Recent Developments in the Law of the Sea: A Synopsis

Each year, as an integral part of its symposium on the law of the sea, the San Diego Law Review presents a synopsis of the major events in the field. This year\u27s precis covers the period from January 1, 1974 to December 31, 1974. The scope of the article prohibits extended scrutiny of the subject matter. However, the manner in which it is presented exposes the reader to a broad spectrum of recent events and allows familiarization with increasingly important facets of a rapidly expanding area. As an added ingredient, this year\u27s synopsis contains coverage of the United Nations Conference on the Law of the Sea

Characterization of HSP90 isoforms in transformed bovine leukocytes infected with Theileria annulata

HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterisation was undertaken for three and localisation confirmed for cytoplasmic (TA12105); endoplasmic reticulum (TA06470) and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin, were demonstrated for recombinant TA12105 and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata-infected counterpart was utilised to test the effects of geldanamycin and the derivative 17-AAG. T. annulata-infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17-AAG. These findings suggest that parasite HSP90 isoform (s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation

Treatment of metastatic hormone‐sensitive prostate cancer

Men with metastatic prostate cancer have a significantly reduced median five-year survival compared with that associated with the cancer overall. Clinical trials are exploring the most effective treatment strategies for metastatic hormone-sensitive prostate cancer to intervene before transformation to castration-resistant prostate cancers when options are limited

Susceptibility to disease (tropical theileriosis) is associated with differential expression of host genes that possess motifs recognised by a pathogen DNA binding protein

BACKGROUND: Knowledge of factors that influence the outcome of infection are crucial for determining the risk of severe disease and requires the characterisation of pathogen-host interactions that have evolved to confer variable susceptibility to infection. Cattle infected by Theileria annulata show a wide range in disease severity. Native (Bos indicus) Sahiwal cattle are tolerant to infection, whereas exotic (Bos taurus) Holstein cattle are susceptible to acute disease. METHODOLOGY/PRINCIPAL FINDINGS: We used RNA-seq to assess whether Theileria infected cell lines from Sahiwal cattle display a different transcriptome profile compared to Holstein and screened for altered expression of parasite factors that could generate differences in host cell gene expression. Significant differences (<0.1 FDR) in the expression level of a large number (2211) of bovine genes were identified, with enrichment of genes associated with Type I IFN, cholesterol biosynthesis, oncogenesis and parasite infection. A screen for parasite factors found limited evidence for differential expression. However, the number and location of DNA motifs bound by the TashAT2 factor (TA20095) were found to differ between the genomes of B. indicus vs. B. taurus, and divergent motif patterns were identified in infection-associated genes differentially expressed between Sahiwal and Holstein infected cells. CONCLUSIONS/SIGNIFICANCE: We conclude that divergent pathogen-host molecular interactions that influence chromatin architecture of the infected cell are a major determinant in the generation of gene expression differences linked to disease susceptibility

The management of sexual dysfunction resulting from radiotherapy and androgen deprivation therapy to treat prostate cancer: a comparison of uro-oncology practice according to disease stage

Objectives To establish current uro‐oncology practice in the management of sexual dysfunction (SD) following radiotherapy (RT) and/or androgen deprivation therapy (ADT) to treat prostate cancer. To identify differences in approach to the management of SD according to disease stage. Subjects and methods A 14‐question mixed methods survey was designed to assess the current UK practice. Closed‐ and open‐ended questions were used to quantify results while allowing participants to expand on answers. The survey was distributed to members of the British Uro‐Oncology Group at the 2019 annual meeting. Results Surveys were completed by 63 uro‐oncologists attending the annual meeting of the British Uro‐Oncology Group (response rate 66%). The major issue highlighted was a difference in approach to managing SD according to disease stage. More than half of the participants (56%) said ‘advanced stage of disease’ was a barrier to discussing SD. Clinicians were less likely to discuss SD, take baseline assessments, refer to a specialist clinic or offer rehabilitation when dealing with patients with advanced disease. Only a minority said that the management of SD was primarily their responsibility (11%). Nearly all clinicians (92%) had access to SD clinics; however, the majority of clinicians did not routinely refer patients. Conclusions This study shows that men with advanced prostate cancer need better support in managing SD. Patients receiving long‐term ADT are less likely to be offered any kind of help or intervention. Specific guidance on managing SD in this cohort may result in improvements in sexual function, emotional well‐being, quality of life, mental health and confidence

Is the digital rectal exam any good as a prostate cancer screening test?

© The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/There is no shortage of references in popular culture to the prostate examination, with many a laugh built on the punchline of the finger up the bum. Interestingly, while cervical, breast, or bowel screening share barriers to uptake around the intimacy of the examination, ‘ick-factor’, or cultural taboos, they have never become comedy tropes — reflecting the uniquely emasculating perception of the rectal examination.Peer reviewe

Theileria lestoquardi displays reduced genetic diversity relative to sympatric Theileria annulata in Oman

The Apicomplexan parasites, Theileria lestoquardi and Theileria annulata, the causative agents of theileriosis in small and large ruminants, are widespread in Oman, in areas where cattle, sheep and goats co-graze. Genetic analysis can provide insight into the dynamics of the parasite and the evolutionary relationship between species. Here we identified ten genetic markers (micro- and mini-satellites) spread across the T. lestoquardi genome, and confirmed their species specificity. We then genotyped T. lestoquardi in different regions in Oman. The genetic structures of T. lestoquardi populations were then compared with previously published data, for comparable panels of markers, for sympatric T. annulata isolates. In addition, we examined two antigen genes in T. annulata (Tams1 and Ta9) and their orthologues in T. lestoquardi (Tlms1 and Tl9). The genetic diversity and multiplicity of infection (MOI) were lower in T. lestoquardi (He = 0.64–0.77) than T. annulata (He = 0.83–0.85) in all populations. Very limited genetic differentiation was found among T. lestoquardi and T. annulata populations. In contrast, limited but significant linkage disequilibrium was observed within regional populations of each species. We identified eight T. annulata isolates in small ruminants; the diversity and MOI were lower among ovine/caprine compared to bovine. Sequence diversity of the antigen genes, Tams1 and Ta9 in T. annulata (π = 0.0733 and π = 0.155 respectively), was 10-fold and 3-fold higher than the orthologous Tlms1 and Tl9 in T. lestoquardi (π = 0.006 and π = 0.055, respectively). Despite a comparably high prevalence, T. lestoquardi has lower genetic diversity compared to sympatric T. annulata populations. There was no evidence of differentiation among populations of either species. In comparison to T. lestoquardi, T. annulata has a larger effective population size. While genetic exchange and recombination occur in both parasite species, the extent of diversity, overall, is less for T. lestoquardi. It is, therefore, likely that T. lestoquardi evolved from an ancestor of present day T. annulata and that this occurred either once or on a limited number of occasions

A bovine lymphosarcoma cell line infected with theileria annulata exhibits an irreversible reconfiguration of host cell gene expression

Theileria annulata, an intracellular parasite of bovine lymphoid cells, induces substantial phenotypic alterations to its host cell including continuous proliferation, cytoskeletal changes and resistance to apoptosis. While parasite induced modulation of host cell signal transduction pathways and NFκB activation are established, there remains considerable speculation on the complexities of the parasite directed control mechanisms that govern these radical changes to the host cell. Our objectives in this study were to provide a comprehensive analysis of the global changes to host cell gene expression with emphasis on those that result from direct intervention by the parasite. By using comparative microarray analysis of an uninfected bovine cell line and its Theileria infected counterpart, in conjunction with use of the specific parasitacidal agent, buparvaquone, we have identified a large number of host cell gene expression changes that result from parasite infection. Our results indicate that the viable parasite can irreversibly modify the transformed phenotype of a bovine cell line. Fifty percent of genes with altered expression failed to show a reversible response to parasite death, a possible contributing factor to initiation of host cell apoptosis. The genes that did show an early predicted response to loss of parasite viability highlighted a sub-group of genes that are likely to be under direct control by parasite infection. Network and pathway analysis demonstrated that this sub-group is significantly enriched for genes involved in regulation of chromatin modification and gene expression. The results provide evidence that the Theileria parasite has the regulatory capacity to generate widespread change to host cell gene expression in a complex and largely irreversible manner

Increased Radial Access Is Not Associated With Worse Femoral Outcomes for Percutaneous Coronary Intervention in the United Kingdom.

BACKGROUND: The radial artery is increasingly adopted as the primary access site for cardiac catheterization because of patient preference, lower bleeding rates, cost effectiveness, and reduced risk of mortality in high-risk patient groups. Concerns have been expressed that operators/centers have become increasingly unfamiliar with transfemoral access. The aim of this study was to assess whether a change in access site practice toward transradial access nationally has led to worse outcomes in percutaneous coronary intervention procedures performed through the transfemoral access approach. METHODS AND RESULTS: Using the British Cardiovascular Intervention Society (BCIS) database, a retrospective analysis of 235 250 transfemoral access percutaneous coronary intervention procedures was undertaken in all 92 centers in England and Wales between 2007 and 2013. Recent femoral proportion and recent femoral volume were determined, and in-hospital vascular complications and 30-day mortality were evaluated. After case-mix adjustment, no independent association was observed between 30-day mortality for cases undertaken through the transfemoral access and center femoral proportion, the risk-adjusted odds ratio for recent femoral proportion was nonsignificant (odds ratio, 0.99; 95% confidence interval, 0.97-1.02; P=0.472 per 0.1 increase in proportion), and similarly recent femoral volume (per 100 procedures) was not found to be significant (odds ratio, 1.00; 95% confidence interval, 0.98-1.01; P=0.869). The in-hospital vascular complication rate was 1.0%, and this outcome was not significantly associated with recent femoral proportion after risk-adjustment (odds ratio, 0.97; 95% confidence interval, 0.94-1.00; P=0.060 per 0.1 increase in proportion). CONCLUSIONS: The outcome gains achieved by the national adoption of radial access are not associated with a loss of femoral proficiency, and centers should be encouraged to continue to adopt radial access as the default access site for percutaneous coronary intervention wherever possible in line with current best evidence