Challenging gestational trophoblastic disease cases and mimics: An exemplar for the management of rare tumours.

OBJECTIVE: Rare tumour management is challenging for clinicians as evidence bases are limited and clinical trials are difficult to conduct. It is even more difficult for patients where self-reliance alone is insufficient to overcome the challenges of navigating care which is often poorly evidence based. In Ireland, a national Gestational Trophoblastic Disease (GTD) service was established as one of 3 initiatives for rare tumours by the National Cancer Control Programme. The service has a national clinical lead, a dedicated supportive nursing service and a clinical biochemistry liaison team. This study sought to assess the impact of a GTD centre using national clinical guidelines and integrating and networking with European and International GTD groups on the clinical management of challenging GTD cases and to consider the application of this model of care to other rare tumour management. STUDY DESIGN: In this article, we analyse the impact of a national GTD service on five challenging cases, and review how the service affects patient management in this rare tumour type. These cases were selected from a cohort of patients who were voluntarily registered in the service based on the diagnostic management dilemma they posed. RESULTS: Case management was impacted by the identification of GTD mimics, the provision of lifesaving treatment of metastatic choriocarcinoma with brain metastasis, networking with international colleagues, the identification of early relapse, the use of genetics to differentiate treatment pathways and prognosis, and supportive supervision of treatment courses of up to 2 years of therapy in a cohort of patients starting or completing families. CONCLUSION: The National GTD service could be an exemplar for the management of rare tumours (such as cholangiocarcinoma) in our jurisdiction which could benefit from a similar constellation of supports. Our study demonstrates the importance of a nominated national clinical lead, dedicated nurse navigator support, registration of cases and networking. The impact of our service would be greater if registration was mandatory rather than voluntary. Such a measure would also ensure equity of access for patients to the service, assist in quantifying the need for resourcing and facilitate research to improve outcomes.

Advancing the Practice of Contemporary Military Performance Psychology:A Full-Spectrum Approach to Psychological Health and Readiness.

The Department of Defense (DoD) continues to emphasize operational readiness, lethality, and optimal performance. Performance psychology is a critical aspect of and central dimension to human performance optimization in support of Preservation of the Force and Family (POTFF) and Total Force Fitness (TFF). The delivery of performance psychology services must continue to evolve to maximize its potential for enhancing combat performance and supporting psychological readiness in warfighters across all branches of service. The authors (1) provide a brief history of the evolution of military psychology; (2) explore how performance psychology complements and broadens approaches to support warfighter health and readiness; and (3) present a set of strategies to advance performance psychology services toward an aspirational model. Such strategies will more effectively promote best practices to better target operational performance, complement existing health and medical service delivery, and encompass a systems approach to sustainable training. Moreover, these strategies aim to increase return on investment of psychological readiness efforts for warfighters across all branches of service.

Potential exposure to Australian bat lyssavirus is unlikely to prevent future bat handling among adults in South East Queensland.

Despite ongoing public health messages about the risks associated with bat contact, the number of potential exposures to Australian bat lyssavirus (ABLV) due to intentional handling by members of the general public in Queensland has remained high. We sought to better understand the reasons for intentional handling among these members of the public who reported their potential exposure to inform future public health messages. We interviewed adults who resided in a defined geographic area in South East Queensland and notified potential exposure to ABLV due to intentional handling of bats by telephone between 1 January 2012 and 31 December 2013. The participation rate was 54%. Adults who reported they had intentionally handled bats in South East Queensland indicated high levels of knowledge and perception of a moderately high risk associated with bats with overall low intentions to handle bats in the future. However, substantial proportions of people would attempt to handle bats again in some circumstances, particularly to protect their children or pets. Fifty-two percent indicated that they would handle a bat if a child was about to pick up or touch a live bat, and 49% would intervene if a pet was interacting with a bat. Future public health communications should recognize the situations in which even people with highrisk perceptions of bats will attempt to handle them. Public health messages currently focus on avoidance of bats in all circumstances and recommend calling in a trained vaccinated handler, but messaging directed at adults for circumstances where children or pets may be potentially exposed should provide safe immediate management options.

Changing paradigms in ethical issues and urolithiasis.

This article defines the ethics involved in the medical treatment of patients. Using a case example, the authors discuss the treatment of uroliths from an ethical and medical perspective. Uroliths are defined, and treatment is discussed and explained.

Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity.

Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review, we have already discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both these molecules have pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity they play an important role in autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by the signalling cascades set into motion within their target cells. In this second review, we will, once again, describe the signal transduction pathways activated by these two cytokines and focus on how this relates to the pathogenesis of autoimmune diseases. We will also describe some of the therapeutic approaches that are being investigated to curtail the pro-inflammatory activities of these two molecules.

Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity.

Autoimmune diseases such as rheumatoid arthritis are the consequence of a persistent imbalance between pro- and anti-inflammatory immune mechanisms leading to chronic inflammation. The action of several cytokines is at the basis of this complex process. This review is focused on the signalling events triggered by two major groups of cytokines, namely the IL-12 and IL-17 families, which in the past few years have been shown to have a prominent role in the pathogenesis of such diseases. In particular, we will focus on the signalling cascades set in motion by such cytokines and how this may relate to the pathogenesis of human immune and inflammatory disorders as knowledge of such cascades may help in the development of novel therapeutic approaches for such diseases.

Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors.

Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF. This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree. These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role.

Screening for Chlamydia trachomatis in asymptomatic women attending outpatient clinics in a large maternity hospital in Dublin, Ireland.

BACKGROUND: Chlamydia trachomatis can cause a sexually transmitted infection, which, untreated, may result in considerable morbidity. METHODS: A prevalence study was conducted for C trachomatis using nucleic acid amplification technology in asymptomatic women, and certain risk factors that may be used to direct future screening strategies were assessed. RESULTS: The study population comprised 945 asymptomatic women, of whom 783 were attending antenatal clinics, 91 were attending infertility clinics and 71 were attending family planning clinics. An overall C trachomatis prevalence of 3.7% (35/945) was found, with the highest prevalence of 11.2% (22/196) in Irish single women aged <25 years. Logistic regression analysis showed that single status and age <25 years were independent, statistically significant predictors of C trachomatis infection. CONCLUSION: These results support routine screening of asymptomatic women who are sexually active and aged <25 years. An opportunist active screening of all sexually active women independent of age should be additionally considered if resources permit.

Accelerating the induction of Fas-mediated T cell apoptosis: a strategy for transplant tolerance?

Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction of specific tolerance after organ transplantation.

Cerebral salt-wasting syndrome. We need better proof of its existence.

It is widely believed that the cerebral salt-wasting syndrome (CSWS) exists as an entity distinct from the syndrome of inappropriate ADH secretion, and that it is characterized by evidence of severe renal salt wasting that results in volume depletion and hyponatremia. Proof of the existence of CSWS as an entity requires documentation of renal salt wasting and volume depletion. The present review has been undertaken to examine the evidence that the CSWS is a separate entity. In this effort, we have discussed various methods of documentation of volume depletion, and then reviewed reported cases of CSWS to determine whether volume depletion and renal salt wasting have been clearly demonstrated. Our review has led us to conclude that not one case of purported CSWS has demonstrated clear evidence of volume depletion and renal salt wasting. If renal salt wasting had been proven in these cases, we would conclude that the likely site of renal salt transport was the proximal tubule. The proximal site of salt transport defect has been suggested by the absence of hyperreninemia and hypokalemia, which would be a distinguishing feature of Bartter's syndrome and Gitelman's syndrome.

Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican.

Lumican, a prototypic leucine-rich proteoglycan with keratan sulfate side chains, is a major component of the cornea, dermal, and muscle connective tissues. Mice homozygous for a null mutation in lumican display skin laxity and fragility resembling certain types of Ehlers-Danlos syndrome. In addition, the mutant mice develop bilateral corneal opacification. The underlying connective tissue defect in the homozygous mutants is deregulated growth of collagen fibrils with a significant proportion of abnormally thick collagen fibrils in the skin and cornea as indicated by transmission electron microscopy. A highly organized and regularly spaced collagen fibril matrix typical of the normal cornea is also missing in these mutant mice. This study establishes a crucial role for lumican in the regulation of collagen assembly into fibrils in various connective tissues. Most importantly, these results provide a definitive link between a necessity for lumican in the development of a highly organized collagenous matrix and corneal transparency.

D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms.

This report describes a case of d-lactic acidosis observed by the authors and then reviews all case reports of d-lactic acidosis in the literature in order to define its clinical and biochemical features and pathogenetic mechanisms. The report also reviews the literature on metabolism of d-lactic acid in humans. The clinical presentation of d-lactic acidosis is characterized by episodes of encephalopathy and metabolic acidosis. The diagnosis should be considered in a patient who presents with metabolic acidosis and high serum anion gap, normal lactate level, negative Acetest, short bowel syndrome or other forms of malabsorption, and characteristic neurologic findings. Development of the syndrome requires the following conditions 1) carbohydrate malabsorption with increased delivery of nutrients to the colon, 2) colonic bacterial flora of a type that produces d-lactic acid, 3) ingestion of large amounts of carbohydrate, 4) diminished colonic motility, allowing time for nutrients in the colon to undergo bacterial fermentation, and 5) impaired d-lactate metabolism. In contrast to the initial assumption that d-lactic acid is not metabolized by humans, analysis of published data shows a substantial rate of metabolism of d-lactate by normal humans. Estimates based on these data suggest that impaired metabolism of d-lactate is almost a prerequisite for the development of the syndrome.

Mutational Disruption of the Biosynthesis Genes Coding for the Antifungal Metabolite 2,4-Diacetylphloroglucinol Does Not Influence the Ecological Fitness of Pseudomonas fluorescens F113 in the Rhizosphere of Sugarbeets.

The ability of Pseudomonas fluorescens F113 to produce the antibiotic 2,4-diacetylphloroglucinol (DAPG) is a key factor in the biocontrol of the phytopathogenic fungus Pythium ultimum by this strain. In this study, a DAPG-producing strain (rifampin-resistant mutant F113Rif) was compared with a nearly isogenic DAPG-negative biosynthesis mutant (Tn5::lacZY derivative F113G22) in terms of the ability to colonize and persist in the rhizosphere of sugarbeets in soil microcosms during 10 plant growth-harvest cycles totaling 270 days. Both strains persisted similarly in the rhizosphere for 27 days, regardless of whether they had been inoculated singly onto seeds or coinoculated in a 1:1 ratio. In order to simulate harvest and resowing, the roots were removed from the soil and the pots were resown with uninoculated sugarbeet seeds for nine successive 27-day growth-harvest cycles. Strains F113Rif and F113G22 performed similarly with respect to colonizing the rhizosphere of sugarbeet, even after nine cycles without reinoculation. The introduced strains had a transient effect on the size of the total culturable aerobic bacterial population. The results indicate that under these experimental conditions, the inability to produce DAPG did not reduce the ecological fitness of strain F113 in the rhizosphere of sugarbeets.

Season of birth and school attendance.

Previous research has shown that summer compared to autumn or spring born children have been found to do less well educationally, to be more likely to have their abilities underestimated and to be considered to have behaviour problems, but not to differ in terms of school attendance. That last result is refuted by the results of this study which is based on more than 5000 pupils in their last year of primary education and which reveals that: (a) after controlling for gender and size of family, the summer born have the poorest and the autumn born the highest attendance rates; and (b) in the case of pupils with attendance rates of 80 per cent or less, more of them are summer born and fewer, autumn born.

Disorders of sodium metabolism: hypernatremia and hyponatremia.

OBJECTIVE: Discussion of abnormal plasma sodium concentrations with an emphasis on the pathogenesis, diagnosis, and treatment. DATA SOURCES: Relevant literature in the English language and the authors' clinical experience. STUDY SELECTION: No special study has been carried out for the present discussion. DATA EXTRACTION: The information from the literature and the data from the authors' clinical experience have been used to illustrate important points in the discussion. DATA SYNTHESIS: A most important aspect in the approach to hypernatremia is determination of the mechanism responsible for impaired water intake. Various mechanisms of abnormal water loss can be determined from measurement of urine osmolality. Hypernatremia is treated by water replacement and measures to reduce abnormal water loss. In most instances, hyponatremia is caused by inappropriate concentration of urine because of either appropriate or inappropriate antidiuretic hormone secretion. The determination of appropriateness of antidiuretic hormone secretion requires the assessment of effective arterial volume. Treatment depends on the pathogenetic mechanism. CONCLUSIONS: Abnormal plasma sodium concentration results from abnormal water intake or water output. Treatment is guided by determining the pathogenetic mechanism.