Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect.

PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

Red Blood Cell Distribution Width is Associated with Poor Clinical Outcome After Subarachnoid Hemorrhage: A Pilot Study.

INTRODUCTION: The red cell distribution width (RDW) is a biomarker strongly associated with poor outcome in inflammatory and thrombotic diseases. Subarachnoid hemorrhage (SAH) is both an inflammatory and thrombotic state in which many biomarkers have been studied. In this exploratory pilot study, we sought to determine whether RDW predicts poor outcome in patients with SAH. METHODS: Patients with moderate-to-severe SAH were prospectively enrolled in an observational study of biomarkers and outcome. CBC, ESR, high sensitivity CRP, D-dimer, and fibrinogen were obtained on post-bleed days (PBD) 1, 3, 5, 7, and 10. Poor outcome was defined as a modified Rankin score of 3-6 at 90-days. RESULTS: Of 40 patients, 5 (12.5%) died and 19 (47.5%) had a poor outcome. RDW (p = 0.046) when measured serially over the study period, was significantly higher among patients with poor outcome. Maximum RDW (OR 2.3 95% CI 1.2-3.6; p = 0.014) and maximum WBC count (OR 1.29 95% CI 1.04-1.60; p = 0.018) were associated with poor outcome. Stepwise addition of maximum ESR, CRP, D-dimer, and fibrinogen yielded a model with RDW (OR 2.54 95% CI 1.21-5.35; p = 0.014) and fibrinogen (OR 1.01 95% CI 1.002-1.01; p = 0.004) predicting outcome. With addition of age and Hunt and Hess grade, RDW, fibrinogen, and high-grade status remained significantly associated with poor outcome. Use of PBD1 RDW in lieu of maximum RDW, resulted in a similar model. CONCLUSIONS: An elevated RDW is associated with poor outcome in SAH patients. RDW may be a useful predictor of outcomes after SAH.

Physiologic Effects of Xenon in Xenon-CT Cerebral Blood Flow Studies on Comatose Patients.

Despite more than 30 years of clinical use, questions remain about the safety of xenon gas in Xenon-CT cerebral blood flow (XeCTCBF) studies. In particular, xenon's effect on brain oxygen (PbtO2) in comatose patients is not well defined. Our objective was to assess the effect of a 4.5-min inhalation of 28 % stable xenon on several physiologic variables, including intracranial pressure (ICP), cerebral perfusion pressure (CPP), and PbtO2 in comatose patients (Glasgow Coma Scale [GCS] ≤ 8). Thirty-seven comatose patients who underwent 73 XeCTCBF studies were identified retrospectively from a prospective observational database. Changes in MAP, HR, SaO2, EtCO2, ICP, CPP, and PbtO2 measured at the start of xenon administration and every minute for 5 min thereafter were assessed. The maximum change in each variable also was determined for each scan to tabulate clinically relevant changes. Statistically, but not clinically significant changes in MAP, HR, and EtCO2 were seen. Xenon had no effect on ICP, and a small, but clinically insignificant decrease in CPP and PbtO2, was observed. There was a varied response to xenon in most measured variables. Clinically significant changes in each were infrequent, and readily reversed with the cessation of the gas. We conclude that xenon does not appear to have a clinically significant effect on ICP, CPP, and PbtO2 and so appears safe to evaluate cerebral blood flow in comatose patients.

Bone metastases: assessment of therapeutic response through radiological and nuclear medicine imaging modalities.

Radiological and nuclear medicine imaging modalities used for assessing bone metastases treatment response include plain and digitalised radiography (XR), skeletal scintigraphy (SS), dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), magnetic resonance imaging (MRI), [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) and PET/CT. Here we discuss the advantages and disadvantages of these assessment modalities as evident through different clinical trials. Additionally, we present the more established response criteria of the International Union Against Cancer and the World Health Organization and compare them with newer MD Anderson criteria. Even though serial XR and SS have been used to assess the therapeutic response for decades, several months are required before changes are evident. Newer techniques, such as MRI or PET, may allow an earlier evaluation of response that may be quantified through monitoring changes in signal intensity and standard uptake value, respectively. Moreover, the application of PET/CT, which can follow both morphological and metabolic changes, has yielded interesting and promising results that give a new insight into the natural history of metastatic bone disease. However, only a few studies have investigated the application of these newer techniques and further clinical trials are needed to corroborate their promising results and establish the most suitable imaging parameters and evaluation time points. Last, but not least, there is an absolute need to adopt uniform response criteria for bone metastases through an international consensus in order to better assess treatment response in terms of accuracy and objectivity.

Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension.

BACKGROUND: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO(2)) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. METHODS: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO(2) monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO(2), ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. RESULTS: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO(2) (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p<0.01) while mannitol did not affect PbtO(2) (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. CONCLUSIONS: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Cyclic strain activates the pro-survival Akt protein kinase in bovine aortic smooth muscle cells.

BACKGROUND: Pulsatile pressure induced by the beating heart causes cyclic strain on arterial endothelial cells and smooth muscle cells (SMCs). This study examined whether Akt, a serine/threonine protein kinase known to promote cell survival by inhibiting apoptosis, is activated by cyclic strain in bovine aortic SMCs. METHODS: Bovine aortic SMCs were cultured on flexible-bottomed membranes and then serum-starved for 24 to 36 hours. The cells were then exposed to 150-mm Hg repetitive deformations, which created an average of 10% strain on the monolayer SMCs at a frequency of 60 cycles/minute for 0 (negative control) and 30 minutes. Platelet-derived growth factor (PDGF)--stimulated SMCs were used as positive controls. Phosphorylation of Akt was determined by means of Western blot analysis. An apoptosis assay (TUNEL) was also performed on SMCs exposed to cyclic strain. RESULTS: Akt phosphorylation was significantly increased over that of the negative control after 30 minutes of cyclic strain and in the PDGF group. Cyclic strain did not increase the prevalence of apoptosis in SMCs over the control. CONCLUSIONS: Cyclic strain activated the pro-survival Akt kinase. The pro-survival function was supported by the fact that cyclic strain did not increase apoptosis in bovine aortic SMCs. This experiment suggests that cyclic strain may induce arterial wall thickening by tipping the balance toward arterial SMC proliferation through the inhibition of apoptosis.

The integrin-mediated cyclic strain-induced signaling pathway in vascular endothelial cells.

The irregular distribution of plaque in the vasculature results from the interaction of local hemodynamic forces with the vessel wall. One well-characterized force is cyclic circumferential strain, the repetitive pulsatile pressure distention on the arterial wall. This review summarizes current research, which has aimed to elicit the signal transduction pathway by which cyclic strain elicits functional and structural responses in endothelial cells; specifically, it summarizes the signaling pathway that begins with the reorganization of integrins. One method by which these extracellular matrix receptors affect signal transduction is through their ability to initiate the process of phosphorylation on tyrosine residues of cytoplasmic protein kinases, including focal adhesion kinase. The strain-induced pathway appears to also involve ras and the mitogen-activated protein kinase family of enzymes, and preliminary data suggests a role for src as well. Ultimately, it is the regulation of gene expression through the modulation of transcription factors that allows endothelial cells to respond to changes in local hemodynamics.

Intermittent pneumatic compression devices -- physiological mechanisms of action.

There are many reports of how IPC is used effectively in the clinical setting; including the prevention of deep venous thrombosis, improvement of circulation in patients with lower extremity arterial diseases, reduction of lymphoedema, and the healing of venous ulcers. However, despite the widely accepted use of IPC, it is still unclear how IPC actually exerts its beneficial effects. The exact physiological mechanisms of action are unknown. The clinical utility of IPC and the putative mechanisms by which IPC could exert its therapeutic effect will be reviewed. The paper will examine the mechanical effects of IPC exerted on the lower extremity, and the subsequent biochemical changes in the circulation. In vitro studies of the effects of mechanical stress such as compressive strain and shear on cultured endothelial cells, and their clinical relevance to IPC will also be reviewed.

Gender does not impact infrainguinal vein bypass graft outcome.

BACKGROUND: The percentage of women requiring infrainguinal bypass graft operations continues to increase, whereas the effect of gender on postoperative outcome remains unclear. The purpose of this study was to assess the influence of gender on patient selection and outcome in patients requiring infrainguinal vein bypass grafting procedures. METHODS: This retrospective study reviewed 217 infrainguinal vein bypass grafts performed over an 8-year period. Medical records and patient interviews were used to determine study measures and outcomes. Gender and multiple covariables affecting patient survival were analyzed; postoperative complications and graft patencies were examined. Bivariate and life-table analyses were conducted, followed by multivariate analysis with the Cox proportional hazards model. RESULTS: No statistical differences existed between men and women for age, diabetes, cardiac disease, tobacco use, hypertension, stroke, renal disease, or prior contralateral bypass or major amputation. Women were more likely to be black (P =.014) and have a spliced vein graft (P =.035). No differences were noted between the 2 groups for 30-day morbidity rates-except women had more incisional complications (P =.01)-or for survival (P =.45), primary-patency (P =.57), secondary-patency (P =. 79), or limb-salvage rates (P =.40). Multivariate analysis showed that gender had no role in affecting survival rates. CONCLUSIONS: Gender does not affect graft patency, limb salvage, or survival rates. There should be no introduction of a gender bias into management of infrainguinal occlusive disease.

Localization of atherosclerosis: role of hemodynamics.

Atherosclerosis is a chronic disease attributed to risk factors that are systemic in nature. Yet the lesions involved do not occur in random fashion. The coronary arteries, the major branches of the aortic arch, and the abdominal aorta and its visceral and major lower extremity branches are particularly susceptible sites. Hemodynamic forces interacting with an active vascular endothelium are responsible for localizing lesions in a nonrandom pattern of distribution. Shear stress and cyclic circumferential strain are the predominant forces that have been characterized. The modification of endothelial cell structure and function by these mechanical forces sheds insight into the vasculature's propensity for atherogenesis.

Chlorinated hydrocarbon solvents: substituting our way toward human carcinogenicity.

A discussion of the history of substitutions in industrial solvent use is presented, and animal carcinogenicity studies with certain chlorinated hydrocarbon solvents are reviewed. The present knowledge on the association between occupational exposure to chlorinated hydrocarbon solvents and human carcinogenicity is summarized, including a critical review of 23 studies pertaining to human carcinogenicity. Several deficiencies are identified in these studies that make interpretation of the results uncertain, including poor characterization of exposures in qualitative and quantitative terms, the small numbers of deaths or cases, and short follow-up periods. Despite these weaknesses, we conclude that, when viewed collectively, the evidence strongly suggests that occupational exposures to chlorinated hydrocarbon solvents are associated with an excess human cancer risk. The literature supports an association between occupational exposures to chlorinated hydrocarbons and elevated risks of leukemia, lymphoma, and urinary tract cancer. Parental occupational exposures are consistently associated with an elevated childhood cancer risk in the offspring.

Occupational lead exposure in Los Angeles County: an occupational risk surveillance strategy.

To better understand occupational lead exposures in Los Angeles County, we undertook a questionnaire survey of lead-using industrial facilities not previously identified by county health department staff. Previously our staff had identified 112 lead-using companies with approximately 2,000 lead-exposed workers countywide. For this survey, we developed a database of 1,353 possible lead-using industrial facilities from several sources, including community "right-to-know" databases, air pollution or sewer permit records, or other environmental databases. A questionnaire interview was completed with 1,001 (81%) of these companies, yielding 178 previously unidentified facilities employing 7,734 workers with potentially significant occupational lead exposures. Compliance with the OSHA lead standard was often poor in these facilities, particularly for workplaces with 20 or fewer employees. Devoting more public health resources to targeted identification of such industrial facilities and to educational outreach would likely help control occupational lead exposure.