HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

The management of rectal cancer in Ireland in 2007--room for improvement?

INTRODUCTION: Effective management of rectal cancer relies on accurate pre-operative assessment, surgical technical excellence and integrated neoadjuvant and adjuvant chemo and/or radiotherapy. The aim of this study was to examine the management of rectal cancer in Ireland. METHODS: This was a retrospective chart review. All cases of rectal cancer (15 cm or less from the anal verge) diagnosed in Ireland in the year 2007 were included in the audit. RESULTS: In total data for 585 patients were included, under the care of 87 consultant surgeons operating in 48 hospitals. Only data recorded in medical charts were included. Pre-operative investigations were less utilised than recommended by current guidelines and consequently many cancers were inadequately staged. In total 52.5% of cases were discussed at a multi-disciplinary meeting. Overall, 88% of the patients had surgery, and the 30-day mortality rate was 1.7%. The quality of post-operative pathology reporting was variable, with adequacy of total mesorectal excision status unclear or unknown in 74% of cases. Cases were managed in a large number of centres, and in lower volume centres (<5 cases per annum) patients appeared to be less adequately investigated. CONCLUSION: This study gives a snapshot of recent practice in the management of rectal cancer in Ireland but is of necessity limited as the audit was retrospective and long term outcomes have not been assessed. In 2007 rectal cancer was managed in a large number of centres and best practice was frequently not adhered to. The impending centralisation of cancer services is likely to impact on the management of rectal cancer in Ireland.

The use of the RegJoint™ implant for base of thumb osteoarthritis: Results with a minimum follow-up of 2 years.

The RegJoint™ (Scaffdex Oy, Finland) implant is a bio-absorbable poly-L/D-lactide implant which acts as a temporary support in resected joint spaces. It can be used in base of thumb surgery as a spacer to prevent first metacarpal subsidence. However, high rates of adverse tissue reactions and bone osteolysis have been reported recently by one group. The objective of this study was to investigate the outcome of patients treated in our institution with this implant. Patients underwent a postoperative clinical and radiological assessment. The QuickDASH questionnaire, Patient Evaluation Measure (PEM) and a visual analogue scale for pain assessment were used. Grip strength, key pinch, pinch strength, thumb palmar and radial abduction and opposition were measured. Trapeziometacarpal height was used to evaluate thumb shortening compared with the preoperative value. Periprosthetic bone-erosion of the trapezium and metacarpal were measured. Subluxation of the joint was evaluated by measuring the step-off between the radial edge of the trapezium and the base of the first metacarpal bone. Twenty-two patients from 2013-2016 were included. There were no postoperative wound complications. There was no significant difference in grip strength, key pinch or pinch between the operated and the contralateral hand. There was no significant difference in the trapeziometacarpal height, trapezial height or the degree of subluxation pre-or post-operatively. Contrary to recent reports, we did not find any adverse soft tissue reactions or significant bone erosion. There was no significant change in hand function. We consider the RegJoint™ a useful adjunct in the management of a select cohort of patients with base of thumb arthritis.

Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal.

Parafibromin is a nuclear protein with a tumour suppressor role in the development of non-hereditary and hereditary parathyroid carcinomas, and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is associated with renal and uterine tumours. Nuclear localization signal(s), (NLS(s)), of the 61 kDa parafibromin remain to be defined. Utilization of computer-prediction programmes, identified five NLSs (three bipartite (BP) and two monopartite (MP)). To investigate their functionality, wild-type (WT) and mutant parafibromin constructs tagged with enhanced green fluorescent protein or cMyc were transiently expressed in COS-7 cells, or human embryonic kidney 293 (HEK293) cells, and their subcellular locations determined by confocal fluorescence microscopy. Western blot analyses of nuclear and cytoplasmic fractions from the transfected cells were also performed. WT parafibromin localized to the nucleus and deletions or mutations of the three predicted BP and one of the predicted MP NLSs did not affect this localization. In contrast, deletions or mutations of a MP NLS, at residues 136-139, resulted in loss of nuclear localization. Furthermore, the critical basic residues, KKXR, of this MP NLS were found to be evolutionarily conserved, and over 60% of all parafibromin mutations lead to a loss of this NLS. Thus, an important functional domain of parafibromin, consisting of an evolutionarily conserved MP NLS, has been identified.

Correlations between contouring similarity metrics and simulated treatment outcome for prostate radiotherapy.

Many similarity metrics exist for inter-observer contouring variation studies, however no correlation between metric choice and prostate cancer radiotherapy dosimetry has been explored. These correlations were investigated in this study. Two separate trials were undertaken, the first a thirty-five patient cohort with three observers, the second a five patient dataset with ten observers. Clinical and planning target volumes (CTV and PTV), rectum, and bladder were independently contoured by all observers in each trial. Structures were contoured on T2-weighted MRI and transferred onto CT following rigid registration for treatment planning in the first trial. Structures were contoured directly on CT in the second trial. STAPLE and majority voting volumes were generated as reference gold standard volumes for each structure for the two trials respectively. VMAT treatment plans (78 Gy to PTV) were simulated for observer and gold standard volumes, and dosimetry assessed using multiple radiobiological metrics. Correlations between contouring similarity metrics and dosimetry were calculated using Spearman's rank correlation coefficient. No correlations were observed between contouring similarity metrics and dosimetry for CTV within either trial. Volume similarity correlated most strongly with radiobiological metrics for PTV in both trials, including TCPPoisson (ρ = 0.57, 0.65), TCPLogit (ρ = 0.39, 0.62), and EUD (ρ = 0.43, 0.61) for each respective trial. Rectum and bladder metric correlations displayed no consistency for the two trials. PTV volume similarity was found to significantly correlate with rectum normal tissue complication probability (ρ = 0.33, 0.48). Minimal to no correlations with dosimetry were observed for overlap or boundary contouring metrics. Future inter-observer contouring variation studies for prostate cancer should incorporate volume similarity to provide additional insights into dosimetry during analysis.

Terminal myelocystocele and sacrococcygeal teratoma: a comparison of fetal ultrasound presentation and perinatal risk.

This case exemplifies the difficulty in differentiating cystic sacrococcygeal teratoma and terminal myelocystocele. Fetal sonography presentation and perinatal risks of sacrococcygeal teratoma and terminal myelocystocele are compared, and we emphasize the importance of obtaining fetal MR imaging to establish an accurate diagnosis.

2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells.

2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-estradiol, has been implicated as a physiological inhibitor of tumor cell proliferation. In this study, the effects of 2-ME on cultured osteosarcomatous cells were investigated. Dose-dependent growth inhibition was observed in MG63 and TE85 human osteosarcoma cells exposed to 2-ME. The cell killing by 2-ME was ligand-specific; the immediate precursor (2-hydroxyestradiol), the parent compound (17beta-estradiol), and the equivalent metabolite of estrone (2-methoxyestrone) exhibited less potency and efficacy. Furthermore, 2-ME was similarly effective at killing immortalized human fetal osteoblastic cells (hFOB) with and without estrogen receptor-alpha and -beta and rat osteosarcoma cells (ROS17/2.8). The cytotoxicity of 2-ME was selective to transformed and immortalized osteoblastic cells; 2-ME (2 microm) had no effect on the proliferation of primary cultures of human osteoblasts. Co-treatment with the potent estrogen receptor ligand, ICI-182,780, did not reduce 2-ME-induced osteosarcoma cell death, implying that this action is not mediated by conventional estrogen receptors. The expression levels of bone matrix protein genes, type 1 collagen and osteonectin, were transiently reduced after 2-ME treatment, suggesting that the surviving cells are capable of producing bone matrix. The 2-ME-mediated killing of osteosarcoma cells was due to the induction of apoptosis; treatment induced expression of interferon genes within 12 h and histological evidence of apoptosis within 48 h of 2-ME treatment. Thus, our results demonstrate that 2-ME is highly cytotoxic to osteosarcoma cells but not normal osteoblasts. These findings suggest that further study of 2-ME as a potential intervention for treatment of osteosarcoma is warranted.

Clinical and neuroimaging features of familial Alzheimer's disease.

Subtle phenotypic differences between familial Alzheimer's disease (FAD) pedigrees can be identified which may reflect the genetic and allelic heterogeneity of the disease. Positron emission tomography (PET) of APP mutation and chromosome 14-linked FAD pedigree members reveals biparietal bitemporal hypometabolism. Scanning of asymptomatic at-risk individuals reveals a similar, but quantitatively less severe, pattern of hypometabolism.

Alzheimer's disease families with amyloid precursor protein mutations.

Early onset Familial Alzheimer's Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C-terminus of the beta-amyloid domain, APP 717 val-ile, APP 717 val-phe, and APP 717 val-gly, which are associated with autopsy-proven Alzheimer's disease (AD). APP 670/671 lies at the N terminus of the beta-amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val-ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive beta-amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val-gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of beta-amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.

Neuropsychological profiles of familial Alzheimer's disease associated with mutations in the presenilin 1 and amyloid precursor protein genes.

Patients with familial Alzheimer's disease and a subset known to have presenilin mutations were compared with sporadic cases on a comprehensive battery of cognitive tests. These included measures of memory, intelligence, language and perception. The three groups were very comparable, in terms of severity, on global measures of dementia. However, their profiles/patterns of cognitive impairment differed in two respects; the group with sporadic Alzheimer's disease were significantly more impaired on tests of object naming and object perception than either the group with familial Alzheimer's disease or group with familial Alzheimer's disease and presenilin mutations, yet they scored at a significantly higher level on the measure of verbal intelligence. This study provides further evidence of the heterogeneity of the disease process.

Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease.

In order to establish whether positron emission tomography (PET) can identify metabolic changes in Alzheimer's disease at a presymptomatic stage, we have examined 24 asymptomatic at risk individuals from families with Alzheimer's disease. A significant reduction in global cerebral metabolic rate for glucose was found when compared with 16 age-matched controls. There was also a focal, parieto-temporal deficit similar to, although less extensive than, that found in 18 symptomatic individuals from familial Alzheimer's disease (FAD) pedigrees. Follow up of this cohort will establish whether these metabolic changes relate to a presymptomatic stage of the disease.

The use of xenon-133 for measurement of blood flow through systemic arteriovenous malformations before and after therapeutic embolization.

Embolization is increasingly used to treat systemic arteriovenous (AV) shunts although its success, as judged by either angiographic or clinical means, is difficult to quantify. The aim of the study was to quantify blood flow through AV shunts with 133Xe, which, because of its relatively long transit time through peripheral tissues, behaves like microspheres. Following arterial injection, 133Xe entering an AV shunt rapidly arrives in the lung and can be quantified with a scintillation probe. In 17 patients with systemic AV shunts, the reduction in shunt flow following therapeutic embolization was quantified in the angiography theatre by comparing the initial count rates in the lung, recorded by probe, following injection of identical quantities of 133Xe into a supplying artery before and after embolization. By comparing the lung counts with those given by an intravenous injection of 133Xe, the fraction of flow at the catheter tip entering the shunt was also quantified. Tissue perfusion in the vascular territory distal to the shunt was measured at the same time by recording the clearance of non-shunted 133Xe with a second probe over the extremity. Control injections of 133Xe were given in the contralateral limb in order to assess 133Xe transit in the absence of shunting and to compare tissue perfusion between the two sides. Shunt flow ranged from 40% to 100% (of that at the tip of the catheter) (n = 14), while the reduction in shunt flow following embolization ranged from 15% to 96% (n = 19). Tissue perfusion distal to the shunt and in the contralateral limb was about 5 ml 100 ml-1 min-1. Contrast medium had no consistent effect on tissue perfusion in either limb, or on shunt flow. There was no difference in peripheral perfusion between the abnormal and control sides, nor any significant difference in perfusion in the distal tissue on the abnormal side before and after embolization. There was, however, a consistent increase in the fraction of the injected 133Xe delivered to the distal tissue after embolization (median increase 93%, p < 0.001). The technique is relatively simple and merits further development as a means of continuous quantification of systemic AV shunt flow in the angiography theatre at the time of embolization.

MRI of the female pelvis.

MRI is a proven modality to evaluate the female pelvis. Excellent soft tissue contrast, sensitivity for the detection of fluid, and the multiplanar imaging capabilities of MR allow noninvasive demonstration of normal anatomy and pathological processes. Most female pelvic MRI studies are performed to answer specific questions and must, therefore, follow carefully developed protocols, which are discussed in this article. The principal MRI techniques and strategies outlined in this work include: (1) the evaluation of reproductive dysfunction, anatomic variants; (2) specific obstetrical applications; (3) oncologic evaluation and tumor staging; (4) problem solving (i.e., the characterization of abnormalities detected by ultrasound); and (5) the evaluation of urethral disease.

Pressure ulcer prevention: review of literature.

Much has been written about the causes, prevention, and nursing management of pressure ulcers. A review of current literature on the subject reveals that, in spite of the enormity of information available, the problem continues to consume a large percentage of nursing time and energy. Studies of aggressive prevention and ongoing continuing education programs have demonstrated significant reduction of incidence and time of treatment, as well as dramatic cost savings. The Agency for Health Care Policy and Research (AHCPR) has recommended that all patients at risk for pressure ulcer development be placed on some form of pressure-reducing support surface. There is a wide variety of these products available, but a surprisingly limited quantity of published articles specifically compare the efficacy of one product to another.

A case of villoglandular papillary adenocarcinoma of the cervix with vaginal skip metastasis.

► First case of cervical villoglandular cancer with concurrent vaginal skip metastasis. ► Rapid progression to advanced stage with good response to adjuvant therapy.

Coping with stress in surgery: the difficulty of measuring non-technical skills.

BACKGROUND: Non-technical skills are relevant to surgical performance but are difficult to quantify. The aim of this study was to investigate the relationship between self-efficacy, which is a measure of stress-coping ability, and surgical performance. METHODS: Two hundred and sixteen basic surgical trainees were assessed on their performance of three bench model-type open and laparoscopic surgical tasks. They also completed a 10-item General Self-Efficacy (GSE) questionnaire to assess their stress-coping abilities. Their assessment scores were correlated with the GSE scores. RESULTS: The mean GSE score of 31.39 was higher than the recorded population norms. There was no significant correlation between GSE and surgical performance for open or laparoscopic tasks. CONCLUSION: Junior surgical trainees have high self-belief scores, but these abilities are difficult to measure and quantify. More refined methods may be necessary to measure non-technical skills relevant to surgery.

Video gaming enhances psychomotor skills but not visuospatial and perceptual abilities in surgical trainees.

INTRODUCTION: There is considerable interest in the identification and assessment of underlying aptitudes or innate abilities that could potentially predict excellence in the technical aspects of operating. However, before the assessment of innate abilities is introduced for high-stakes assessment (such as competitive selection into surgical training programs), it is essential to determine that these abilities are stable and unchanging and are not influenced by other factors, such as the use of video games. The aim of this study was to investigate whether experience playing video games will predict psychomotor performance on a laparoscopic simulator or scores on tests of visuospatial and perceptual abilities, and to examine the correlation, if any, between these innate abilities. METHODS: Institutional ethical approval was obtained. Thirty-eight undergraduate medical students with no previous surgical experience were recruited. All participants completed a self-reported questionnaire that asked them to detail their video game experience. They then underwent assessment of their psychomotor, visuospatial, and perceptual abilities using previously validated tests. The results were analyzed using independent samples t tests to compare means and linear regression curves for subsequent analysis. RESULTS: Students who played video games for at least 7 hours per week demonstrated significantly better psychomotor skills than students who did not play video games regularly. However, there was no difference on measures of visuospatial and perceptual abilities. There was no correlation between psychomotor tests and visuospatial or perceptual tests. CONCLUSIONS: Regular video gaming correlates positively with psychomotor ability, but it does not seem to influence visuospatial or perceptual ability. This study suggests that video game experience might be beneficial to a future career in surgery. It also suggests that relevant surgical skills may be gained usefully outside the operating room in activities that are not related to surgery.