Changes in blood pressure after Messenger RNA COVID-19 vaccination.

The SARS-Cov-2 (COVID-19) vaccination began in Malaysia in March 2021 among frontliners and healthcare workers. Everyone at our hospital received the tozinameran (BNT162b2) Messenger RNA COVID-19 vaccine. Although hypertension has not been mentioned explicitly as an adverse event, concerns were raised after some healthcare staff observed an increase in their blood pressures. In response to that, the hospital began collecting vital signs during second-dose appointments. Vital signs were measured before, immediately after and 15-30 minutes postvaccination. We report our findings from the institution-wide effort to monitor changes in blood pressure among its staff and respond to any possible unwanted events.

Transfer of fresh or frozen embryos: a randomised controlled trial.

STUDY QUESTION: Is IVF with frozen-thawed blastocyst transfer (freeze-all strategy) more effective than IVF with fresh and frozen-thawed blastocyst transfer (conventional strategy)? SUMMARY ANSWER: The freeze-all strategy was inferior to the conventional strategy in terms of cumulative ongoing pregnancy rate per woman. WHAT IS KNOWN ALREADY: IVF without transfer of fresh embryos, thus with frozen-thawed embryo transfer only (freeze-all strategy), is increasingly being used in clinical practice because of a presumed benefit. It is still unknown whether this new IVF strategy increases IVF efficacy. STUDY DESIGN, SIZE, DURATION: A single-centre, open label, two arm, parallel group, randomised controlled superiority trial was conducted. The trial was conducted between January 2013 and July 2015 in the Netherlands. The intervention was one IVF cycle with frozen-thawed blastocyst transfer(s) versus one IVF cycle with fresh and frozen-thawed blastocyst transfer(s). The primary outcome was cumulative ongoing pregnancy resulting from one IVF cycle within 12 months after randomisation. Couples were allocated in a 1:1 ratio to the freeze-all strategy or the conventional strategy with an online randomisation programme just before the start of down-regulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were subfertile couples with any indication for IVF undergoing their first IVF cycle, with a female age between 18 and 43 years. Differences in cumulative ongoing pregnancy rates were expressed as relative risks (RR) with 95% CI. All outcomes were analysed following the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Two-hundred-and-five couples were randomly assigned to the freeze-all strategy (n = 102) or to the conventional strategy (n = 102). The cumulative ongoing pregnancy rate per woman was significantly lower in women allocated to the freeze-all strategy (19/102 (19%)) compared to women allocated to the conventional strategy (32/102 (31%); RR 0.59; 95% CI 0.36-0.98). LIMITATIONS, REASONS FOR CAUTION: As this was a single-centre study, we were unable to study differences in study protocols and clinic performance. This, and the limited sample size, should make one cautious in using the results as the basis for definitive policy. All patients undergoing IVF, including those with a poor prognosis, were included; therefore, the outcome could differ in women with a good prognosis of IVF treatment success. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that there might be no benefit of a freeze-all strategy in terms of cumulative ongoing pregnancy rates. The efficacy of the freeze-all strategy in subgroups of patients, different stages of embryo development, and different freezing protocols needs to be further established and balanced against potential benefits and harms for mothers and children. STUDY FUNDING/COMPETING INTEREST(S): The Netherlands Organisation for Health Research and Development (ZonMW grant 171101007). S.M., F.M. and M.v.W. stated they are authors of the Cochrane review 'Fresh versus frozen embryo transfers in assisted reproduction'. TRIAL REGISTRATION NUMBER: Dutch Trial Register, NTR3187. TRIAL REGISTRATION DATE: 9 December 2011. DATE OF FIRST PATIENT'S ENROLMENT: 8 January 2013.

Age-related gene expression profiles of immature human oocytes.

STUDY QUESTION: What is the difference between the gene expression profiles of single human germinal vesicle (GV) oocytes from women of different ages? SUMMARY ANSWER: There were no statistically significant differences in gene expression profiles of human GV oocytes from women of different ages (range: 25-43). WHAT IS KNOWN ALREADY: It is well established that reproductive capacity declines as women age, which is attributed to oocyte quality since this decline is counterbalanced in older women receiving young donor oocytes. Altered gene expression of human oocytes at different stages of development in relation to female age is one of the suggested mechanisms that could explain the decrease in oocyte quality. STUDY DESIGN, SIZE, DURATION: Between 2012 and 2014, 40 human GV oocytes of 40 women were obtained during follicular aspiration as part of routine ICSI treatment. Gene expression profiles of 38 GV oocytes were determined in four different age groups: 25-30, 31-35, 36-38 and 39-43 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: GV oocytes were donated for research and frozen between 3.5 and 7.5 h after follicular aspiration. Subsequently, GV oocytes were thawed and prepared for gene expression profile analysis using Agilent microarrays containing ~42 000 Human Gene Expression probe-sets. Gene expression profiles were visualized by hierarchical clustering and the top 500 most differing genes were determined by multidimensional scaling (MDS). Transcripts were analysed in a class comparison between the four age groups and for indicators of biological age: antral follicle count (AFC) and the total dosage of FSH needed for ovarian stimulation. Individual transcripts were analysed using linear regression. A false discovery rate <0.05 was considered statistically significant. MAIN RESULTS AND THE ROLE OF CHANCE: Visualization of gene expression profiles of GV oocytes with hierarchal clustering and MDS demonstrated no clear grouping of samples based on female age, AFC or FSH dosage. The gene expression profile of GV oocytes classified in four age groups revealed no significantly differentially expressed genes between the four different age groups. There were also no significantly differentially expressed genes in the linear regression analysis for individual transcripts against age. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Immature (GV) oocytes obtained from ovarian stimulation cycles were used. Findings may therefore differ for oocytes at other developmental stages and for in-vivo matured oocytes under physiological conditions. Due to our relatively large, but still limited study sample (40 GV oocytes), we cannot exclude that there might be smaller age-related gene-expression differences, i.e. due to a lack of power. WIDER IMPLICATIONS OF THE FINDINGS: We did not find an effect of female age on gene expression profiles of individual human GV oocytes. Other studies have suggested that gene-expression profiles are affected in mature oocytes, which might imply that female age affects oocyte maturation. Alternatively, other mechanisms in human oocytes might cause the age-related fertility decline. STUDY FUNDING/COMPETING INTEREST(S): This study received no external funding and there are no competing interests.

Factors affecting the gene expression of in vitro cultured human preimplantation embryos.

STUDY QUESTION: What is the relative effect of common environmental and biological factors on transcriptome changes during human preimplantation development? SUMMARY ANSWER: Developmental stage and maternal age had a larger effect on the global gene expression profile of human preimplantation embryos than the culture medium or oxygen concentration used in in vitro culture. WHAT IS KNOWN ALREADY: Studies on mouse and bovine embryos have shown that different conditions in the in vitro culture of embryos can lead to changes in transcriptome profiles. For humans, an effect of developmental stage on the transcriptome profile of embryos has been demonstrated, but studies on the effect of maternal age or culture conditions are lacking. STUDY DESIGN, SIZE, DURATION: Donated, good quality, day 4 cryopreserved human preimplantation embryos (N = 89) were randomized to be cultured in one of two culture media (G5 medium or HTF medium) and one of two oxygen concentrations (5% or 20%), with stratification for maternal age. Next to these variables, developmental stage after culture was taken into account in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos that developed to morula or blastocyst stage during these 2 days whose amplified mRNA passed our quality control criteria for microarray hybridization were individually examined for genome-wide gene expression (N = 37). MAIN RESULTS AND THE ROLE OF CHANCE: Based on the number of differentially expressed genes (DEGs), developmental stage (3519 DEGs) and maternal age (1258 DEGs) had a larger effect on the global gene expression profile of human preimplantation embryos than either tested culture medium (596 DEGs) or oxygen concentration (492 DEGs) used during in vitro culture. Interactions between the factors were found, indicating that culture conditions might have a different effect depending on the developmental stage or the maternal age of the embryos. Affected pathways included metabolism, cell cycle processes and oxidative phosphorylation. LIMITATIONS, REASONS FOR CAUTION: Culture of embryos for only 2 days might have limited the effect on global gene expression by the investigated culture conditions. Earlier stages of development (Day 0 until Day 4) were not analyzed and these embryos might respond differently to the experimental conditions. The freezing and thawing procedures might have had an effect on gene expression. RT-PCR validation was not performed due to scarcity of the material. WIDER IMPLICATIONS OF THE FINDINGS: Our results show that when studying gene expression in single human preimplantation embryos under various experimental conditions, one should take into account the confounding effect of biological variables, such as developmental stage and maternal age. This makes these experiments different from gene expression experiments where these variables can be tightly controlled, for example when using cell lines. STUDY FUNDING/COMPETING INTERESTS: This study received no external funding and there were no competing interests.

Diagnostic accuracy of the BACs-on-Beads™ assay versus karyotyping for prenatal detection of chromosomal abnormalities: a retrospective consecutive case series.

OBJECTIVE: To evaluate the diagnostic performance of the BACs-on-Beads(™) (BoBs(™)) assay for prenatal detection of chromosomal abnormalities. DESIGN: Retrospective study. SETTING: Tertiary prenatal diagnosis centre. POPULATION: Women referred for prenatal diagnosis. METHODS: We retrieved 2153 archived DNA samples collected between January 2010 and August 2011 for the BoBs(™) assay. These samples had previously been tested by quantitative fluorescence polymerase chain reaction (QF-PCR) and karyotyping. In the BoBs(™) assay a sample was defined as normal disomic when the ratio of the fluorescence intensities in a chromosome locus lay within the threshold (mean ratio ± 2SD), and as deleted or duplicated when the ratio was below the lower threshold (0.6-0.8) or above the upper threshold (1.3-1.4), respectively. The BoBs(™) results were further validated by microarray and compared in a blinded manner with the original QF-PCR and karyotyping results. MAIN OUTCOME MEASURES: Concordance of any numerical, structural, and submicroscopic chromosomal abnormalities between the methods. RESULTS: BACs-on-Beads(™) was similar to karyotyping and QF-PCR in detecting trisomy 13, trisomy 18, trisomy 21, and sex chromosomal aneuploidies, and superior to QF-PCR in detecting major structural abnormalities (53.3 versus 13.3%) and mosaicism (28.6 versus 0%) involving chromosomal abnormalities other than the common aneuploidies. BoBs(™) detected six microdeletion syndromes missed by karyotyping and QF-PCR; however, BoBs(™) missed two cases of triploidy identified by QF-PCR. Therefore, the sensitivity of BoBs(™) is 96.7% (95% CI 92.6-98.7%), and its specificity is 100% (95% CI 99.8-100%). CONCLUSIONS: BACs-on-Beads(™) can replace QF-PCR for triaging in prenatal diagnosis, and gives a better diagnostic yield than current rapid aneuploidy tests.

Prediction of recurrence of hypertensive disorders of pregnancy between 34 and 37 weeks of gestation: a retrospective cohort study.

OBJECTIVE: To assess the recurrence risk of late-preterm hypertensive disease of pregnancy, and to determine whether potential risk factors are predictive. DESIGN: Retrospective cohort study. SETTING: Three secondary and three tertiary care hospitals in the Netherlands. POPULATION: We identified women with a hypertensive disorder in the index pregnancy and delivery at 34-37 weeks of gestation, between January 2000 and December 2002. METHODS: Data were extracted from medical files and women were approached for additional information on subsequent pregnancies. An adverse outcome was defined as the recurrence of a hypertensive disorder in the next subsequent pregnancy. MAIN OUTCOME MEASURES: Absolute risk of recurrence and a prediction model containing demographic and clinical factors predictive for adverse outcome. RESULTS: We identified 425 women who matched the criteria, of whom 351 could be contacted. Of these women, 189 (54%) had had a subsequent pregnancy. Hypertensive disorders recurred in 96 (51%, 95% CI 43-58%) women, of whom 17 (9%, 95% CI 5-14%) delivered again before 37 weeks of gestation. Chronic hypertension and maternal age were the strongest predictors for recurrence. Women undergoing recurrence had a nine-fold chance of developing chronic hypertension (37% versus 6%, OR 8.7, 95% CI 3.3-23). CONCLUSIONS: Women with hypertensive disorders and late-preterm delivery have a 50% chance of recurrence, but only a 9% chance of recurrence resulting in delivery before 37 weeks of gestation. Women with chronic hypertension are prone to develop recurrence, and women with a recurrence more often developed chronic hypertension.

Neurocognitive Characteristics of Individuals with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a systems-based brain-gut axis disorder. Cognitive functions reflect central affective and attentional processes that are driven by genetic and epigenetic influences and effect complex brain-gut interactions. These interactions include stress-induced changes in hypothalamic-pituitary-adrenal axis and autonomic nervous system, remodelling of the immune system, and alterations in microbiota composition. This review summarises current neurocognitive findings on patients with IBS. 13 studies of neurocognition in IBS patients were identified from PubMed, Ovid MEDLINE, EMBASE, and PsycINFO. The methodology and relevant findings were systematically analysed. There are alterations in both hot and cold cognitions in IBS patients. Consistently, attentional bias towards negative emotionally valenced and gastrointestinal symptom-related stimuli is found in hot cognition tasks, with other cold cognition differences including frontal executive dysfunction and stress-related hippocampal-mediated cognitive alterations. The effect of psychiatric comorbidity on a disorder level, as well as illness chronicity, on cognitive alterations requires further examination. Attentional bias and executive dysfunction in IBS gave support to its neural network alterations accounting for visceral hypersensitivity. Further prospective neuropsychological studies should examine the effect of chronicity, current symptom severity, and psychiatric comorbidity on the cognition in different IBS subtypes.

Identification, sexual dimorphism and aspects of the natural history of Sapria himalayana (Rafflesiaceae) on Vietnam's Lang Biang Plateau.

BACKGROUND: Sapria is a distinctive and narrowly host-specific holoparasitic genus belonging to the Rafflesiaceae. Sapria himalayana, rare throughout its range from NE India, SW China, Thailand to Vietnam, is a little-understood species first recorded for Vietnam in 1959, and only recollected there over half a century later in February 2017. This has facilitated an assessment of its taxonomic identity and our understanding of its morphology and natural history aspects. RESULTS: Six populations of Sapria at Vietnam's Tuyen Lâm Lake, and another two populations at the Nam Ban Protection Forest and the Cam Ly area were found, in an area of about 20 km in radius. Previously documented size attributes, morphological details and colour patterns allowed clear identification of the Vietnamese taxon as Sapria himalayana f. albovinosa. A full description of the species for Vietnam is provided. Past authors have distinguished the sexes by column form and structure, colour of the upper disk, details of the inner surface of the perigone tube, and presence of ovarial chambers below the column in the female. We present additional observations that male flowers consistently have more steeply held perigone lobes than females, in which the lobes were more spread out at wider angles in fully open flowers, and that males have a much lower cupule than females. The latter difference, especially, appears to be useful for quick determination of the sex even in the advanced floral bud stage. The host plant was the lianescent Tetrastigma laoticum (Vitaceae), but superficially it was not possible to ascertain the clonal relationship of neighbouring host lianas. Male and female flowers were found mixed together in the same cluster from one individual liana. Potential pollinators included Calliphorid and Stratiomyid flies observed visiting open flowers. CONCLUSIONS: Our observations have added to an increased understanding of the morphology of this highly specialized parasitic life form. More than this, we have ascertained its occurrence in Vietnam, with information made available to authorities of the Lâm Dong Province where our studies were conducted, for the sites to be specially demarcated for conservation and carefully managed tourism use.

Altered expression of protein kinase C, lck, and CD45 in a 12-O-tetradecanoylphorbol-13-acetate-dependent leukemic T-cell variant that expresses a high level of interleukin-2 receptor.

The compound 12-O-tetradecanoylphorbol-13-acetate (TPA) is extremely toxic to the P13 subclone of the Jurkat human T-cell leukemia line. By selecting for growth in the presence of TPA, we have isolated two TPA-resistant variants of these cells, P13-50 and P13-5/A8. Studies of protein kinase C (PKC) enzyme activity, immunoblot analyses, and assays for PKC mRNAs indicate that both of these variants express lower levels of PKC than do the parental P13 cells. We suggest that this protects them from the toxic effects of TPA. The P13-5/A8 cells are of particular interest because not only are they resistant to TPA toxicity but they actually require TPA for optimal growth. These cells have a more profound decrease in PKC expression that do P13-50 cells. In addition, P13-5/A8 cells display very little, if any, surface expression of CD45, a receptor-linked tyrosine protein phosphatase, and lck, a lymphocyte-specific tyrosine kinase. On the other hand, they express a very high level of interleukin-2 receptor. A model is proposed that suggests that these cells are dependent on TPA because they have defects in both the PKC and tyrosine kinase signal transduction pathways, and that TPA compensates for these defects by providing a strong stimulus to the residual level of PKC. This variant may be useful for studying the interactions between tyrosine kinase and PKC pathways in controlling the various functions of T lymphocytes.

Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression.

By using a retrovirus-derived vector system, we generated derivatives of the human colon cancer cell line HT29 that stably overexpress a full-length cDNA encoding the beta 1 isoform of rat protein kinase C (PKC). Two of these cell lines, PKC6 and PKC7, displayed an 11- to 15-fold increase in PKC activity when compared with the C1 control cell line that carries the vector lacking the PKC cDNA insert. Both of the overexpresser cell lines exhibited striking alterations in morphology when exposed to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Following exposure to TPA, PKC6 and PKC7 cells displayed increased doubling time, decreased saturation density, and loss of anchorage-independent growth in soft agar; but these effects were not seen with the C1 cells. Also, in contrast to the control cells, the PKC-overproducing cells failed to display evidence of differentiation, as measured by alkaline phosphatase activity, when exposed to sodium butyrate. In addition, the PKC-overexpresser cells displayed decreased tumorigenicity in nude mice, even in the absence of treatment with TPA. These results provide the first direct evidence that PKC can inhibit tumor cell growth. Thus, in some tumors, PKC might act as a growth-suppressor gene.

Three-Dimensional Accuracy of Digital Implant Impressions: Effects of Different Scanners and Implant Level.

PURPOSE: To compare the three-dimensional (3D) accuracy of conventional direct implant impressions with digital implant impressions from three intraoral scanners, as well as different implant levels-bone level (BL) and tissue level (TL). MATERIALS AND METHODS: Two-implant master models were used to simulate a threeunit implant-supported fixed dental prosthesis. Conventional test models were made with direct impression copings and polyether impressions. Scan bodies were hand-tightened onto master models and scanned with the three scanners. This was done for the TL and BL test groups, for a total of eight test groups (n = 5 each). A coordinate measuring machine measured linear distortions (dx, dy, dz), global linear distortion (dR), angular distortions (dθy, dθx), and absolute angular distortions (Absdθy, Absdθx) between the master models, test models, and .stl files of the digital scans. RESULTS: The mean dR ranged from 35 to 66 µm; mean dθy angular distortions ranged from -0.186 to 0.315 degrees; and mean dθx angular distortions ranged from -0.206 to 0.164 degrees. Two-way analysis of variance showed that the impression type had a significant effect on dx, dz, and Absdθy, and the implant level had a significant effect on dx and Absdθx (P < .05). Among the BL groups, the mean dR of the conventional group was lower than and significantly different from the digital test groups (P = .010), while among the TL groups, there was no statistically significant difference (P = .572). CONCLUSION: The 3D accuracy of implant impressions varied according to the impression technique and implant level. For BL test groups, the conventional impression group had significantly lower distortion than the digital impression groups. Among the digital test groups, the TR system had comparable mean linear and absolute angular distortions to the other two systems but exhibited the smallest standard deviations.

Mechanism of the biomolecular synthesis of PEDOT:PSS: importance of heme degradation by hydrogen peroxide.

The use of biomolecules as oxidants for the synthesis of conducting polymers provides an important tool for the control of polymer properties. Using PEDOT: PSS as a representative conducting polymer, we compare a set of heme proteins (soybean peroxidase, cytochrome c, and horseradish peroxidase) used as oxidants. The resulting PEDOT: PSS was characterized with visible and near IR spectroscopy, Fourier transform infrared spectroscopy, electron spin resonance spectroscopy, and four point probe conductivity measurements. We find that the relative concentrations of bipolarons and polarons vary as a function of the protein used for polymerization. We then show that heme degradation by hydrogen peroxide plays a critical role in determining polymer properties.

Role of c-Jun N-terminal kinase 1 (JNK1) in cell cycle checkpoint activated by the protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal.

The cysteine protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) inhibited the growth of the Calu-1 lung carcinoma cells and induced a prolonged cell cycle arrest in the S phase. c-Jun N-terminal kinases (JNKs) participate in cellular responses to mitogenic stimuli, environmental stresses, and apoptotic signals but its role in cell cycle checkpoint control has not been elucidated. In this report, we examined the role of JNK in LLnL-induced S phase checkpoint by overexpression of a dominant-negative mutant of JNK1 (JNK1-APF) in Calu-1 cells. Expression of high levels of JNK1-APF blocked the growth-inhibitory effects of LLnL and abrogated S phase arrest induced by LLnL. These results support the role of JNK in the activation of cell cycle checkpoint induced by LLnL.

Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor.

Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular differentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These effects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor differentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches.

Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta.

To evaluate the role of the NF-kappaB signaling pathway in oncogenic transformation, we expressed IkappaBbeta, a specific inhibitor of NF-kappaB, in two human lung adenocarcinoma cell lines, A549 and H441. Expression of IkappaBbeta significantly reduced NF-kappaB activation induced by cotransfection with p65/RelA or TNF-alpha and abrogated the basal NF-kappaB activity in A549 cells. Transfection of IkappaBbeta into A549, H441 and K-ras-transformed NIH3T3 cells suppressed anchorage-independent growth as measured by colony formation in soft agar. Anchorage-independent growth of vector-transfected A549 cells in reduced serum could be enhanced by both EGF and IGF-I. In contrast, only EGF but not IGF-I could induce anchorage-independent growth of IkappaBbeta-expressing A549 cells, suggesting that the IGF-I signaling pathway regulating growth and survival may be blocked by IkappaBbeta. Interestingly, expression of IkappaBbeta suppressed growth of A549 cells in low serum in vitro without affecting in vivo growth subcutaneously in nude mice. However, metastatic growth of IkappaBbeta-expressing A549 cells in the lungs of nude mice was significantly inhibited. These results provide evidence that NFkappaB plays an important role in anchorage-independent growth and metastatic growth of lung carcinoma cells.

Range extension of Christisonia scortechinii from mainland Southeast Asia into Borneo, and notes on the distinction between Aeginetia and Christisonia (Orobanchaceae).

BACKGROUND: Christisonia is a little-documented and poorly studied root-parasitic genus in the Orobanchaceae occurring in India, China, Indochina and part of the Malesian region. Recent collection of a Christisonia taxon in Kinabalu Park in Sabah, Borneo, taxonomically identical to earlier Sabah collections that have hitherto not been recorded in the literature, led to an assessment of the taxonomic identity of the species against Christisonia scortechinii, C. siamensis, C. sinensis and related species. RESULTS: Some taxa in China, Indochina, the Malay Peninsula, and the Philippines are morphologically identical to the Borneo taxon except in the number of calyx lobes, but differ by several distinctive characters from other well-distinguished species in the region. Studies of dried herbarium specimens, augmented by photographic images of different stages of fresh flowering material and a scrutiny of available descriptions confirmed that the calyx has two primary lobes in the bud that may separate into 3-5 portions, giving a variable number of apparent lobes in specimen material collected at different localities. This new scrutiny of the calyx also permitted an improved description of the calyx differences that separate Christisonia and the closely related Aeginetia, which have not been clearly elucidated in the past. CONCLUSIONS: Christisonia scortechinii Prain (Orobanchaceae), the only species that was described as having an initially spathaceous calyx among species of this root-parasitic genus, is newly recorded for Borneo (including Kinabalu Park, where its presence has been overlooked). The range of the species in mainland Southeast Asia, previously extended from Peninsular Malaysia to Thailand and Vietnam, is here further extended to Laos and China. Christisonia wightii Elmer (relevant to the Philippines) and C. sinensis Beck (China) are reduced to synonymy.

Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer.

Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib.

Effects of acoustic trauma on the auditory system of the rat: The role of microglia.

Exposure to loud, prolonged sounds (acoustic trauma, AT) leads to the death of both inner and outer hair cells (IHCs and OHCs), death of neurons of the spiral ganglion and degeneration of the auditory nerve. The auditory nerve (8cn) projects to the three subdivisions of the cochlear nuclei (CN), the dorsal cochlear nucleus (DC) and the anterior (VCA) and posterior (VCP) subdivisions of the ventral cochlear nucleus (VCN). There is both anatomical and physiological evidence for plastic reorganization in the denervated CN after AT. Anatomical findings show axonal sprouting and synaptogenesis; physiologically there is an increase in spontaneous activity suggesting reorganization of circuitry. The mechanisms underlying this plasticity are not understood. Recent data suggest that activated microglia may have a role in facilitating plastic reorganization in addition to removing trauma-induced debris. In order to investigate the roles of activated microglia in the CN subsequent to AT we exposed animals to bilateral noise sufficient to cause massive hair cell death. We studied four groups of animals at different survival times: 30 days, 60 days, 6 months and 9 months. We used silver staining to examine the time course and pattern of auditory nerve degeneration, and immunohistochemistry to label activated microglia in the denervated CN. We found both degenerating auditory nerve fibers and activated microglia in the CN at 30 and 60 days and 6 months after AT. There was close geographic overlap between the degenerating fibers and activated microglia, consistent with a scavenger role for activated microglia. At the longest survival time, there were still silver-stained fibers but very little staining of activated microglia in overlapping regions. There were, however, activated microglia in the surrounding brainstem and cerebellar white matter.

Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients.

The area under the concentration time curve (AUC) for oral tacrolimus (FK) may provide a more precise model for FK monitoring after renal transplantation. The purpose of this study is to identify a simple, cost-effective method for predicting FK AUC. FK concentrations were measured at 0, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The predicted AUCs (AUC(p)s) derived from regression equations were used to estimate the actual 12-hour AUCs (AUC(12)s). The relationship between AUC(p) and AUC(12) was validated by determining the coefficient of multiple determination (R(2)), percentage of prediction error (PE%), and percentage of absolute prediction error (APE%). Eighteen stable Oriental renal transplant recipients (9 men, 9 women) with a mean age of 42.6 +/- 6 years and mean body weight of 62.7 +/- 10 kg were recruited for the study. The FK AUC(12), trough, 2-hour, and 4-hour concentrations were 125 +/- 24 h. ng/mL (range, 87.7 to 181.9 h. ng/mL), 6 +/- 1.3 ng/mL, 18.1 +/- 4.7 ng/mL, and 11 +/- 2.4 ng/mL, respectively. Trough FK concentration did not have a significant correlation with AUC(12) (r = 0.34; P = 0.17). AUC(p) obtained by a two-time point regression equation using 2-hour (C2) and 4-hour (C4) FK concentrations: (AUC(P) = 16.2 + 2.4*C2 + 5.9*C4) obtained an R(2), PE%, and APE% of 0.93, -0.2% +/- 5.2% (range, -13% to 9.3%), and 3. 6% +/- 3.7% (range, 0.02% to 13%), respectively. We conclude that a two-point sampling method using C2 and C4 may be a more cost-effective FK monitoring strategy than morning FK trough levels in transplant recipients.

Spontaneous renal allograft rupture attributed to acute tubular necrosis.

A renal allograft recipient receiving triple immunosuppressive therapy developed spontaneous allograft rupture 5 days after her second cadaveric renal transplantation. Renal biopsy showed interstitial edema with severe acute tubular necrosis (ATN). There was no evidence of acute rejection or renal vein thrombosis. The ruptured renal graft was salvaged by an aggressive fluid resuscitation therapy and surgical hemostasis. The renal function was satisfactory on discharge. We conclude that renal allograft rupture can be the result of interstitial edema solely attributed to ATN in the absence of graft rejection. The ruptured graft kidney is potentially salvageable for those patients whose hemodynamic status can be stabilized by appropriate supportive therapy.