Applications of inhibin A and inhibin B immunoassays and their impact in human medicine

Pioneering new immunoassays for inhibin A and B, developed by Professor Nigel Groome at Oxford Brookes University, have contributed to a significant improvement in the accuracy of pre-natal screening for Downs Syndrome. Use of inhibin A in the ‘Quad’ and ‘integrated’ tests, protected by international patents, is widespread in the US (c.3million screened annually) and was recommended by the NHS in 2010, leading to a significant increase in the use of the assays (c.120,000 annually) in the UK. They are also used in clinical diagnostic and monitoring applications for male and female infertility, abnormalities in sexual development in children and ovarian granulosa tumours. Commercialisation has led to royalty income to Brookes from sales which totalled approximately c.£5million in the period January 2008 to December 2012, indicative of the c.US$135million earned in worldwide sales in the same period

The onset of classical QCD dynamics in relativistic heavy ion collisions

The experimental results on hadron production obtained recently at RHIC offer a new prospective on the energy dependence of the nuclear collision dynamics. In particular, it is possible that parton saturation -- the phenomenon likely providing initial conditions for the multi--particle production at RHIC energies -- may have started to set in central heavy ion collisions already around the highest SPS energy. We examine this scenario, and make predictions based on high density QCD for the forthcoming 22 GeV run at RHIC.Comment: 4 pages, 2 figures, revte

Heterogeneous Subgreenschist Deformation in an Exhumed Sediment-Poor Mélange

Many described subduction complexes (or mélanges) exhumed from seismogenic depths comprise thick, turbidite-dominated sequences with deformed zones containing clasts or boudins of more competent sandstone and/or basalt. In contrast, many active subduction zones have a relatively small thickness of sedimentary inputs (<2 km), turbidite sequences are commonly accreted rather than subducted, and the role of pelagic sediments and basalt (lavas and hyaloclastites) in the deforming zone near the plate interface at <20 km depth is poorly understood. Field investigation of Neoproterozoic oceanic sequences accreted in the Gwna Complex, Anglesey, UK, reveals repeated lenticular slices of variably sampled ocean plate stratigraphy (OPS) bounded by thin mélange-bearing shear zones. Mélange matrix material is derived from adjacent OPS lithologies and is either dominantly illitic, likely derived from altered siliciclastic sediment, or chloritic, likely derived from altered volcanics. In the illitic mélange, mutually cross-cutting phyllosilicate foliation and variably deformed chlorite-quartz-calcite veins suggest ductile creep was cyclically punctuated by transient, localized fluid pulses. Chlorite thermometry indicates the veins formed at 260 ± 10°C. In the chloritic mélange, recrystallized through-going calcite veins are deformed to shear strains of 4–5 within a foliated chlorite matrix, suggesting calcite veins in subducting volcanics may localize deformation in the seismogenic zone. Shear stress-strain rate curves constructed using existing empirical relationships in a simplified shear zone geometry predict that slip velocities varied depending on pore fluid pressure; models predict slow slip velocities preferentially by frictional sliding in chlorite, at pore fluid pressures greater than hydrostatic but less than lithostatic

Presence of exon 5-deleted oestrogen receptor in human breast cancer: functional analysis and clinical significance.

A variant form of the human oestrogen receptor (ER) mRNA lacking sequences encoded within exon 5 has been described (Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malloy BW, McGuire WL 1991, Cancer Res 51: 105-109). We have examined the expression of the exon 5-deleted ER (HE delta5) mRNA variant in breast biopsies using reverse transcriptase polymerase chain reaction (RT - PCR). HE delta5 mRNA was present in only 13% of non-malignant breast tissues compared with 32% of carcinomas (95% CI, P=0.05). Presence of the HE delta5 mRNA was associated with the presence of immunohistochemically detected ER (P=0.015) and progesterone receptor (PR) (P=0.02). There was a positive correlation between the presence of HE delta5 and disease-free survival (P=0.05), suggesting that the presence of HE delta5 may be an indicator of better prognosis. We have raised a monoclonal antibody specific to the C-terminal amino acids of HE delta5. This antibody recognized the variant but not the wild-type ER protein. We show that HE delta5 protein is present in breast cancer using immunohistochemical techniques. We also analysed trans-activation by HE delta5 in mammalian cells and showed that, in MCF-7 cells, HE delta5 competes with wild-type ER to inhibit ERE-dependent trans-activation. Our results indicate that this variant is unlikely to be responsible for endocrine resistance of breast cancer, but its presence at both the mRNA and protein level suggest that it may, nevertheless, be involved in regulating the expression of oestrogen-responsive genes in breast cancer

Heterogeneous subgreenschist deformation in an exhumed sediment‐poor mélange

Many described subduction complexes (or mélanges) exhumed from seismogenic depths comprise thick, turbidite‐dominated sequences with deformed zones containing clasts or boudins of more competent sandstone and/or basalt. In contrast, many active subduction zones have a relatively small thickness of sedimentary inputs (<2 km), turbidite sequences are commonly accreted rather than subducted, and the role of pelagic sediments and basalt (lavas and hyaloclastites) in the deforming zone near the plate interface at <20 km depth is poorly understood. Field investigation of Neoproterozoic oceanic sequences accreted in the Gwna Complex, Anglesey, UK, reveals repeated lenticular slices of variably sampled ocean plate stratigraphy (OPS) bounded by thin mélange‐bearing shear zones. Mélange matrix material is derived from adjacent OPS lithologies and is either dominantly illitic, likely derived from altered siliciclastic sediment, or chloritic, likely derived from altered volcanics. In the illitic mélange, mutually cross‐cutting phyllosilicate foliation and variably deformed chlorite‐quartz‐calcite veins suggest ductile creep was cyclically punctuated by transient, localized fluid pulses. Chlorite thermometry indicates the veins formed at 260 ± 10°C. In the chloritic mélange, recrystallized through‐going calcite veins are deformed to shear strains of 4–5 within a foliated chlorite matrix, suggesting calcite veins in subducting volcanics may localize deformation in the seismogenic zone. Shear stress‐strain rate curves constructed using existing empirical relationships in a simplified shear zone geometry predict that slip velocities varied depending on pore fluid pressure; models predict slow slip velocities preferentially by frictional sliding in chlorite, at pore fluid pressures greater than hydrostatic but less than lithostatic

Phase II trial of tamoxifen and goserelin in recurrent epithelial ovarian cancer

Endocrine therapy is a recognised option in the treatment of chemo-resistant ovarian cancer. We conducted a nonrandomised phase II evaluation of combination endocrine therapy with tamoxifen and goserelin in patients with advanced ovarian cancer that had recurred following chemotherapy. In total, 26 patients entered the study, of which 17 had platinum-resistant disease. The median age was 63 years and enrolled patients had received a median of three chemotherapy regimens prior to trial entry. Patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. Using the definition of endocrine response that included patients with stable disease (SD) of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (CR) (3.8%), two partial responses (PR) (7.7%) and 10 patients with SD (38.5%). The median progression-free interval (PFI) was 4 months (95% CI 2.4–9.6) while the median overall survival (OS) was 13.6 months (95% CI 5.5–30.6). Four patients received treatment for more than 2 years (range 1–31) and one of them is still on treatment. In none of the four patients was there any evidence of recurrent or cumulative treatment related toxicity. Treatment-limiting toxicity was not seen in any of the study population. Endocrine data demonstrated a marked suppression of luteinising hormone (LH) and follicle-stimulating hormone (FSH) to less than 4% of baseline values. No consistent correlation could be established between LH/FSH suppression and tumour response. Likewise no relationship was observed between Inhibin A/B and pro-alpha C levels and tumour response. Inhibin is unlikely to be a useful surrogate marker for response in locally advanced or metastatic ovarian cancer. Combination endocrine therapy with tamoxifen and goserelin is an active regimen in platinum-resistant ovarian cancer patients. Hormonal therapy is advantageous in its relative lack of toxicity, ease of administration and tolerability, thus making it suitable for patients with heavily pretreated disease, compromised bone marrow function and other comorbid conditions that contraindicate cytotoxic therapy as well as in patients with indolent disease

Extraspinal osteoarticular multidrug-resistant tuberculosis in children: A case series

Background. South Africa (SA) is known to have a high disease burden of tuberculosis (TB). Extraspinal osteoarticular multidrug-resistant tuberculosis (ESOA MDR-TB) in children has only been described in a few case reports worldwide.Objectives. To describe the epidemiology and highlight the potential problem of ESOA MDR-TB infections as seen in children from a single academic hospital in SA.Methods. A retrospective record review was performed on all children diagnosed with ESOA TB infection at Chris Hani Baragwanath Academic Hospital, Johannesburg, between 1 January 2006 and 31 December 2015. All patients with a positive TB culture (fluid or tissue) from the surgical site of biopsy (bone or joint) and who were hospitalised were included. Organism culture and drug sensitivity testing were performed.Results. Overall 19 cases of ESOA TB were identified. Areas involved included the shoulder (2 cases), elbow (2 cases), hip (7 cases), knee (4 cases), ankle (3 cases) and humerus (1 case). The mean age of the population was 7.7 (range 2.0 - 14.0) years. The mean white cell count was 11.3 (range 5 - 28.9) × 109/L, the mean C-reactive protein level 53.8 (range 1.0 - 364.0) mg/L and the mean erythrocyte sedimentation rate 35.5 (range 4.0 - 85.0) mm/h. Two cases (10.5%) were MDR, and a further case (5.3%) was resistant to isoniazid only. Four of 12 patients tested positive for HIV. One of the HIV-positive patients was isoniazid resistant. The two positive ESOA MDR-TB cases are discussed in detail.Conclusions. These findings indicate that ESOA MDR-TB is a reality in this paediatric population (10.5%) and a high index of suspicion should be maintained, especially when cultures are negative in children with signs and symptoms of ESOA TB. The effect of HIV infection on the incidence of ESOA MDR-TB requires further study.

Macrophages exert homeostatic actions in pregnancy to protect against preterm birth and fetal inflammatory injury

Macrophages are commonly thought to contribute to the pathophysiology of preterm labor by amplifying inflammation — but a protective role has not previously been considered to our knowledge. We hypothesized that given their antiinflammatory capability in early pregnancy, macrophages exert essential roles in maintenance of late gestation and that insufficient macrophages may predispose individuals to spontaneous preterm labor and adverse neonatal outcomes. Here, we showed that women with spontaneous preterm birth had reduced CD209⁺CD206⁺ expression in alternatively activated CD45⁺CD14⁺ICAM3⁻ macrophages and increased TNF expression in proinflammatory CD45⁺CD14⁺CD80⁺HLA-DR⁺ macrophages in the uterine decidua at the materno-fetal interface. In Cd11b(DTR/DTR) mice, depletion of maternal CD11b⁺ myeloid cells caused preterm birth, neonatal death, and postnatal growth impairment, accompanied by uterine cytokine and leukocyte changes indicative of a proinflammatory response, while adoptive transfer of WT macrophages prevented preterm birth and partially rescued neonatal loss. In a model of intra-amniotic inflammation–induced preterm birth, macrophages polarized in vitro to an M2 phenotype showed superior capacity over nonpolarized macrophages to reduce uterine and fetal inflammation, prevent preterm birth, and improve neonatal survival. We conclude that macrophages exert a critical homeostatic regulatory role in late gestation and are implicated as a determinant of susceptibility to spontaneous preterm birth and fetal inflammatory injury.Nardhy Gomez-Lopez, Valeria Garcia-Flores, Peck Yin Chin, Holly M. Groome, Melanie T. Bijland, Kerrilyn R. Diener, Roberto Romero, and Sarah A. Robertso