A direct experimental comparison of single-crystal CVD diamond and silicon carbide X-ray beam position monitors.

Single-crystal chemical vapour deposition (CVD) diamond detectors are an established transmissive synchrotron beamline diagnostic instrument used for beam position and beam intensity monitoring. A recently commercialized alternative is silicon carbide (4H-SiC) devices. These have the potential to provide the same diagnostic information as commercially available single-crystal CVD diamond X-ray beam position monitors, but with a much larger transmissive aperture. At Diamond Light Source an experimental comparison of the performance of single-crystal CVD diamond and 4H-SiC X-ray beam position monitors has been carried out. A quantitative comparison of their performance is presented in this paper. The single-crystal diamond and 4H-SiC beam position monitors were installed in-line along the synchrotron X-ray beam path enabling synchronous measurements at kilohertz rates of the beam motion from both devices. The results of several tests of the two position monitors' performance are presented: comparing signal uniformity across the surface of the detectors, comparing kHz intensity measurements, and comparing kHz beam position measurements from the detectors. Each test is performed with a range of applied external bias voltages. A discussion of the benefits and limitations of 4H-SiC and single-crystal CVD diamond detectors is included.

Modelling the effects of optical vibrations on photon beam parameters using ray-tracing software.

A method to simulate beam properties observed at the beamline sample-point in the presence of motion of optical components has been developed at Diamond Light Source. A series of stationary ray-tracing simulations are used to model the impact on the beam stability caused by dynamic motion of optical elements. Ray-tracing simulations using SHADOW3 in OASYS, completed over multiple iterations and stitched together, permit the modelling of a pseudo-dynamic beamline. As beamline detectors operating at higher frequencies become more common, beam stability is crucial. Synchrotron ring upgrades to low-emittance lattices require increased stability of beamlines in order to conserve beam brightness. By simulating the change in beam size and position, an estimate of the impact the motion of various components have on stability is possible. The results presented in this paper focus on modelling the physical vibration of optical elements. Multiple beam parameters can be analysed in succession without manual input. The simulation code is described and the initial results obtained are presented. This method can be applied during beamline design and operation for the identification of optical elements that may introduce large errors in the beam properties at the sample-point.

Management of lateral abdominal hernias.

PURPOSE: Lateral abdominal wall hernias are rare defects but, due to their location, repair is difficult, and recurrence is common. Few studies exist to support a standard protocol for repair of these lateral hernias. We hypothesized that anchoring our repair to fixed bony structures would reduce recurrence rates. METHODS: A retrospective review of all patients who underwent lateral hernia repair at our institution was performed. RESULTS: Eight cases (seven flank and one thoracoabdominal) were reviewed. The median defect size was 105 cm2 (range 36-625 cm2). The median operative time was 185 min (range 133-282 min). There were no major complications. One patient who was repaired without mesh attachment to bony landmarks developed a recurrence at ten months and subsequently underwent reoperation. Patients with mesh secured to bony landmarks were recurrence free at a median follow-up of 171 days. CONCLUSIONS: Lateral hernias present a greater challenge due to their anatomic location. An open technique with mesh fixation to bony structures is a promising solution to this complex problem.

Cold knife versus laser cone biopsy for adenocarcinoma in situ of the cervix--a comparison of management and outcome.

Eighty-two patients with adenocarcinoma in situ of the cervix managed at Royal Prince Alfred Hospital were reviewed and data were collected on those treated by cold knife cone biopsy (n= 38) and laser cone biopsy (n= 44). No differences were found in patient age, cytologic or referral history, or outcomes. Having laser excision did not compromise margin status or subsequent management. Invasive disease was found in 24 patients, 16 of whom were managed conservatively with good outcome. Twelve of these were in the laser cone group. In those patients from both groups managed conservatively, there was only one recurrence, squamous preinvasive disease after 8 years. Laser cone biopsy is as effective as cold knife cone biopsy with no compromise of outcome for these patients.

Parental experiences and perceptions of infant complementary feeding: a qualitative evidence synthesis.

BACKGROUND: Interventions to prevent childhood obesity increasingly focus on infant feeding, but demonstrate inconsistent effects. A comprehensive qualitative evidence synthesis is essential to better understand feeding behaviours and inform intervention development. The aim of this study is to synthesize evidence on perceptions and experiences of infant feeding and complementary feeding recommendations. METHODS: Databases CINAHL, EMBASE, MEDLINE, PsycINFO, Academic Search Complete, SocIndex and Maternity and Infant Care were searched from inception to May 2017. Eligible studies examined parents' experiences of complementary feeding of children (<2 years). Data were synthesized using thematic synthesis. RESULTS: Twenty-five studies met inclusion criteria for review. Four key themes emerged. 'Guidelines and advice' highlights variety and inconsistencies between sources of complementary feeding information. 'Stage of weaning' describes infant feeding as a process involving different stages. 'Knowing and trying' outlines parents' engagement in feeding approaches based on instinct, prior experience or trial and error. 'Daily life' highlights problematic cost and time constraints for parents. DISCUSSION: Parents predominantly understand and want to engage in healthy feeding processes. Consideration of infant feeding as a process that changes over time is necessary to support parents. Provision of clear, consistent information and guidance from trusted sources on when, what and how to feed is also essential.

Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma.

Mutations in the RET proto-oncogene are associated with the pathogenesis of medullary thyroid carcinoma (MTC). In an attempt to understand this process, we examined microdissected subpopulations from MTC and multiple metastases from these tumors. Approximately 80% of sporadic MTC's had at least one subpopulation with the RET codon 918 mutation, which is a mutation previously detected in sporadic MTC as a somatic mutation and in multiple endocrine neoplasia type 2B as a germline mutation. However, the distribution of this mutation was nonhomogeneous, occurring only in subpopulations in most tumors and among subsets of multiple metastases, thus implying that although the codon 918 mutation could be an early event, it is not necessarily an early or essential event in tumorigenesis. This heterogeneity suggests either that the codon 918 mutation can arise as an event in progression within a metastatic clone or within a single tumor, or that MTC can be of polyclonal origin. Of significance, one of two multiple endocrine neoplasia type 2A MTCs carried a somatic mutation at codon 918, in addition to the RET mutation present in the germline. We found no correlation between the presence of other somatic genetic events, such as loss of heterozygosity on chromosome arms 1p and 22q, and RET mutation status in the various subpopulations of MTC.

Germline and somatic mutations in an oncogene: RET mutations in inherited medullary thyroid carcinoma.

Inherited cancer syndromes predispose an individual to development of specific tumors. Somatic and germline mutations in the same tumor suppressor gene, as described in Knudson's two-mutation model, are well recognized. Inherited mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major component tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have not been identified in tumors from individuals with MEN 2, although they have been well documented in sporadic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well-defined RET germline mutations, a somatic missense mutation at codon 918 of RET in 3 of 15 MTCs and in a sample with hyperplastic C-cells (presumed precursor to hereditary MTC). We suggest that the presence of a somatic mutation, in addition to the preexisting germline mutation in hereditary MTCs, may contribute to tumorigenesis in vivo.

Germline mutation of RET codon 883 in two cases of de novo MEN 2B.

Germline mutations in the RET proto-oncogene are seen in the majority of patients with the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2 (MEN 2). The clinical subtypes of MEN 2 (MEN 2A, MEN 2B and familial MTC) all have medullary thyroid carcinoma, but vary in the involvement of pheochromocytoma, parathyroid adenoma/hyperplasia and developmental abnormalities. A single RET mutation, resulting in the substitution M918T, has been identified in 94% of cases of MEN 2B (which consists of MTC, pheochromocytoma and developmental abnormalities). Here we report the identification of a new germline RET mutation (A883F) in two de novo cases of MEN 2B. Identification of this new mutation will contribute to understanding the molecular basis of MEN 2B, and will assist in the clinical management of families harbouring this mutation.

C-cell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET.

Gain-of-function mutations in the gene encoding the receptor tyrosine kinase RET have been identified as the aetiological factor for multiple endocrine neoplasia type 2A (MEN2A). MEN2A is a dominantly-inherited cancer predisposition syndrome characterized by medullary thyroid carcinoma, a tumour of the calcitonin-producing thyroid C-cells. There are three isoforms of RET: RET9, RET43 and RET51, and although in vitro evidence suggests they vary in cellular transformation activities, little is known about their function in tumorigenesis in vivo. To address this, we used RET51 cDNA to construct mice in which the most frequent MEN2A mutation, Cys-634-Arg, was expressed under the control of the human calcitonin promoter (CT-2A mice). These mice developed C-cell tumours resembling human MTC and follicular tumours resembling human papillary thyroid carcinoma (PTC) depending on the founder line examined. One founder line developed compound MTC/PTC at low frequency (8%) and pancreatic cystadenocarcinoma. CT-2A mice also displayed a developmental defect in thyroid follicular structure, in which much of the thyroid was occupied by large irregular cystic follicles thought to be derived from the ultimobranchial body, a developmental precursor of the thyroid gland. The CT-2A mice will provide a suitable model to further study the effects of the MEN 2A RET mutation in vivo.

RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2.

Activating germline mutations of the RET receptor tyrosine kinase are found in the majority of cases of inherited cancer syndrome MEN 2, and inactivating mutations in some cases of dominantly inherited Hirschsprung disease. Using RET activated by a MEN 2 mutation, we show that both the SH2 and PTB domains of the adaptor protein Shc interact with RET, and we identify the PTB domain interaction site. Interaction with both the SH2 and PTB domains of Shc contributes to the transcriptional activation of a serum response element. RET alternate splicing affects the strength of interaction with both the Shc SH2 and PTB domains. In addition, a splice isoform-specific HSCR missense mutation, which does not inactivate the RET kinase activity, decreases the strength of the PTB domain interaction and the level of RET-dependent Shc phosphorylation.

Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma.

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.

Persisting cyclical uterine bleeding in patients treated with radical radiation therapy and hormonal replacement for carcinoma of the cervix.

Radical radiation therapy used for carcinoma of the cervix will ablate ovarian function. Since January 1986, our policy has been to administer oral combination oestrogen-progesterone replacement hormonal therapy to all premenopausal patients undergoing radical radiation with or without synchronous chemotherapy, for invasive cervix cancer. Five out of 22 (23%) such patients unexpectedly experienced between one and four episodes of cyclical per vaginal bleeding after the completion of radiation therapy. Bleeding episodes occurred in the absence of persistent tumor or radiation reaction, and suggest persisting endometrial response to exogenous hormonal stimulation. Uterine activity was temporarily retained in these five patients despite a minimal endometrial surface dose of between 4800 and 6490 cGy. The limited number of cycles before bleeding spontaneously ceased may represent the slow death of endometrial cells subsequent to radiation or radiochemotherapy treatment, and has not previously been described. In view of the paucity of data on the radiosensitivity of normal endometrium, we have carefully examined these patients who appear to have retained endometrial sensitivity to hormonal stimuli after radical radiation-chemotherapy for uterine cervix cancer.

Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin-2 release from murine splenocytes by interacting with a 'low-affinity' phosphodiesterase 4 conformer.

1. We have investigated the suppressive effects of rolipram, RP 73401 (piclamilast) and other structurally diverse inhibitors of cyclic AMP-specific phosphodiesterase 4 (PDE4) on interleukin (IL)-2 generation from Balb/c mouse splenocytes exposed to the superantigen, Staphylococcocal enterotoxin-A (Staph. A). The purpose was to determine whether their potencies are more closely correlated with inhibition of PDE4 from CTLL cells, against which rolipram displays weak potency (low-affinity PDE4), or displacement of [3H]-(+/-)-rolipram from its high-affinity binding site (HARBS) in mouse brain cytosol. 2. RP 73401 (IC50 0.46 +/- 0.07 nM, n = 4) was a very potent inhibitor of Staph. A-induced IL-2 release from Balb/c mouse splenocytes, being > 1100 fold more potent than (+/-)-rolipram (IC50 540 +/- 67 nM, n = 3). 3. A close correlation (r = 0.95) was observed between suppression of IL-2 release by PDE inhibitors and inhibition of PDE4. In contrast, little correlation (r = 0.39) was observed between suppression of IL-2 release and their affinities for the high-affinity rolipram binding site (HARBS). 4. RP 73401 only inhibited partially (30-40%) Staph. A-induced incorporation of [3H]-thymidine into splenocyte DNA. The PDE3 inhibitor, siguazodan (10 microM), had little or no effect on IL-2 release or DNA synthesis. This concentration of siguazodan did not enhance the inhibitory action of RP 73401 on IL-2 release but potentiated its effect on DNA synthesis, increasing potency and efficacy. 5. Staph. A-induced DNA synthesis was only partially inhibited by anti-IL-2 neutralizing antibody, whereas dexamethazone (100 nM) and cyclosporine A (100 nM) completely blocked the response. 6. RP 73401 (IC50 6.3 +/- 1.9 nM, n = 4) was 140 fold more potent than rolipram (IC50 900 +/- 300 nM, n = 3) in inhibiting Staph. A-induced [3H]-thymidine incorporation into splenocyte DNA. 7. The results implicate a low-affinity form of PDE4 in the suppression of Staph. A-induced IL-2 release from murine splenocytes by PDE inhibitors. The data also indicate that mitogenic factors other than IL-2, whose elaboration or responses to which are regulated by PDE3 as well as PDE4, contribute to the superantigen-induced DNA synthesis.

Suppression of anti-CD3-induced interleukin-4 and interleukin-5 release from splenocytes of Mesocestoides corti-infected BALB/c mice by phosphodiesterase 4 inhibitors.

We investigated the suppressive effects of rolipram, RP 73401 (piclamilast), and other structurally diverse inhibitors of adenosine 3'5'-cyclic monophosphate (cAMP)-specific phosphodiesterase (PDE4) on anti-CD3-stimulated interleukin (IL)-4 and IL-5 generation by splenocytes from BALB/c mice infected with Mesocestoides (M) corti. RP 73401 (IC40: 0.011 +/- 0.004 microM) was a very potent inhibitor of anti-CD3-induced IL-4 release, being approximately 40-fold more potent than (+/-)-rolipram (IC40: 0.43 +/- 0.09 microM). A maximal inhibition of 60-70% of the response was achieved at the top concentrations of RP 73401 (1 microM) and rolipram (100 microM). These PDE inhibitors also suppressed IL-5 generation over the same concentration ranges, but the maximal suppression achieved was only 30-40%. R-(-)-rolipram (IC40: 0.39 +/- 0.09 microM) was approximately 6-fold more potent than S-(+)- rolipram (IC40: 2.6 +/- 0.95 microM) in inhibiting IL-4 release. A close correlation (r2 = 0.82) was observed between suppression of IL-4 release by PDE inhibitors and inhibition of CTLL cell PDE4, a form against which R-(-)-rolipram displayed relatively weak inhibitory potency. A poorer correlation (r2 = 0.26) was observed between suppression of IL-4 release and affinities of cAMP PDE inhibitors for the high-affinity rolipram binding site in mouse brain membranes. The cGMP-inhibited PDE (PDE3) inhibitor, siguazodan, had little or no effect (IC40 > 100 microM) on anti-CD3-stimulated release of either IL-4 or IL-5 and did not significantly enhance the inhibitory action of RP 73401 on the release of either of these cytokines. Finally, RP 73401 (IC50: 0.41 +/- 0.19 nM) inhibited anti-CD3-stimulated DNA synthesis in splenocyte preparations from M. corti-infected mice and siguazodan (10 microM) had no effect on this response, either alone or in combination with the PDE4 inhibitor. The results show that PDE4 inhibitors suppress the release of Th2 cytokines from anti-CD3-stimulated murine spenocytes and that this effect is correlated with inhibition of a low-affinity PDE4 form.

Investigation of loss of heterozygosity at specific loci on chromosomes 3p, 6q, 11p, 17p and 17q in ovarian cancer.

In an attempt to further define the genetic events in the pathogenesis and progression of human ovarian cancer, an analysis of constitutional and ovarian carcinoma DNA samples revealed loss of heterozygosity (LOH) at specific loci on chromosomes 3p (38%), 6q (23%), 11p (33%), 17p (82%) and 17q (62%). In contrast, LOH was not observed in benign or borderline tumors. No significant association could be demonstrated between LOH at the loci studied and tumor stage, histologic subtype, grade or patient outcome. Further analyses of large tumor panels are now required to determine the relationship between LOH at these loci and the clinicopathological behavior of ovarian tumors.

Malignant melanoma of the vulva. Australian experience.

Malignant melanoma is an uncommon but aggressive tumor, and the vulva seems to have an increased predisposition for developing it. Vulvar melanoma appears to behave similarly to truncal melanoma, but its later presentation, due to its less accessible and less visible site, gives the false impression of more aggressive behavior. In spite of that the survival, stage by stage, is not markedly different from that of truncal melanoma. Traditionally it has been treated in the same manner as vulvar squamous cell carcinoma, with extreme but often therapeutically inadequate radical surgery. For lesions less than 0.75 mm in depth, wide excision with a 2-cm margin is adequate. Deeper lesions require radical local excision and bilateral groin lymphadenectomy through separate incisions.

Effects of a gliadin-combined plant superoxide dismutase extract on self-perceived fatigue in women aged 50-65 years.

Fatigue syndromes exist on a continuum of severity from mild and transient to the disabling chronic fatigue syndrome, with oxidative stress linked to its pathogenesis. A thermolabile gliadin-combined plant superoxide dismutase (SOD) extract has shown potential in clinical trials as a therapeutic antioxidant. This study investigated the effects of 12 weeks of 500 mg/day of a SOD/gliadin supplement on fatigue. Thirty-eight women aged 50-65 years with self-perceived fatigue entered this randomized, double-blind, placebo-controlled trial. The primary outcome measure was general fatigue determined by the Multidimensional Fatigue Inventory (MFI). Secondary outcome measures included other measures of fatigue from the MFI and blood measures of oxidative stress, antioxidant status and hormones. There were no significant (P>0.05) differences between, or within groups, for decreases in general fatigue (active=1.6%, placebo=4.1%). There were no within or between group differences (P>0.05) in other measures of fatigue (physical fatigue, reduced activity, reduced motivation, mental fatigue and total fatigue score). In regard to the biochemical measures, there were non-significant (P>0.05) differences in increases in plasma SOD activity (active=7.1%, placebo=12.2%), plasma GPx activity (active=2.4%, placebo=0.7%), red blood cell GPx activity (active=9.8%, placebo=4.4%). Markers of oxidative stress were decreased but there were no differences (P>0.05) within or between groups; malondialdehyde (active=4.1%, placebo=1.6%), F-2 isoprostanes (active=14.7%, placebo=22.4%). There was a trend (P=0.08) for a decrease in cortisol in the active group (24.6%), however this was not significantly different from the decrease in the placebo participants (4.1%). DHEA differences were not significant (P<0.05) and declined 1.3% in the active group and 14.4% in the placebo group. In summary, the thermolabile SOD/gliadin supplement had no significant effect on self-perceived fatigue, antioxidants, oxidative stress or hormones in women aged 50-65 years.

Bronchoprotective and bronchodilator effects of an HFA pMDI vs. a CFC pMDI and a DPI containing formoterol in asthma patients.

In this double-blind, placebo-controlled, crossover study we compared the bronchoprotective effects of formoterol 12 microg inhaled via an HFA-134a inhaler (Modulite HFA) versus a CFC and a DPI device in 38 patients with mild-to-moderate persistent asthma. All three formoterol preparations significantly increased methacholine PD20 and FEV1 and improved small airway function parameters compared with placebo (p < 0.001). No significant differences were observed between formoterol formulations. In conclusion, Modulite HFA formoterol was found to be an effective and well tolerated treatment in patients with asthma, with comparable efficacy to current formoterol preparations.