrosis factor-alpha (TNF-alpha) promoter was used to explore the molecular mechanisms of estradiol (E(2))-dependent repression of gene transcription. E(2) inhibited basal activity and abolished TNF-alpha activation of the TNF-alpha promoter. The E(2)-inhibitory element was mapped to the -125 to -82 region of the TNF-alpha promoter, known as the TNF-responsive element (TNF-RE). An AP-1-like site in the TNF-RE is essential for repression activity. Estrogen receptor (ER) beta is more potent than ERalpha at repressing the -1044 TNF-alpha promoter and the TNF-RE upstream of the herpes simplex virus thymidine kinase promoter, but weaker at activating transcription through an estrogen response element. The activation function-2 (AF-2) surface in the ligand-binding domain is required for repression, because anti-estrogens and AF-2 mutations impair repression. The requirement of the AF-2 surface for repression is probably due to its capacity to recruit p160 coactivators or related coregulators, because overexpressing the coactivator glucocorticoid receptor interacting protein-1 enhances repression, whereas a glucocorticoid receptor interacting protein-1 mutant unable to interact with the AF-2 surface is ineffective. Furthermore, receptor interacting protein 140 prevents repression by ERbeta, probably by interacting with the AF-2 surface and blocking the binding of endogenous coactivators. These studies demonstrate that E(2)-mediated repression requires the AF-2 surface and the participation of coactivators or other coregulatory proteins.


Biomolecular and Genetic Prognostic Factors That Can Facilitate Fertility-Sparing Treatment (FST) Decision Making in Early Stage Endometrial Cancer (ES-EC): A Systematic Review.
Endometrial cancer occurs in up to 29% of women before 40 years of age. Seventy percent of these patients are nulliparous at the time. Decision making regarding fertility preservation in early stage endometrial cancer (ES-EC) is, therefore, a big challenge since the decision between the risk of cancer progression and a chance to parenthood needs to be made. Sixty-two percent of women with complete remission of ES-EC after fertility-sparing treatment (FST) report to have a pregnancy wish which, if not for FST, they would not be able to fulfil. The aim of this review was to identify and summarise the currently established biomolecular and genetic prognostic factors that can facilitate decision making for FST in ES-EC. A comprehensive search strategy was carried out across four databases; Cochrane, Embase, MEDLINE, and PubMed; they were searched between March 1946 and 22nd December 2022. Thirty-four studies were included in this study which was conducted in line with the PRISMA criteria checklist. The final 34 articles encompassed 9165 patients. The studies were assessed using the Critical Appraisal Skills Program (CASP). PTEN and POLE alterations we found to be good prognostic factors of ES-EC, favouring FST. MSI, CTNNB1, and K-RAS alterations were found to be fair prognostic factors of ES-EC, favouring FST but carrying a risk of recurrence. PIK3CA, HER2, ARID1A, P53, L1CAM, and FGFR2 were found to be poor prognostic factors of ES-EC and therefore do not favour FST. Clinical trials with bigger cohorts are needed to further validate the fair genetic prognostic factors. Using the aforementioned good and poor genetic prognostic factors, we can make more confident decisions on FST in ES-EC.


Integrative Analysis of MicroRNA and mRNA Sequencing Data Identifies Novel Candidate Genes and Pathways for Developmental Dysplasia of Hip.
Our aim is to explore the candidate pathogenesis genes and pathways of developmental dysplasia of hip (DDH). Proliferating primary chondrocytes from hip cartilage were used for total RNA extraction including 5 DDH patients and 5 neck of femur fracture (NOF) subjects. Genome-wide mRNA and microRNA (miRNA) were then sequenced on the Illumina platform (HiSeq2500). Limma package was used for difference analysis of mRNA expression profiles. edgeR was used for difference analysis of miRNA expression profiles. miRanda was used to predict miRNA-target genes. The overlapped DDH associated genes identified by mRNA and miRNA integrative analysis were further compared with the differently expressed genes in hip osteoarthritis (OA) cartilage. Differential expression analysis identified 1,833 differently expressed mRNA and 186 differently expressed miRNA for DDH. Integrative analysis of mRNA and miRNA expression profiles identified 175 overlapped candidate genes (differentially expressed genes, DEGs) for DDH, such as VWA1, TMEM119, and SCUBE3. Further gene ontology enrichment analysis detected 111 candidate terms for DDH, such as skeletal system morphogenesis (P = 4.92 × 10-5) and skeletal system development (P = 8.85 × 10-5). Pathway enrichment analysis identified 14 candidate pathways for DDH, such as Hedgehog signaling pathway (P = 4.29 × 10-5) and Wnt signaling pathway (P = 4.42 × 10-2). Among the identified DDH associated candidate genes, we also found some genes were detected in hip OA including EFNA1 and VWA1. We identified multiple novel candidate genes and pathways for DDH, providing novel clues for understanding the molecular mechanism of DDH.


Sphincter-saving surgery for rectal carcinoma. Comparison of two five-year periods from 1980 to 1989.
The early results of treatment for rectal adenocarcinoma in 290 patients were compared in two five-year periods, from 1980 to 1989, considering sphincter preservation. Altogether, 223 patients (77%) had radical surgery and the primary tumour was excised in 267 cases (92%). Operative mortality was 2.8% (8 patients), 3.2% in the first and 2.3% in the second five-year period. Sphincter-saving surgery was undertaken in 68 of 157 patients (43%) and in 90 of 133 patients (68%) within the two periods. This failed in one (1.5%) and five (5.6%) patients (P greater than 0.05), respectively. Anastomotic leak rates were 1.4, 18 and 38% after anterior resections for tumours of the upper, middle and lower thirds of the rectum. Both mortality (1.4 vs 3.8%) and the total number of complications (23 vs 39%) were less after anterior resection than after abdominoperineal excision of the rectum. In conclusion, increased use of low anterior resection for rectal carcinoma has not led to higher mortality or overall morbidity, but the high leak rate after very low anastomoses remains to be solved.


Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia.
Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) shortly after systemic infection and can result in the subsequent development of HIV-1-associated dementia (HAD) in a subset of infected individuals. Genetically compartmentalized virus in the CNS is associated with HAD, suggesting autonomous viral replication as a factor in the disease process. We examined the source of compartmentalized HIV-1 in the CNS of subjects with HIV-1-associated neurological disease and in asymptomatic subjects who were initiating antiretroviral therapy. The heteroduplex tracking assay (HTA), targeting the variable regions of env, was used to determine which HIV-1 genetic variants in the cerebrospinal fluid (CSF) were compartmentalized and which variants were shared with the blood plasma. We then measured the viral decay kinetics of individual variants after the initiation of antiretroviral therapy. Compartmentalized HIV-1 variants in the CSF of asymptomatic subjects decayed rapidly after the initiation of antiretroviral therapy, with a mean half-life of 1.57 days. Rapid viral decay was also measured for CSF-compartmentalized variants in four HAD subjects (t(1/2) mean = 2.27 days). However, slow viral decay was measured for CSF-compartmentalized variants from an additional four subjects with neurological disease (t(1/2) range = 9.85 days to no initial decay). The slow decay detected for CSF-compartmentalized variants was not associated with poor CNS drug penetration, drug resistant virus in the CSF, or the presence of X4 virus genotypes. We found that the slow decay measured for CSF-compartmentalized variants in subjects with neurological disease was correlated with low peripheral CD4 cell count and reduced CSF pleocytosis. We propose a model in which infiltrating macrophages replace CD4(+) T cells as the primary source of productive viral replication in the CNS to maintain high viral loads in the CSF in a substantial subset of subjects with HAD.


Investigating the coenzyme specificity of phenylacetone monooxygenase from Thermobifida fusca.
Type I Baeyer-Villiger monooxygenases (BVMOs) strongly prefer NADPH over NADH as an electron donor. In order to elucidate the molecular basis for this coenzyme specificity, we have performed a site-directed mutagenesis study on phenylacetone monooxygenase (PAMO) from Thermobifida fusca. Using sequence alignments of type I BVMOs and crystal structures of PAMO and cyclohexanone monooxygenase in complex with NADP(+), we identified four residues that could interact with the 2'-phosphate moiety of NADPH in PAMO. The mutagenesis study revealed that the conserved R217 is essential for binding the adenine moiety of the nicotinamide coenzyme while it also contributes to the recognition of the 2'-phosphate moiety of NADPH. The substitution of T218 did not have a strong effect on the coenzyme specificity. The H220N and H220Q mutants exhibited a ~3-fold improvement in the catalytic efficiency with NADH while the catalytic efficiency with NADPH was hardly affected. Mutating K336 did not increase the activity of PAMO with NADH, but it had a significant and beneficial effect on the enantioselectivity of Baeyer-Villiger oxidations and sulfoxidations. In conclusion, our results indicate that the function of NADPH in catalysis cannot be easily replaced by NADH. This finding is in line with the complex catalytic mechanism and the vital role of the coenzyme in BVMOs.


The relationship between the structure and activity of rat skeletal muscle mitochondria after thyroidectomy and thyroid hormone treatment.
The fine structure of rat gastrocnemius muscle fibers has been studied after changes were induced in the basal metabolic rate (BMR) by thyroidectomy and L-thyroxine administration under anabolic conditions. Biochemical analysis of skeletal muscle mitochondrial respiration and phosphorylation from the same tissue preparations has been summarized, details having been published earlier (3). As estimated from electron micrographs, the total amount of mitochondria from thyroidectomized animals was enlarged 1.5 times over that from normal controls. The total amount of mitochondria from thyroidectomized or normal animals made hypermetabolic with thyroxine was increased 2.5 to 3.5 times over that from their corresponding controls. In all cases, there was an increase in the mitochondrial population and the profile ratio of cristae to matrix was also considerably increased, thus indicating both relative and absolute enlargements of the entire surface of the cristae per unit fiber. The major structural changes persisted for at least 3 weeks after the cessation of thyroxine treatment, by which time the elevated mitochondrial respiratory and phosphorylative activity had declined to normal values. The hypertrophy and increase in mitochondrial population was more prominent in the perinuclear and subsacrolemmic regions near blood vessels than in the interstices of the fibrils. The very long interfibrillar mitochondria found in both the hypo- and hypermetabolic tissues are more likely to be derived from outgrowths of the original mitochondria rather than from a fusion of smaller ones. These findings are compatible with the ideas expressed elsewhere (see 1, 3, 10) that, under conditions close to the physiological, thyroid hormones control mitochondrial metabolic activity by a subtle alteration in mitochondrial composition with respect to their respiratory and phosphorylative constituents. The possible application of using thyroid hormones in the study of biogenesis of mitochondria and the synthesis of mitochondrial constituents are discussed.


Functional analysis of Survivin in spindle assembly in Xenopus egg extracts.
Survivin is a member of the inhibitor of apoptosis (IAP) protein family that serves critical roles in mitosis and cytokinesis. Many studies have suggested Survivin's involvement in spindle regulation, but direct biochemical evidence for this has been lacking. Using the cell-free system of Xenopus egg extracts, we tested whether Survivin was necessary for the assembly of metaphase spindles. Removal or inhibition of Xenopus Survivin causes the disruption in the formation of metaphase spindles. In particular, we observe the generation of microtubule (MT) asters or poorly formed shortened spindle structures. In the latter phenotype the spindle structures display a decrease pole-to-pole length and a reduction of MTs around the chromatin indicating that Survivin may promote the stabilization of MT-chromatin interactions. In addition, function analysis of Survivin's conserved phosphorylation site Thr34 (Thr43 in Xenopus) and tubulin-binding domain was also assessed in regulating spindle assembly. Treatment of Xenopus egg extracts with a recombinant Survivin mutant that contained an alanine residue substitution at Thr43 (SURT43A mutant) or that was missing the C-terminal tubulin-binding domain (SURCL mutant) produced an increased frequency of MT asters and shorten abnormal spindle structures in Xenopus egg extracts. Interestingly, a phosphomimetic mutation made at residue Thr43 of Survivin (SURT43E mutant) generated a high frequency of MT asters implying that premature 'activation' of Survivin may interfere with an early stage of spindle assembly. Taken together, we propose that Survivin is a necessary component of the mitotic spindle and its phosphorylation at residue Thr43 is important for Survivin function in spindle assembly.


Hepcidin-orchestrated Hemogram and Iron Homeostatic Patterns in Two Models of Subchronic Hepatic injury.
This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 μL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.


Neurotrophin-3 increases intracellular calcium in a rat insulin-secreting cell line through its action on a functional TrkC receptor.
Pancreatic beta cells and neuronal cells show a large number of similarities. For example, functional receptors for nerve growth factor are present in beta cells. Here we investigate whether TrkC, a neuronal high affinity receptor for neurotrophin-3, is expressed in the insulin-secreting cell line INS-1. We demonstrate the expression in INS-1 cells of mRNAs coding for TrkC identical in size to those found in the brain. As in neuronal cells, different alternatively spliced forms of TrkC mRNA, differing by the insertion of an alternative exon in their kinase domain, were expressed in INS-1 cells. TrkC protein is also expressed in INS-1 cells and is functional. Indeed, when INS-1 cells were treated with neurotrophin-3, TrkC became phosphorylated on tyrosine residues, and the expression of early response genes was induced. This activation of the receptor was paralleled by a rapid and transient increase in cytosolic free calcium due to an influx of extracellular calcium. Functional receptors for NT-3 are thus expressed in INS-1 cells. This cell line provides a new model for the study of NT-3 signal transduction and should be useful in the understanding of the role of neurotrophins in insulin-secreting cells.


Early-life trauma is associated with rapid eye movement sleep fragmentation among military veterans.
The role of sleep in the relations between early-life trauma and the development of adverse psychological trajectories is relatively unknown and was the primary aim of the present study. Military veterans were evaluated for posttraumatic stress disorder, combat exposure, trauma history, sleep quality, disruptive nocturnal behaviors, and a subsample completed overnight polysomnography that yielded objectively measured sleep parameters. When relevant variables were controlled, increased earlier-life traumatic event exposure was associated with increased rapid-eye-movement sleep (REMs) fragmentation, and increased REMs fragmentation was associated with increased later-life disruptive nocturnal behaviors. REMs fragmentation carried an indirect relation between earlier-life trauma and later-life disruptive nocturnal behaviors. Objectively measured sleep parameters were used to describe REMs fragmentation physiology. The current findings elucidate the important role that earlier-life trauma exposure may have in the development of REM sleep physiology, and how this altered sleep physiology may have dynamic influences on subsequent posttraumatic stress symptoms in adulthood.


Human rotavirus detection in stool specimens using enzyme-linked immunosorbent assays and latex agglutination test.
A total of 194 stool samples from sick and healthy children were tested by three commercial tests: two Rotavirus enzyme-linked immunosorbent assays (ELISA) and one latex agglutination test (LTX). The concordance, sensibility and specificity of these tests were calculated. The results suggest to consider as positive the samples reactive to two enzyme immunoassays at least. The latex test, although less sensitive than Enzygnost-Rotavirus and Rotazyme II, was found to be especially useful for the rapid diagnosis of rotavirus gastroenteritis when used to test the first available stool sample from acutely ill patients.


CpG-island methylation and epigenetic control of resistance to chemotherapy.
Aberrant methylation of CpG islands (CpG-rich regions of DNA associated with the promoters of many genes) is associated with transcriptional inactivation of genes involved in tumour development. Genes involved in key DNA damage response pathways, such as cell-cycle control, apoptosis signalling and DNA repair can frequently become epigenetically silenced and methylated in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, chemotherapy itself may exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Clinical trials of epigenetic therapies are now in progress, and epigenetic profiling using DNA methylation will provide guidance on optimization of the use of these therapies with conventional chemotherapy, as well as helping to identify patient populations who may particularly benefit from such approaches.


Characterization and function of pig intestinal sucrase-isomaltase and its separate subunits.
Papain-solubilized pig intestinal sucrase-isomaltase was purified to homogeneity in a four-step process with a yield of 50%. The substrate specificities of the two enzyme activities were studied together and separately after inactivation or inhibition of one of the activities. Michaelis constants, maximum velocities and time courses of hydrolysis of several substrates, in particular alpha-limit dextrins, were used to characterize this complex of alpha-glucosidases. The participation of the enzyme complex in the hydrolysis of alpha-limit dextrins and more generally in pathways for starch breakdown in the pig digestive tract is examined and discussed.


Tolerance development and arterial and venous tissue-/plasma levels of glyceryl trinitrate and glyceryl dinitrate in patients treated with nitroglycerin infusion.
Venous vessels (vena saphena magna) and arteries (left internal mammary artery) from patients treated with long-term ( > 24 h) intravenous infusions of nitroglycerin (CAS 55-63-0, glyceryl trinitrate, GTN) prior to coronary by-pass surgery were studied. Tissue concentrations of GTN and its dinitrate metabolites were determined as well as plasma-concentrations of GTN and glyceryl dinitrates (GDN's) on both the arterial and the venous side. The relaxant effect of GTN on the isolated vein preparations was studied and compared with those from two other groups of patients, one not exposed to GTN and the other exposed to a short-term infusion of GTN. Wide variations were found both in plasma and in tissue concentrations of GTN and GDN's on the venous and the arterial side. However, no extraction across the arterial-venous bed could be observed. Correlations were found between the dose given and the concentrations of drug and metabolites in both venous and arterial plasma as well as between 1,2-GDN in venous plasma and venous tissue, between 1,2-GDN in arterial plasma and arterial tissue and the same applied to 1,3-GDN on the arterial side. No correlations were found between the tissue concentrations of drug or metabolites and the relaxation induced by GTN in vitro. Venous vessels from patients treated with long-term infusions of GTN showed a pronounced decrease in relaxation as compared to vessels from patients not treated with nitroglycerin infusions and a slight decrease as compared to veins from patients treated with a shortterm infusion.


The usefulness of electromagnetic neuronavigation in the pediatric neuroendoscopic surgery.
Neuroendoscopy is applied to various intracranial pathologic conditions. But this technique needs informations for the anatomy, critically. Neuronavigation makes the operation more safe, exact and lesser invasive procedures. But classical neuronavigation systems with rigid pinning fixations were difficult to apply to pediatric populations because of their thin and immature skull. Electromagnetic neuronavigation has used in the very young patients because it does not need rigid pinning fixations. The usefulness of electromagnetic neuronavigation is described through our experiences of neuroendoscopy for pediatric groups and reviews for several literatures. Between January 2007 and July 2011, nine pediatric patients were managed with endoscopic surgery using electromagnetic neuronavigation (AxiEM, Medtronics, USA). The patients were 4.0 years of mean age (4 months-12 years) and consisted of 8 boys and 1 girl. Totally, 11 endoscopic procedures were performed. The cases involving surgical outcomes were reviewed. The goal of surgery was achieved successfully at the time of surgery, as confirmed by postoperative imaging. In 2 patients, each patient underwent re-operations due to the aggravation of the previous lesion. And one had transient mild third nerve palsy due to intraoperative manipulation and the others had no surgery related complication. By using electromagnetic neuronavigation, neuroendoscopy was found to be a safe and effective technique. In conclusion, electromagnetic neuronavigation is a useful adjunct to neuroendoscopy in very young pediatric patients and an alternative to classical optical neuronavigation.


Fact retrieval or compacted counting in arithmetic-A neurophysiological investigation of two hypotheses.
There is broad consensus on the assumption that adults solve single-digit multiplication problems almost exclusively by fact retrieval from memory. In contrast, there has been a long-standing debate on the cognitive processes involved in solving single-digit addition problems. This debate has evolved around two theoretical accounts. Proponents of a fact-retrieval account postulate that these are also solved through fact retrieval, whereas proponents of a compacted-counting account propose that solving very small additions (with operands between 1 and 4) involves highly automatized and unconscious compacted counting. In the present electroencephalography (EEG) study, we put these two accounts to the test by comparing neurophysiological correlates of solving very small additions and multiplications. Forty adults worked on an arithmetic production task involving all (nontie) single-digit additions and multiplications. Afterward, participants completed trial-by-trial strategy self-reports. In our EEG analyses, we focused on induced activity (event-related synchronization/desynchronization, ERS/ERD) in three frequency bands (theta, lower alpha, upper alpha). Across all frequency bands, we found higher evidential strength for similar rather than different neurophysiological processes accompanying the solution of very small addition and multiplication problems. In the alpha bands, evidence for similarity was even stronger when operand-1-problems were excluded. In two additional analyses, we showed that ERS/ERD can differentiate between self-reported problem-solving strategies (retrieval vs. procedure) and between very small n × 1 and n + 1 problems, demonstrating its high sensitivity to cognitive processes in arithmetic. The present findings support a fact-retrieval account, suggesting that both very small additions and multiplications are solved through fact retrieval. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


A Greener Stability-Indicating High-Performance Thin-Layer Chromatography Approach for the Estimation of Topiramate.
Despite various reported analytical methods for topiramate (TPM) analysis, greener analytical approaches are scarce in literature. As a consequence, the objective of the current research is to design a normal-phase stability-indicating high-performance thin-layer chromatography (SI-HPTLC) methodology for TPM analysis in marketed tablet dosage forms that is rapid, sensitive, and greener. TPM was derivatized densitometrically and analyzed at 423 nm in visible mode with anisaldehyde-sulfuric acid as the derivatizing agent. The greener SI-HPTLC technique was linear in the 30-1200 ng band-1 range. In addition, the suggested SI-HPTLC methodology for TPM analysis was simple, rapid, cheaper, precise, robust, sensitive, and environmentally friendly. The greener SI-HPTLC method was able to detect TPM along with its degradation products under acid, base, and oxidative degradation conditions. However, no TPM degradation was recorded under thermal and photolytic stress conditions. TPM contents in commercial tablet dosage forms were recorded as 99.14%. Using 12 different principles of green analytical chemistry, the overall analytical GREEnness (AGREE) score for the greener SI-HPTLC method was calculated to be 0.76, confirming the proposed normal-phase SI-HPTLC method's good greener nature. Overall, these results demonstrated that the suggested SI-HPTLC technique for TPM measurement in pharmaceutical products was reliable and selective.


The vestibular implant: quo vadis?
To assess the progress of the development of the vestibular implant (VI) and its feasibility short-term. A search was performed in Pubmed, Medline, and Embase. Key words used were "vestibular prosth*" and "VI." The only search limit was language: English or Dutch. Additional sources were medical books, conference lectures and our personal experience with per-operative vestibular stimulation in patients selected for cochlear implantation. All studies about the VI and related topics were included and evaluated by two reviewers. No study was excluded since every study investigated different aspects of the VI. Data was extracted by the first author from selected reports, supplemented by additional information, medical books conference lectures. Since each study had its own point of interest with its own outcomes, it was not possible to compare data of different studies. To use a basic VI in humans seems feasible in the very near future. Investigations show that electric stimulation of the canal nerves induces a nystagmus which corresponds to the plane of the canal which is innervated by the stimulated nerve branch. The brain is able to adapt to a higher baseline stimulation, while still reacting on a dynamic component. The best response will be achieved by a combination of the optimal stimulus (stimulus profile, stimulus location, precompensation), complemented by central vestibular adaptation. The degree of response will probably vary between individuals, depending on pathology and their ability to adapt.


Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages.
The submandibular glands, as major salivary glands, participate in rumen digestion in goats. Sialic acid, lysozyme, immunoglobulin A (IgA), lactoferrin and other biologically active substances secreted in the submandibular glands were reported in succession, which suggests that the submandibular gland may have immune functions in addition to participating in digestion. The aim of this study was to map the expression profile of differentially expressed genes (DEGs) at three different stages by transcriptome sequencing, screen immune-related genes and pathways by bioinformatics methods, and predict the immune function of submandibular glands at different developmental stages. Nine submandibular gland tissue samples were collected from groups of 1-month-old kids, 12-month-old adolescent goats and 24-month-old adult goats (3 samples from each group), and high-throughput transcriptome sequencing was conducted on these samples. The DEGs among the three stages were screened and analysed. Key genes and signalling pathways were selected via protein-protein interaction (PPI) network analysis. The results revealed 2,706, 2,525 and 52 DEGs between 1-month-old and 12-month-old goats, between 1-month-old and 24-month-old goats, and between 12-month-old and 24-month-old goats, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that most of the DEGs were enriched in immune- related GO terms and pathways. Based on functional enrichment analysis and network analysis, 10 genes (PTPRC, CD28, SELL, LCP2, MYC, LCK, ZAP70, ITGB2, SYK and CCR7), two signalling pathways (the T cell receptor signalling pathway and the NF-κβ signalling pathway) and eight GO terms (T cell receptor signalling pathway, neutrophil mediated immunity, B cell mediated immunity, regulation of alpha-beta T cell activation, positive regulation of T cell proliferation, regulation of leukocyte differentiation, positive regulation of antigen receptor-mediated signalling pathway, positive regulation of lymphocyte proliferation) that may play key roles in the immune functions of the goat submandibular glands at different developmental stages were identified. Moreover, we found that eight antibacterial peptide-encoding genes were downregulated in the tuberculosis and salivary secretion pathways, while all immunoglobulins were upregulated in 10 immune system pathways. These findings indicate that the submandibular glands may be important immunological organs during the growth process of goats and that the immune function of these glands gradually weakens with age up to 12 months but remains relatively stable after 12 months of age. Overall, this study will improve our understanding of transcriptional regulation related to goat submandibular gland immune function.


Different appearance and pathogenic roles of serum IgA against autologous IgG Fc and Fab in patients with IgA nephropathy.
The serum levels of IgA class antibodies against autologous IgG Fc and Fab fragments were measured by ELISA in 62 patients with primary IgA nephropathy (IgAN) and 20 normal healthy volunteers. Both antibodies were significantly higher in the patients (P less than 0.01). The total IgA levels were correlated with those of IgA anti-IgG Fc antibodies (IgA anti-Fc) (rs = 0.57, P less than 0.001), but not with those of the IgA anti-IgG Fab antibodies (IgA anti-Fab). A histopathological comparison revealed that the sera of patients with severe glomerulonephritis had significantly higher levels of IgA anti-Fc than those with milder lesions (P less than 0.01). On the other hand, no correlation was observed between the serum levels of IgA anti-Fab and the histopathological severity. A comparison before and after treatment in 12 patients demonstrated a significant decrease of IgA anti-Fc (P less than 0.01) and an increase of IgA anti-Fab (P less than 0.05) after the treatment. Size analysis in serial sera from 3 patients was performed using HPLC under neutral (pH = 7.0) and under acid (pH = 3.5) buffer conditions. A markedly increased ratio of both antibodies with the polymeric form was observed in the active phase. In the remission phase, the amounts of acid-dissociable polymeric form IgA anti-Fc were decreased. In contrast, high levels of polymeric form IgA anti-Fab continued to be observed in 2 patients at this phase. These results suggest that abnormally stimulated production of IgA class autoantibodies especially with the polymeric form against both IgG Fc and Fab fragments, occurs in IgAN, involving separate regulation with differing reactions to treatment and a distinct relationship between IgA anti-Fc and active histopathological lesions.


[Current status of transplantation medicine in the field of heart and lung transplantation].
Transplantation medicine in Germany is clearly structured and strictly regulated. In recent years, various legal changes have been implemented to improve organ donation. Nevertheless, the restricted availability of donor organs remains the main limitation of the treatment, also in the field of heart and lung transplantation. Both procedures have now become established treatment options for selected patients with end-stage organ failure. The aim is to improve the quality of life as well as survival. The success of the treatment largely depends on the selection of suitable recipients as well as optimal perioperative and postoperative management including a lifelong specialized follow-up. The complexity of the treatment requires a high degree of specialized knowledge and skills. This article summarizes the current state of transplantation medicine of thoracic organs with a focus on the new additional subspecialty of transplantation medicine.


GSP-1 genes are linked to the grain hardness locus (Ha) on wheat chromosome 5D.
An important determinant of wheat grain quality is the hardness of the grain. The trait is controlled by a major locus, Ha, on the short arm of chromosome 5D. Purified starch granules from soft-grained wheats have associated with them 15-kDa polypeptides called grain softness proteins (GSPs) or "friabilins." Genes that encode one family of closely related GSP polypeptides - GSP-1 genes - were mapped using chromosome substitution lines to the group 5 chromosomes. An F2 population segregating for hard and soft alleles at the Ha locus on a near-isogenic background was used in a single-seed study of the inheritance of grain softness and of GSP-1 alleles. Grain softness versus grain hardness was inherited in a 3:1 ratio. The presence versus absence of GSPs in single seed starch preparations was coinherited with grain softness versus hardness. This showed that grain softness is primarily determined by seed, and not by maternal, genotype. In addition, no recombination was detected in 44 F2 plants between GSP-1 restriction fragment length polymorphisms and Ha alleles. Differences between hard and soft wheat grains in membrane structure and lipid extractability have been described and, of the three characterized proteins that are part of the mixture of 15-kDa polypeptides called GSPs, at least two, and probably all three, are proteins that bind polar lipids. The data are interpreted to suggest that the Ha locus may encode one or more members of a large family of lipid-binding proteins.


Subcellular localization of rice leaf aryl acylamidase activity.
The intracellular localization of aryl acylamidase (aryl-acylamide amidohydrolase, EC 220.127.116.11) in rice (Oryza sativa L. var Starbonnet) leaves was investigated. The enzyme hydrolyzes and detoxifies the herbicide propanil (3,4-dichloropropionanilide) thereby accounting for immunity of the rice plant to herbicidal action. Fractionation of mesophyll protoplasts by differential centrifugation yielded the highest specific activity of amidase in the crude mitochondrial fraction. Further separation of density gradients of the silica sol Percoll also indicated that this enzyme was mitochondrial. By the use of biochemical markers, the purified mitochondrial fraction was shown to be substantially free of contamination from nuclei, chloroplasts, golgi, and plasma membranes. Subfractionation of the purified mitochondria suggests that this enzyme is located on the outer membrane.


Validity and Reliability of Interactive Virtual Reality in Assessing the Musculoskeletal System: a Systematic Review.
Assessment of the musculoskeletal system requires consideration of its integrated function with the nervous system. This may be assisted by using valid and reliable methods that simulate real-life situations. Interactive virtual reality (VR) technology may introduce various auditory and visual inputs that mimic real-life scenarios. However, evidence supporting the quality and strength of evidence regarding the adequacy of its psychometric properties in assessing the musculoskeletal function has not been evaluated yet. Therefore, this study reviewed the validity and reliability of VR games and real-time feedback in assessing the musculoskeletal system. Nine studies were included in quality assessment. Based on outcome measures, studies were categorized into range of motion (ROM), balance, reaction time, and cervical motion velocity and accuracy. The majority of the studies were of moderate quality and provided evidence of VR adequate concurrent and, in some cases, known-groups validity. Also, VR showed high intra-rater reliability for most of the measured outcomes. Based on the included studies, there is a limited promising evidence that interactive VR using games or real-time feedback is highly valid and reliable in assessing ROM in asymptomatic participants and patients with chronic neck pain and radial fracture. For the remaining outcomes, evidence is limited to draw a robust conclusion. Future studies are recommended to test VR psychometric properties in different patients' population using a rigor research methodology.


Elevated levels of interleukin-18 are associated with several indices of general and visceral adiposity and insulin resistance in women with polycystic ovary syndrome.
Our aim was to analyze levels of proinflammatory biomarker interleukin-18 (IL-18) in healthy controls and patients with polycystic ovary syndrome (PCOS) focusing on its association with obesity, clinical, hormonal, and metabolic characteristics. Fifty-eight patients with PCOS were enrolled in the study fulfilling the Rotterdam criteria and were matched for age, body mass index (BMI), and ethnicity with 30 healthy controls. Detailed anthropometric measurements, clinical investigations, hormonal and biochemical tests were obtained between the 3rd and 5th day of a menstrual cycle. A subanalysis of the PCOS group was performed separating patients into several groups according to a waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum IL-18 levels were measured using the ELISA method. Levels of IL-18 were similar between PCOS patients and controls. IL-18 was higher in overweight/obese women compared to normal-weight women when analyzing all participants together and separately PCOS or controls group (p < 0.001, p < 0.001, p = 0.01, respectively). Additionally, IL-18 levels were higher in high-WHtR and IR subgroups compared to low-WHtR (p < 0.001) and non-IR PCOS women (p < 0.001). PCOS women with high FAI had greater serum IL-18 levels than normal-FAI patients (p = 0.002). Levels of IL-18 correlated positively with most of the anthropometric and metabolic parameters. In multiple linear regression, age, waist circumference, and fasting insulin were independently related factors with IL-18. Elevated levels of IL-18 were related to several indices of general and visceral adiposity and insulin resistance in PCOS.


Hyperintense basal ganglia on T1-weighted MR images in patients receiving parenteral nutrition.
Patterns of intracranial signal intensity on magnetic resonance (MR) images were studied in nine patients undergoing long-term total parenteral nutrition therapy. The duration of therapy ranged from 5 months to 11 years (mean, 5.3 years). Symmetric increased signal intensity on T1-weighted MR images (hyperintense relative to white matter) was observed in the basal ganglia of all patients, without corresponding abnormality on T2-weighted images. Analysis of signal-intensity characteristics and distribution pattern suggests that the basis for these changes may be deposition of intravenously administered paramagnetic trace elements, especially manganese, and/or an astrogliotic reaction to such deposition.


Delays in diagnosis and treatment among children with cancer: Egyptian perspective.
Delayed diagnosis is one of the contributing factors to lower cure rates for cancer in low-income countries. This was a cross-sectional study of 138 children with cancer who were treated at the Pediatric Oncology Unit, Oncology Center of Mansoura University, Egypt. One hundred and sixteen patients were initially misdiagnosed. The median total delay was 37 days, including median patient/parent delay of 3 days and median physician delay of 28 days. The type of cancer significantly influenced the diagnostic delay. Patients' sex, level of parents' education, and residence did not significantly affect the median total delay, while patients aged < 5 years and those who had an initial provisional diagnosis of cancer had the shortest median total delay. We suggest implementation of continuing medical education programmes, improving access to diagnostic facilities, and facilitating referral to give priority to those with suspected cancer to shorten the time for cancer diagnosis.


That's not what you said the first time: A theoretical account of the relationship between consistency and accuracy of recall.
Over multiple response opportunities, recall may be inconsistent. For example, an eyewitness may report information at trial that was not reported during initial questioning-a phenomenon called reminiscence. Such inconsistencies are often assumed by lawyers to be inaccurate and are sometimes interpreted as evidence of the general unreliability of the rememberer. In two experiments, we examined the output-bound accuracy of inconsistent memories and found that reminisced memories were indeed less accurate than memories that were reported consistently over multiple opportunities. However, reminisced memories were just as accurate as memories that were reported initially but not later, indicating that it is the inconsistency of recall, and not the later addition to the recall output, that predicts lower accuracy. Finally, rememberers who exhibited more inconsistent recall were less accurate overall, which, if confirmed by more ecologically valid studies, may indicate that the common legal assumption may be correct: Witnesses who provide inconsistent testimony provide generally less trustworthy information overall.


Quetiapine Combined with Sodium Valproate in Patients with Alzheimer's Disease with Mental and Behavioral Symptoms Efficacy Observation.
Quetiapine combined with sodium valproate is an effective and more suitable drug treatment for Alzheimer's disease. At present, there are relatively few studies on the combined action mechanism of these two drugs. This study has certain practical value. Alzheimer's disease is a multifaceted, highly genetically heterogeneous neurodegenerative disease. The main clinical manifestations are memory loss, abnormal mental behavior, and loss of various cognitive functions. In order to improve the symptoms of patients with Alzheimer's disease, especially those with mental symptoms, this article combines quetiapine and sodium valproate, two commonly used drugs for the treatment of mental illnesses, and applies them to different levels of Alzheimer's and observes the results of the combination's curative effect. This article introduces Alzheimer's disease and its potential mental behaviors in the method section, and it also introduces the mechanism of action of quetiapine and sodium valproate. For the algorithm, this paper introduces a data mining algorithm to understand the effect of drug efficacy. In the experimental part, firstly, it introduces the experimental objects, the proportion of medicines, and the statistical methods. Secondly, this article covers adverse reactions, inflammatory factors and vascular endothelial indicators, Alzheimer's disease performance, MOAS score, treatment effect evaluation, and satisfaction surveys. It can be seen from the experiment that, in mental behavior, the experimental group decreased from 8.2 before treatment to 0.5, and the control group decreased from 7.1 before treatment to 2.6. It can be seen that the scores of the experimental group changed after receiving the treatment of quetiapine combined with sodium valproate.


Additivity of nonconscious affect: combined effects of priming and exposure.
Affect deriving from 2 independent sources--repeated exposure and affective priming--was induced, and the combined effects were examined. In each of 4 studies, participants were first shown 72 Chinese ideographs in which the frequency of exposure was varied (0, 1, or 3). In the second phase participants rated ideographs that were primed either positively, negatively, or not at all. The 4 studies were identical except that the exposure duration--suboptimal (4 ms) or optimal (1 s)--of both the initial exposure phase and the subsequent priming phase was orthogonally varied. Additivity of affect was obtained only when affective priming was suboptimal, suggesting that nonconscious affect is diffuse. Affect whose source was apparent was more constrained. Interestingly, increases in liking generated through repeated exposures did not differ as a function of exposure duration.


Inflammasome Activation in Pulmonary Arterial Hypertension.
Inflammasomes are multi-protein complexes that sense both infectious and sterile inflammatory stimuli, launching a cascade of responses to propagate danger signaling throughout an affected tissue. Recent studies have implicated inflammasome activation in a variety of pulmonary diseases, including pulmonary arterial hypertension (PAH). Indeed, the end-products of inflammasome activation, including interleukin (IL)-1β, IL-18, and lytic cell death ("pyroptosis") are all key biomarkers of PAH, and are potentially therapeutic targets for human disease. This review summarizes current knowledge of inflammasome activation in immune and vascular cells of the lung, with a focus on the role of these pathways in the pathogenesis of PAH. Special emphasis is placed on areas of potential drug development focused on inhibition of inflammasomes and their downstream effectors.


Differential cardiac geometry during pregnancy in lean versus obese mice.
Pregnancy is a sensitive window where factors adversely affecting maternal cardiac health may leave women vulnerable to cardiovascular disease (CVD) later in life. However, it is not clear how cardiac changes during pregnancy influence long-term cardiovascular health. Obesity, an independent risk factor for CVD, promotes adverse cardiac remodeling. Effects of obesity-mediated cardiac remodeling concurrent with physiologic cardiac hypertrophy of pregnancy are not well-studied. Female C57BL/6J mice (8 weeks old) were fed a high fat (HF; 60% kcal from fat) or a control low fat (LF; 10% kcal from fat) diet for 8 weeks, then were crossed with male mice to become pregnant (P) or remained non-pregnant (NP) controls. After 18 days, cardiac morphology and function was quantified by echocardiography in LF and HF P and NP mice. Lean mice had increased left ventricular (LV) mass and LV end-diastolic diameter with pregnancy. In contrast, although LV mass was greater with obesity, it was not augmented with pregnancy in obese mice. Further, pregnant obese mice had decreased LV chamber diameter and increased relative wall thickness compared to lean mice. We report a differential cardiac geometry during pregnancy in lean versus obese mice in a mouse model of diet-induced obesity. These data suggest obesity during pregnancy promotes concentric remodeling, versus eccentric remodeling in lean mice. Adverse effects of obesity on cardiac remodeling during pregnancy may be an important contributor to subsequent maternal cardiovascular risk.


[Stress myocardial gammatomography in the diagnosis of multivessel coronary disease].
The aim of the study was to evaluate the diagnostic yield of 99m-Technetium-methoxy-isobutyl-isonitrile (MIBI) SPET for identification of individual coronary artery disease and in the prediction of multivessel involvement. Stress/rest myocardial SPET and coronary arteriography were evaluated in 231 consecutive patients (age 58 +/- 10 years, 26% women) without prior myocardial infarction. 149 patients had coronary narrowing > 50%: 104 with multivessel disease and 45 with one vessel disease. Tomographic stress defect score was obtained by semiquantitative analysis (maximal score 65). Univariate and multivariate analysis was performed to identify discriminant parameters between one vessel and multivessel patients. The sensitivity and specificity for the identification of individual artery disease was 74% and 85% for left anterior descending artery, 79% and 85% for right coronary and 45% and 96% for circumflex artery. In the prediction of multivessel involvement the sensitivity was 65%, specificity 87%, positive predictive value 81% and negative predictive value 76%. In the bivariate analysis, four parameters differed significantly between one vessel and multivessel disease patients: ST downslope > 1 mm (p = 0.01), ST downslope/heart rate corrected (p = 0.005), reversible defects in two or more regions (p = 0.009) and SPET score (p = 0.002). In the multivariate analysis the probability of multivessel disease was 90% when ST depression > 1 mm and SPET score > 20 were associated and the probability was lowered to 16% when these criteria were not present. Myocardial SPET with MIBI offers an accurate localization of individual coronary artery disease, mainly in left anterior descending artery and right coronary artery lesions. Combined evaluation of ST depression and extension of myocardial stress defects improved prediction of multivessel involvement.


Anosognosia and confabulation during the Wada test.
Feinberg et al. proposed that right-hemisphere-damaged stroke patients with anosognosia for hemiplegia (AHP) confabulate seeing stimuli on the left side but those without AHP admit to having inadequate visual information. This study examines the relationship between AHP and confabulation using selective anesthesia of the cerebral hemispheres. Seventeen patients with intractable epilepsy were tested during intracarotid methohexital infusion. For half of the trials, subjects were stimulated on their paretic hand with a material (sandpaper, metal, or cloth), and for the remaining trials they were not stimulated. The subjects were trained to use a pointing response to indicate if they been stimulated and the type of material they had felt. Admission of uncertainty was defined as pointing to a question mark. Confabulation was defined as any material response to a no-touch trial. During anesthesia of either hemisphere, subjects with and without AHP confabulated responses. The AHP and non-AHP groups did not differ in admission of uncertainty. Our results support the postulate that confabulation and AHP are independent disorders, and therefore confabulation cannot fully account for AHP.


Fast response Fabry-Perot interferometer microfluidic refractive index fiber sensor based on concave-core photonic crystal fiber.
We report a fast response microfluidic Fabry-Perot (FP) interferometer refractive index (RI) fiber sensor based on a concave-core photonic crystal fiber (CPCF), which is formed by directly splicing a section CPCF with a section of single mode fiber. The CPCF is made by cleaving a section of multimode photonic crystal fiber with an axial tension. The shallow concave-core of CPCF naturally forms the FP cavity with a very short cavity length. The inherent large air holes in the cladding of CPCF are used as the open channels to let liquid sample come in and out of FP cavity. In order to shorten the liquid channel length and eliminate the harmful reflection from the outside end face of the CPCF, the CPCF is cleaved with a tilted tensile force. Due to the very small cavity capacity, the short length and the large sectional area of the microfluidic channels, the proposed sensor provides an easy-in and easy-out structure for liquids, leading to great decrement of the measuring time. The proposed sensor exhibits fast measuring speed, the measuring time is less than 359 and 23 ms for distilled water and pure ethanol, respectively. We also experimentally study and demonstrate the superior performances of the sensor in terms of high RI sensitivity, good linear response, low temperature cross-sensitivity and easy fabrication.


Nociceptin/orphanin FQ causes non-quantal slowing of respiratory rhythm in brainstem-spinal cord preparation from newborn rat.
Nociceptin/orphanin FQ (N/OFQ) is the endogenous agonist of the N/OFQ peptide receptor, an inhibitory G protein-coupled receptor. N/OFQ acts as a neuromodulator to depress respiratory rhythm in the brainstem. Although the mechanisms of respiratory rhythm generation remain poorly understood, the pre-inspiratory neuron (Pre-I) and the pre-Bötzinger complex (preBötC) inspiratory neuron (Insp) network in the rostral ventrolateral medulla (RVLM) have been proposed to be essential for respiratory rhythm generation. Opioids presumably cause quantal slowing via selective depression of preBötC Insps. However, it is unclear whether N/OFQ depresses respiratory rhythm via the same mechanism. In this study, using in vitro newborn rat en bloc preparations, we examined the slowing pattern of N/OFQ (quantal or non-quantal) and the effects of N/OFQ on the extracellularly recorded discharge of Pre-Is and Insps in the RVLM. N/OFQ caused non-quantal slowing with a synchronous decrease in burst rates of Insps and of C4 discharge whereas the intraburst spike number in Insps remained unchanged. It also caused a significant decrease in burst rates and intraburst spike numbers in Pre-Is, while the 1:1 coupling of Pre-Is bursts to C4 bursts was preserved. When superfusate K(+) was elevated from 6.2 to 11.2mM, Pre-I activity was increasingly uncoupled from C4 bursts. After the application of N/OFQ in a high [K(+)] superfusate, the 1:1 coupling of Pre-Is to C4 bursts was restored. We conclude that N/OFQ suppresses burst and spike generation of Pre-Is, and that suppression of Pre-Is activity with synchronous coupling to the Insps network contributes to N/OFQ-induced non-quantal slowing.


Interrelationships and evolution of the tapeworms (Platyhelminthes: Cestoda).
Interrelationships of the tapeworms (Platyhelminthes: Cestoda) were examined by use of small (SSU) and large (LSU) subunit ribosomal DNA sequences and morphological characters. Fifty new complete SSU sequences were added to 21 sequences previously determined, and 71 new LSU (D1-D3) sequences were determined for the complementary set of taxa representing each of the major lineages of cestodes as currently understood. New sequences were determined for three amphilinidean taxa, but were removed from both alignments due to their excessively high degree of divergence from other cestode sequences. A morphological character matrix coded for supraspecific taxa was constructed by the modification of matrices from recently published studies. Maximum-parsimony (MP) analyses were performed on the LSU, SSU, LSU+SSU, and morphological data partitions, and minimum-evolution (ME) analyses utilizing a general time reversible model of nucleotide substitution including estimates of among-site rate heterogeneity were performed on the molecular data partitions. Resulting topologies were rooted at the node separating the Gyrocotylidea from the Eucestoda. The LSU data were found to be more informative than the SSU data and were more consistent with inferences from morphology, although nodal support was generally weak for most basal nodes. One class of transitions was found to be saturated for comparisons between the most distantly related taxa (gyrocotylideans vs cyclophyllideans and tetrabothriideans). Differences in the topologies resulting from MP and ME analyses were not statistically significant. Nonstrobilate orders formed the basal lineages of trees resulting from analysis of LSU data and morphology. Difossate orders were basal to tetrafossate orders, the latter of which formed a strongly supported clade. A clade including the orders Cyclophyllidea, Nippotaeniidea, and Tetrabothriidea was supported by all data partitions and methods of analysis. Paraphyly of the orders Pseudophyllidea, Tetraphyllidea, and Trypanorhyncha was consistent among the molecular data partitions. Inferences are made regarding a monozoic (nonsegmented) origin of the Eucestoda as represented by the Caryophyllidea and for the evolution of the strobilate and acetabulate/tetrafossate conditions having evolved in a stepwise pattern.


Stoichiometry of Kir channels with phosphatidylinositol bisphosphate.
Phosphatidylinositol bisphosphate (PIP(2)) is the most abundant phosphoinositide in the plasma membrane of cells and its interaction with many ion channel proteins has proven to be a critical factor enabling ion channel gating. All members of the inwardly rectifying potassium (Kir) channel family depend on PIP(2) for their activity, displaying distinct affinities and stereospecificities of interaction with the phosphoinositide. Here, we explored the stoichiometry of Kir channels with PIP(2). We first showed that PIP(2) regulated the activity of Kir3.4 channels mainly by altering their bursting behavior. Detailed burst analysis indicates that the channels assumed up to four open states and a connectivity of four between open and closed states depending on the available PIP(2) levels. Moreover, by controlling the number of PIP(2)-sensitive subunits in the stoichiometry of a tetrameric Kir2.1 channel, we showed that characteristic channel activity was obtained when at least two wild-type subunits were present. Our studies support a kinetic model for gating of Kir channels by PIP(2), where each of the four open states corresponds to the channel activated by one to four PIP(2) molecules.


Office and ambulatory blood pressure-lowering effects of combination valsartan/hydrochlorothiazide vs. hydrochlorothiazide-based therapy in obese, hypertensive patients.
The authors evaluated the blood pressure (BP)-lowering effects of combination valsartan/hydrochlorothiazide (HCTZ) vs. amlodipine/HCTZ in a 16-week, double-blind, randomized, forced-titration study and ambulatory BP monitoring (ABPM) substudy involving centrally obese hypertensive patients 40 years and older. Patients were started on valsartan/HCTZ 160/12.5 mg or HCTZ 12.5 mg monotherapy, force-titrated at week 4 to valsartan/HCTZ 320/25 mg and HCTZ 25 mg, respectively. The HCTZ group initiated amlodipine 5 mg at week 8 and 10 mg at week 12. A subset of patients had 24-hour ABPM at baseline and weeks 8 and 16. At week 16 in the intent-to-treat population (n=401), valsartan/HCTZ and amlodipine/HCTZ lowered office systolic BP (-30.6 vs. -28.3 mm Hg; P=.14). In the ABPM subgroup (n=111), valsartan/HCTZ was more effective than amlodipine/HCTZ in reducing 24-hour systolic BP (-20.6 vs. -14.5 mm Hg; P=.011). In obese hypertensive patients, valsartan/HCTZ reduced office BP similar to amlodipine/HCTZ but lowered 24-hour systolic BP more.


The genetic control of arista lateral morphogenesis in Drosophila.
The sensory bristles and epidermal hairs of Drosophila have proven to be valuable model cell types for studying the role of the cytoskeleton in cellular morphogenesis. We have recently begun to use the arista laterals as a third model cell type. The laterals display a combination of bristle and hair characteristics and provide a system where we can compare the relative importance of specific genes and subcellular structures for the morphogenesis of different polarized cellular extensions. We have characterized the lateral phenotype of a collection of mutations selected because of their phenotypes in hairs and bristles. In many but not all ways the lateral phenotypes are similar to the hair and bristle phenotypes. We provide compelling genetic evidence for the importance of the actin cytoskeleton in lateral elongation, shaping and integrity. Our observations provide evidence that defects in actin bundling can destabilize laterals so that they split during growth. Temperature shift experiments suggest that a defect in lateral initiation can lead to subsequent splitting. These observations provide a link between multiple hair and lateral cells forming by both multiple initiation events and by the splitting of individual cellular extensions. We also found that mutations that lead to lateral splitting typically alter the stereotypic arrangement of actin filament bundles and microtubules in laterals.


[Application of Raman spectroscopy in the stomatology].
Raman spectroscopy is an optical technology based on the theory of Raman scattering, which is generally used in the research of medical and biological science. Raman spectroscopy can be used to detect the molecular structures and components of proteins, lipids, DNA, and other biological molecules, and provide substantial information about molecules. Thus, Raman spectroscopy is generally considered a "molecular fingerprint", and it has exceptional advantages in medical research. Moreover, this technique can reflect the changes in molecular structures and detect the alterations of chemical constituents in the samples. Raman spectroscopy, given its high sensitivity and specificity in the detection of the biological samples, has been successfully used to detect and diagnose diseases in numerous sites, such as skin, oral mucosa, breast, head, and neck. In this paper, we introduce the application of Raman spectroscopy in stomatology by conducting a review of the literature.


Treatment of parainfluenza virus type 3 bronchiolitis and pneumonia in a cotton rat model using topical antibody and glucocorticosteroid.
Treatment of parainfluenza virus type 3 bronchiolitis and pneumonia in the cotton rat using topical IgG cleared infectious virus within 24 h but did not reduce pulmonary pathology. Treatment with topical triamcinolone acetonide dramatically reduced pathology but increased virus titers >10-fold. Combined therapy, however, demonstrated both favorable effects. Animals treated 3,4, and 5 days after infection showed a rebound of lung lesions to levels of untreated animals without reappearance of virus, but treatment through 8 days resulted in virus-free lungs without rebound of lesions. There was no difference in response to rechallenge 21 days after the original infection between treated and untreated animals. Combined antiviral and antiinflammatory therapy looks promising for viral bronchiolitis and pneumonia, but further questions relating to mechanism of action and to range of infections that can be treated in this fashion will need to be answered in animal models.


Endocervical tubal metaplasia and adenocarcinoma in situ: role of immunohistochemistry for carcinoembryonic antigen and vimentin in differential diagnosis.
Eighteen cases of endocervical tubal metaplasia (tubal metaplasia) and 16 cases of adenocarcinoma in situ were reacted immunohistochemically for carcinoembryonic antigen (CEA) and vimentin. Whereas CEA was more frequently positive in adenocarcinoma in situ cases (63%) than in tubal metaplasia cases (39%), vimentin was not expressed in adenocarcinoma but was positive in 78% of cases of tubal metaplasia.


Measurement of antioxidant activity and antioxidant compounds under versatile extraction conditions: II. The immuno-biochemical antioxidant properties of black sour cherry (Prunus cerasus) extracts.
Retrospectively, we have measured the antioxidant activity and a variety of antioxidant compounds under versatile extraction conditions of sweet cherry (Prunus avium) extracts. Further in this study, in order to understand the biochemical constituents and antioxidant activities of a variety of extracts of black sour cherries (P. cerasus), a related species, antioxidant compounds, including L-ascorbic acid (vitamin C), phenols, flavonoids, and anthocyanins, and the total antioxidant activity were simultaneously measured under varying extraction conditions (mild heating and brief microwave exposure) for: i) whole juice extracts (WJE), ii) methanol-extracted juice (MEJ), iii) ddH2O-extracted pomace (dPOM), and iv) methanol-extracted pomace (mPOM). The antioxidant activity for WJE was substantially increased with mild and prolonged exposure to either heating or microwave, such that the % inhibition against 2,2-diphenyl-1-bspicrylhydrazyl (DPPH) followed a positive correlation (heating, 5-20 min.; microwave, 1-2 min.), insignificant with MEJ and dPOM, whereas with mPOM there was sharp downregulation. L-Ascorbic acid content was not affected with mild to prolonged heating or microwave exposure (WEJ and mPOM), except a mild increase with MEJ and dPOM. Similarly, total phenols assessed showed no significant variations, as compared with control extracts, except a mild decrease with exposure for mPOM. In a manner similar to L-ascorbic acid, total flavonoid content was increased under varying conditions for WEJ and MEJ, and slightly decreased for dPOM and mPOM. On the other hand, anthocyanins showed differential variations with exposure (up- and downregulation). Assessment of extraction means as compared with WJE revealed sharp increase in the antioxidant activity for MEJ, dPOM and mPOM, significant increase in L-ascorbic acid, total phenol, and flavonoid contents for MEJ, dPOM and mPOM, and mild decrease in anthocyanin contents for MEJ, dPOM, and mPOM. These results substantiate the measurable antioxidant activities and contents of P. cerasus extracts under versatile conditions of mild exposure, an effect bearing significant fluctuation with biochemical properties. Since many of those molecules are known to have immuno-biochemical constituencies, antioxidant compounds in sour cherries may have putative antiinflammatory potential and applications in medicinal chemistry, corroborating the observation of regulating and attenuating the growth of microorganisms of medical importance in vitro.


Results of radiotherapy for localised prostatic carcinoma treated at the Prince of Wales Hospital, Sydney.
Between 1980 and 1986 a total of 218 patients with localised prostatic carcinoma received radical pelvic radiotherapy at The Prince of Wales Hospital, Sydney. The mean follow-up time was 4.6 years. The five-year actuarial overall survival rate was 63% (death from all causes) and the five-year cancer-specific survival rate was 73% (death from or with prostate cancer). The overall survival was significantly worse with more advanced clinical stage of the disease (P = 0.003) and with poor histological differentiation of the tumour (P = 0.001). The five-year actuarial rate for local control of tumour in the pelvis was 84%. Late treatment-related complications (occurring or persisting beyond six months) were mild or moderate and the majority settled with conservative management. Only five patients experienced severe complications (necessitating surgical treatment). Of 42 patients with normal potency documented before radiotherapy who were not subsequently hormonally manipulated 23 (55%) retained potency at two years. These results for definitive radiotherapy for localised prostatic carcinoma indicate good local control with minimal morbidity and compare favourably with other published results.


[Anesthetic management of a patient with microcephaly associated with cerebral atrophy].
We describe the management of a 35-year-old female with microcephaly, cerebral atrophy especially in frontal lobes, dwarfism and severe mental retardation. The patient underwent open reduction of fracture of the humerus neck suffered from traffic accident. Authors could not find any article on the anesthetic management of microcephaly but could locate some about mentally retarded patients claiming the difficulty in anesthetic induction as well as emergence and frequent incidence of convulsions. We anesthetized the patient with modified NLA with nitrous oxide-oxygen and interestingly very small doses of fentanyl (1.7 micrograms.kg-1) were required. The anesthetic and surgical courses were uneventful. The patient emerged immediately with intravenously administered naloxone and flumazenil with no excitement nor convulsion. We conclude that fentanyl is the drug of choice for mentally retarded patient with microcephaly and smaller doses per kg.weight are sufficient for orthopedic surgery.


Enhanced early vascular permeability in gelatinase B (MMP-9)-deficient mice: putative contribution of COX-1-derived PGE2 of macrophage origin.
Increased vascular permeability leading to vascular leakage is a central feature of all inflammatory reactions and is critical for the formation of an inflammatory exudate. The leakage occurs because of gap formation between endothelial cells and breakdown of the basement membrane barriers. The present study aimed to investigate the role of gelatinase B [matrix metalloproteinase 9 (MMP-9)], known to be involved in neutrophil exudation, in changes of vascular permeability at the early stages of acute zymosan peritonitis. We show that although MMP-9 is being released already within the first minutes of peritonitis, its lack, induced pharmacologically or genetically, does not decrease but rather increases vasopermeability. In mice treated with an inhibitor of gelatinases (A and B), a tendency to increased vasopermeability existed, and in MMP-9-/- mice [knockout (KO)], the difference was statistically significant in comparison with their controls. Moreover, in intact KO mice, significantly augmented production of prostaglandin E(2) (PGE(2)) of cyclooxygenase 1 (COX-1) origin was detected, and depletion of peritoneal macrophages, but not mast cells, decreased vasopermeability in KO mice. Thus, the increase of vasopermeability observed on KO mice is a result of the increased production of COX-1-derived PGE(2) by peritoneal macrophages. We conclude that genetic deficiency in gelatinase B might lead to the development of a compensatory mechanism involving the COX pathway.