CNS germinoma with extensive calcification: An unusual histologic finding.

INTRODUCTION: Intratumoral calcification is a feature that is more often observed in pineal parenchymal tumour than germinoma. We describe a 13-year-old male with pineal region germinoma demonstrating extensive intratumoral calcification. CASE REPORT: He presented with worsening headache that was associated with fatigue, nausea and vomiting. Radiologic examination revealed a multilobular mass in the pineal region with internal calcifications. Biopsy showed a pure germinoma with unusually extensive calcification. DISCUSSION: Although a diagnosis may be suggested with a careful evaluation of imaging, there is no pathognomonic pattern. Thus, histologic verification is necessary for most pineal region masses.

Risk factors for heat illness among British soldiers in the hot Collective Training Environment.

BACKGROUND: Heat illness is a preventable disorder in military populations. Measures that protect vulnerable individuals and contribute to effective Immediate Treatment may reduce the impact of heat illness, but depend upon adequate understanding and awareness among Commanders and their troops. OBJECTIVE: To assess risk factors for heat illness in British soldiers deployed to the hot Collective Training Environment (CTE) and to explore awareness of Immediate Treatment responses. METHODS: An anonymous questionnaire was distributed to British soldiers deployed in the hot CTEs of Kenya and Canada. Responses were analysed to determine the prevalence of individual (Intrinsic) and Command-practice (Extrinsic) risk factors for heat illness and the self-reported awareness of key Immediate Treatment priorities (recognition, first aid and casualty evacuation). RESULTS: The prevalence of Intrinsic risk factors was relatively low in comparison with Extrinsic risk factors. The majority of respondents were aware of key Immediate Treatment responses. The most frequently reported factors in each domain were increased risk by body composition scoring, inadequate time for heat acclimatisation and insufficient briefing about casualty evacuation. CONCLUSIONS: Novel data on the distribution and scale of risk factors for heat illness are presented. A collective approach to risk reduction by the accumulation of 'marginal gains' is proposed for the UK military. This should focus on limiting Intrinsic risk factors before deployment, reducing Extrinsic factors during training and promoting timely Immediate Treatment responses within the hot CTE.

Thoracic aortopathies in the military patient.

Thoracic aortic disease is an important contributor to arterial disease and therefore, mortality in the UK. It has close associations with hypertension, atherosclerosis and genetic conditions such as Marfan syndrome. The cardiovascular consequences of acute aortic dissection or the rupture of a thoracic aneurysm are life threatening with a 1% increase in mortality per hour with a type A aortic dissection and a high 30-day mortality rate. The clinical diagnosis can be difficult for the general physician as the symptoms can mimic more common conditions such as acute coronary syndrome, pulmonary embolism or acute abdomen. The investigations that carry the highest sensitivity and specificity, CT, transoesophageal echocardiography and MRI are not usually first-line investigations in most patients so a high index of clinical suspicion is key. The management of acute aortic syndromes involves good initial resuscitation and early discussion with the cardiothoracic surgeons. Given the serious consequences of acute aortic syndromes, it is important for all military doctors to be aware of these presentations and to appreciate the difficulties that can be encountered when trying to accurately diagnose them. Routine medicals, particularly entrance medicals, present a unique clinical opportunity to recognise the clinical features that would warrant further investigation and specialist advice.

Pericarditis and pericardial effusions in the military patient.

The pericardium is the thin double-walled sac encapsulating the heart which has a number of important physiological roles including fixing the heart in the mediastinum, protecting it from cross-organ infection (eg, lung) and lubricating cardiac contraction. The pericardium is associated with several disease syndromes that occasionally affect the military population. These include acute and recurrent pericarditis, pericardial effusion and tamponade, which may result from a large number of different aetiological agents. Pericardial diseases have a wide range of clinical manifestations and the diagnosis of pericardial diseases can be a challenge. This article reviews the anatomy and pathophysiology of pericarditis and pericardial effusions before outlining their clinical features, recommended investigations and management options. Particular emphasis is placed on the impact of these diseases for patients in a military occupational environment.

Myocarditis and the military patient.

Myocarditis, simply defined as inflammation of the heart muscle, is a commonly encountered cardiac disease in primary and secondary care, both in the UK and on Operational deployments. In the UK Armed Forces, myocarditis results in deaths as well as the premature termination of military careers on medical grounds. The aetiology is usually the result of a number of infectious aetiologies with viruses being the most common pathogens in the vast majority of cases. However, it may also be the result of autoimmune activation, chemical or pharmacological toxins, environmental insult or hypersensitivity reactions. Particular aetiologies that are more likely to be seen in a military population are discussed and include certain infections, smallpox vaccine, and hyperthermia and hypothermia. The clinical features can be highly variable ranging from an asymptomatic infection to fulminant heart failure. Features pertinent to the military doctor, including the natural history, investigative modalities and management strategies, with a particular emphasis on the occupational impact of myocarditis in the UK Armed Forces are reviewed.

Delivery of bevacizumab to atheromatous porcine carotid tissue using echogenic liposomes.

Ultrasound is both a valuable diagnostic tool and a promoter of beneficial tissue bioeffects for the treatment of cardiovascular disease. Vascular effects can be mediated by mechanical oscillations of circulating microbubbles that may also encapsulate and shield therapeutic agents in the bloodstream. Here, the effect of color-Doppler ultrasound exposure on bevacizumab-loaded liposome delivery into the vascular bed was assessed in atheromatous porcine carotids. Bevacizumab, an anti-angiogenic antibody to vascular endothelial growth factor (VEGF-A), was loaded into echogenic liposomes (BEV-ELIP) and confirmed to be immunoreactive. BEV-ELIP flowing within the lumen were exposed to color-Doppler ultrasound at three acoustic pressures for 3.5 min during treatment at physiologic temperature and fluid pressure. To confirm the presence of bubble activity, cavitation was detected within the lumen by a single-element passive cavitation detector. After treatment, the artery was fixed at physiologic pressure and subjected to immunohistochemical analysis to assess the penetration of bevacizumab within the carotid wall. The results suggest that other factors may more strongly influence the deposition of bevacizumab into carotid tissue than color-Doppler ultrasound and cavitation. In both sets of arteries, preferential accumulation of bevacizumab occurred in locations associated with atheroma progression and neointimal thickening: fibrous tissue, necrotic plaque and areas near macrophage infiltration. The delivery of bevacizumab to carotid vascular tissue correlated with the properties of the tissue bed, such as permeability, or affinity for growth-factor binding. Future investigations using this novel therapeutic strategy may focus on characterizing the spatial extent of delivery and bevacizumab colocalization with biochemical markers of atheroma.

A novel meningococcal outer membrane vesicle vaccine with constitutive expression of FetA: A phase I clinical trial.

OBJECTIVES: Outer membrane vesicle (OMV) vaccines are used against outbreaks of capsular group B Neisseria meningitidis (MenB) caused by strains expressing particular PorA outer membrane proteins (OMPs). Ferric enterobactin receptor (FetA) is another variable OMP that induces type-specific bactericidal antibodies, and the combination of judiciously chosen PorA and FetA variants in vaccine formulations is a potential approach to broaden protection of such vaccines. METHODS: The OMV vaccine MenPF-1 was generated by genetically modifying N. meningitidis strain 44/76 to constitutively express FetA. Three doses of 25 µg or 50 µg of MenPF-1 were delivered intra-muscularly to 52 healthy adults. RESULTS: MenPF-1 was safe and well tolerated. Immunogenicity was measured by serum bactericidal assay (SBA) against wild-type and isogenic mutant strains. After 3 doses, the proportion of volunteers with SBA titres ≥1:4 (the putative protective titre) was 98% for the wild-type strain, and 77% for the strain 44/76 FetA(on)PorA(off) compared to 51% in the strain 44/76 FetA(off)PorA(off), demonstrating that vaccination with MenPF-1 simultaneously induced FetA and PorA bactericidal antibodies. CONCLUSION: This study provides a proof-of-concept for generating bactericidal antibodies against FetA after OMV vaccination in humans. Prevalence-based choice of PorA and FetA types can be used to formulate a vaccine for broad protection against MenB disease.

N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists.

The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds 3-[-(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino}methyl]-1,2,4-triazole (11) and 5-[¿(2S,3S)-3-(((3,5-bis(trifluoromethyl)-phenyl)methyl)oxy)-2- phenylpiperidino}methyl]-3-oxo-1,2,4-triazolone (12)), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.

Initial investigation of acoustic droplet vaporization for occlusion in canine kidney.

Acoustic droplet vaporization (ADV) shows promise for spatially and temporally targeted tissue occlusion. In this study, substantial tissue occlusion was achieved in operatively exposed and transcutaneous canine kidneys by generating ADV gas bubbles in the renal arteries or segmental arteries. Fifteen canines were anesthetized, among which 10 underwent laparotomy to externalize the left kidney and five were undisturbed for transcutaneous ADV. The microbubbles were generated by phase conversion of perfluoropentane droplets encapsulated in albumin or lipid shells in the blood. A 3.5-MHz single-element therapy transducer was aligned with an imaging array in a water tank with direct access to the renal artery or a segmental artery. In vivo color flow and spectral Doppler imaging were used to identify the target arteries. Tone bursts of 1 kHz pulse repetition frequency with 0.25% duty cycle vaporized the droplets during bolus passage. Both intracardiac (IC) and intravenous (IV) injections repeatedly produced ADV in chosen arteries in externalized kidneys, as seen by B-mode imaging. Concurrent with this in two cases was the detection by pulse-wave Doppler of blood flow reversal, along with a narrowing of the waveform. Localized cortex occlusion was achieved with 87% regional flow reduction in one case using IC injections. Vaporization from IV injections resulted in a substantial echogenicity increase with an average half-life of 8 min per droplet dose. Gas bubbles sufficient to produce some shadowing were generated by transcutaneous vaporization of intrarenal artery or IV-administered droplets, with a tissue path up to 5.5 cm.

Information at the touch of a button.

At a time of increasing interest in the development of computerised supplies information systems, N. Evers-Crabtree, K. Haworth and J. Batchelor describe the development and implementation of an on-line stock control and stores accounting system in North Western RHA.

Developing Techniques and Strategies for the Management of Cancer Pain.

The past 20 years have seen a great surge of interest in understanding and treating pain. The introduction of sustained-release opioid delivery systems has tremendously advanced our ability to provide improved pain control. Parenteral opioid delivery systems, although available in many developed nations, remain expensive and cumbersome. New advances in parenteral sustained-release systems are currently in development. These advances include liposomal opioid preparations for intrathecal use, transcutaneous patient-controlled delivery, and implantable diffusion reservoirs. Even more exciting are new developments in tissue engineering that may allow the transplantation of human or animal cells, capable of producing natural analgesic substances, into the vicinity of the spinal cord.

The expression of receptor tyrosine phosphatases is responsive to sciatic nerve crush.

Given the importance of phosphotyrosine signaling in growth cone dynamics, we have examined the embryonic and adult expression of receptor-like protein tyrosine phosphatases in sensory neurons and studied their responsiveness to nerve lesions in young adult animals. The phosphatases LAR, PTPsigma, and PTPalpha are expressed in most neurons of E14 and E18 rat embryo dorsal root ganglia, while BEM-1 is expressed in a more restricted subset of these neurons. These phosphatases continue to be expressed in young adult animals, suggesting that they have roles in mature as well as in developing dorsal root ganglia neurons. After an experimental sciatic nerve crush, the expression of the phosphatase genes was significantly and differentially altered in these neurons. PTPsigma mRNA was increased by 50% after 3 days, while LAR and PTPalpha expression dropped by 50 and 20%, respectively. BEM-1 mRNA levels were unaltered. These data show that mRNA levels of specific tyrosine phosphatase genes are highly responsive to nerve damage and may be reset to a new and potentially optimal pattern of expression more conducive for nerve regeneration. We propose that tyrosine phosphatases are not only involved in primary axonogenesis but can also now be implicated in the molecular control of adult nerve repair.

The canine homeobox gene MSX2: sequence, chromosome assignment and genetic analysis in dogs of different breeds.

The MSX2 gene encodes a homeodomain transcription factor important for normal head and face morphogenesis. MSX2 is expressed in key craniofacial structures during development and mutations in the human gene give rise to various craniofacial abnormalities. We are interested in the genetic basis of non-pathogenic variation in skull and face shape. As part of this study we have analysed DNA from a panel of different dog breeds, selected for the differences they show in these traits and investigated MSX2 as a candidate gene. In this paper we describe the cloning of the canine homologue of MSX2, the determination of its structure, sequence and localization of the gene to dog chromosome 4q23. The DNAs from 11 individual domestic dogs belonging to 10 different breeds were sequenced in a search for genetic variation. Our studies show that variation in MSX2 does not contribute to the diversity of face shape observed in these domestic dogs and that the MSX2 sequence is strongly conserved between different dog breeds. The proximal promoter shows a high level of interspecies sequence conservation and several conserved transcription factor binding motifs have been identified and their significance discussed.

Canine homolog of the T-box transcription factor T; failure of the protein to bind to its DNA target leads to a short-tail phenotype.

Domestic dog breeds show a wide variety of morphologies and offer excellent opportunities to study the molecular genetics of phenotypic traits. We are interested in exploring this potential and have begun by investigating the genetic basis of a short-tail trait. Our focus has been on the T gene, which encodes a T-box transcription factor important for normal posterior mesoderm development. Haploinsufficiency of T protein underlies a short-tail phenotype in mice that is inherited in an autosomal dominant fashion. We have cloned the dog homolog of T and mapped the locus to canine Chromosome (Chr) 1q23. Full sequence analysis of the T gene from a number of different dog breeds identified several polymorphisms and a unique missense mutation in a bob-tailed dog and its bob-tailed descendants. This mutation is situated in a highly conserved region of the T-box domain and alters the ability of the T protein to bind to its consensus DNA target. Analysis of offspring from several independent bobtail x bobtail crosses indicates that the homozygous phenotype is embryonic lethal.

A study of peroxidase levels in human cervical mucus as an index of ovulation.

Fourteen healthy women were screened for the following parameters throughout one complete menstrual cycle: levels of urinary oestrogens and pregnanediol; levels of plasma and urinary gonadotrophins; and pH, protein content and levels of peroxidase in the cervical mucus. It was found that concentrations of peroxidase in the cervical mucus were not a reliable index of ovulation.

PIP: Samples of cervical mucus, plasma, and urine were collected daily through 1 complete menstrual cycle from 14 healthy volunteers not taking oral contraceptives and screened for pH, protein content, levels of peroxidase in the cervical mucus, and for levels of urinary estrogens and pregnanediol and plasma and urinary gonadotropins. Ovulation occurred in 13 of the women. It was found that although peroxidase concentrations are a reliable indication of ovulation in veterinary science, it is a poor indicator in human beings. Only 2 of the women had a peak of peroxidase activity at ovulation. Others had 1 or 2 peaks before and/or after ovulation. In the anovulatory cycle a wide fluctuation is seen. Charts present the findings.

TTY2: a multicopy Y-linked gene family.

Genes involved in human male sex determination and spermatogenesis are likely to be located on the Y chromosome. In an effort to identify Y-linked, testis-expressed genes, a cDNA selection library was generated by selecting testis cDNA with Y-cosmid clones. Resultant clones containing repetitive or vector material were eliminated, and 79 of the remaining clones were sequenced. Nineteen cDNAs showed homology with the TTY2 gene, and indicated that TTY2 is part of a large gene family. Screening of a panel of Y-linked cosmids revealed that the TTY2 gene family includes at least 26 members organized in 14 subfamilies. Further investigation revealed that TTY2 genes are arranged in tandemly arrayed clusters on both arms of the Y chromosome, and each gene comprises a series of tandemly arranged repeats. RT-PCR studies for two of these genes revealed that they are expressed in adult and fetal testis, as well as in the adult kidney. None of the genes investigated in detail contain an open reading frame. We conclude that the TTY2 gene family is composed of multiple copies, some of which may function as noncoding RNA transcripts and some may be pseudogenes.

Canine TCOF1; cloning, chromosome assignment and genetic analysis in dogs with different head types.

We describe the construction of a dog embryonic head/neck cDNA library and the isolation of the dog homolog of the Treacher Collins Syndrome gene, TCOF1. The protein shows a similar three-domain structure to that described for human TCOF1, but the dog gene lacks exon 10 and contains two exons not present in the human sequence. In addition, exon 19 is differentially spliced in the dog. How these structural differences relate to TCOF1 phosphorylation is discussed. Isolation of a genomic clone allowed the exon/intron boundaries to be characterized and the dog TCOF1 gene to be mapped to CF Chr 4q31, a region syntenic to human Chr 5. Genetic analysis of DNA of dogs from 13 different breeds identified nine DNA sequence variants, three of which gave rise to amino acid substitutions. Grouping dogs according to head type showed that a C396T variant, leading to a Pro117Ser substitution, is associated with skull/face shape in our dog panel. The numbers are small, but the association between the T allele and brachycephaly, broad skull/short face, was highly significant (p = 0.000024). The short period of time during which the domestic dog breeds have been established suggests that this mutation has arisen only once in the history of dog domestication.