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1.  Changes in procoagulants track longitudinally with insulin resistance: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) study 
To examine the association between changes in procoagulants (fibrinogen factors VII and VIII and von Willebrand factor) and the risk of insulin resistance.
Using data from the Coronary Artery Risk Development in Young Adults study, we followed 2398 black and white adults without diabetes, aged 25–37 years at year 7, to year 20. Levels of fibrinogen factors VII and VIII and von Willebrand factor were divided in tertiles (low/middle/high) at years 7 and 20 and four groups reflecting changes were defined: ‘low’ (low at years 7 and 20), ‘stable’ (low/middle at years 7 and 20, but not both low at years 7 and 20), ‘high’ (high at year 7 and low/middle at year 20; or low/middle at year 7 and high at year 20) and ‘highest’ (high at years 7 and 20). Linear regression models were used to evaluate 13-year changes (year 20–year 7) in fibrinogen level and factors VII, VIII and von Willebrand change groups in relation to insulin resistance measures.
Homeostasis model assessment of insulin resistance (year 20) and changes in log homeostasis model assessment of insulin resistance (year 20–year 7) were significantly associated with the 13-year increase in fibrinogen (P < 0.001). Compared with participants in the low group, those in the high group had significantly higher levels of homeostasis model assessment of insulin resistance (year 20) and changes in homeostasis model assessment of insulin resistance (year 20–year 7) for fibrinogen factor VII and von Willebrand factor (P < 0.017). No significant associations were observed between fibrinogen VIII and insulin resistance measures.
An increase in fibrinogen level and persistently high levels of factor VII and von Willebrand factor are significantly associated with increased risk of insulin resistance. These findings provide new insight into the mechanisms to explain the heightened risk for thrombosis in adults with insulin resistance/diabetes.
PMCID: PMC3959576  PMID: 24344794
2.  Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 
Galluzzi, L | Bravo-San Pedro, J M | Vitale, I | Aaronson, S A | Abrams, J M | Adam, D | Alnemri, E S | Altucci, L | Andrews, D | Annicchiarico-Petruzzelli, M | Baehrecke, E H | Bazan, N G | Bertrand, M J | Bianchi, K | Blagosklonny, M V | Blomgren, K | Borner, C | Bredesen, D E | Brenner, C | Campanella, M | Candi, E | Cecconi, F | Chan, F K | Chandel, N S | Cheng, E H | Chipuk, J E | Cidlowski, J A | Ciechanover, A | Dawson, T M | Dawson, V L | De Laurenzi, V | De Maria, R | Debatin, K-M | Di Daniele, N | Dixit, V M | Dynlacht, B D | El-Deiry, W S | Fimia, G M | Flavell, R A | Fulda, S | Garrido, C | Gougeon, M-L | Green, D R | Gronemeyer, H | Hajnoczky, G | Hardwick, J M | Hengartner, M O | Ichijo, H | Joseph, B | Jost, P J | Kaufmann, T | Kepp, O | Klionsky, D J | Knight, R A | Kumar, S | Lemasters, J J | Levine, B | Linkermann, A | Lipton, S A | Lockshin, R A | López-Otín, C | Lugli, E | Madeo, F | Malorni, W | Marine, J-C | Martin, S J | Martinou, J-C | Medema, J P | Meier, P | Melino, S | Mizushima, N | Moll, U | Muñoz-Pinedo, C | Nuñez, G | Oberst, A | Panaretakis, T | Penninger, J M | Peter, M E | Piacentini, M | Pinton, P | Prehn, J H | Puthalakath, H | Rabinovich, G A | Ravichandran, K S | Rizzuto, R | Rodrigues, C M | Rubinsztein, D C | Rudel, T | Shi, Y | Simon, H-U | Stockwell, B R | Szabadkai, G | Tait, S W | Tang, H L | Tavernarakis, N | Tsujimoto, Y | Vanden Berghe, T | Vandenabeele, P | Villunger, A | Wagner, E F | Walczak, H | White, E | Wood, W G | Yuan, J | Zakeri, Z | Zhivotovsky, B | Melino, G | Kroemer, G
Cell Death and Differentiation  2014;22(1):58-73.
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
PMCID: PMC4262782  PMID: 25236395
3.  Male infertility in long-term survivors of pediatric cancer: A report from the Childhood Cancer Survivor Study 
The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors.
Within the Childhood Cancer Survivor Study, 1622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1622; 57.8%) and siblings (174/274; 63.5%) who tried to become pregnant. Relative risks (RR) and 95% confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided.
Among those who provided self-report data, the prevalence of infertility was 46.0% in survivors versus 17.5% in siblings (RR=2.64, 95% CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37% had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose score (AAD) ≥ 3 (RR= 2.13, 95% CI 1.69-2.68 for AAD ≥ 3 versus AAD<3), surgical excision of any organ of the genital tract (RR=1.63, 95% CI 1.20-2.21), testicular radiation ≥ 4Gy (RR=1.99, 95% CI 1.52-2.61), and exposure to bleomycin (RR=1.55, 95% CI 1.20-2.01).
Many survivors who experience infertility father their own children suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation.
Implications for Cancer Survivors
Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.
PMCID: PMC4276596  PMID: 24711092
infertility; cancer; male; long-term survivors; pediatrics
4.  Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice 
Cell Death and Differentiation  2013;20(9):1174-1182.
Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates Eμ-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2−/−/MMTV mice compared with Casp2+/+/MMTV and Casp2+/−/MMTV mice. Cells from Casp2−/−/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2+/+/MMTV and Casp2+/−/MMTV tumors never displayed this phenotype. Tumors from Casp2−/−/MMTV animals had a significantly higher mitotic index than tumors from Casp2+/+/MMTV and Casp2+/−/MMTV animals. Cell cycle analysis of Casp2−/− E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase-2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability.
PMCID: PMC3741497  PMID: 23645210
caspase; apoptosis; oncogene
6.  Osteoarthritis and the Rule of Halves 
Osteoarthritis and Cartilage  2014;22(4):535-539.
Symptomatic osteoarthritis poses a major challenge to primary health care but no studies have related accessing primary care (‘detection’), receiving recommended treatments (‘treatment’), and achieving adequate control (‘control’).
To provide estimates of detection, treatment, and control within a single population adapting the approach used to determine a Rule of Halves for other long-term conditions.
General population.
400 adults aged 50+ years with prevalent symptomatic knee osteoarthritis.
Prospective cohort with baseline questionnaire, clinical assessment, and plain radiographs, and questionnaire follow-up at 18 and 36 months and linkage to primary care medical records.
Outcome measures
‘Detection’ was defined as at least one musculoskeletal knee-related GP consultation between baseline and 36 months. ‘Treatment’ was self-reported use of at least one recommended treatment or physiotherapy/hospital specialist referral for their knee problem at all three measurement points. Pain was ‘controlled’ if characteristic pain intensity <5 out of 10 on at least two occasions.
In 221 cases (55.3%; 95%CI: 50.4, 60.1) there was evidence that the current problem had been detected in general practice. Of those detected, 164 (74.2% (68.4, 80.0)) were receiving one or more of the recommended treatments at all three measurement points. Of those detected and treated, 45 (27.4% (20.5, 34.3)) had symptoms under control on at least two occasions. Using narrower definitions resulted in substantially lower estimates.
Osteoarthritis care does not conform to a Rule of Halves. Symptom control is low among those accessing health care and receiving treatment.
PMCID: PMC3988991  PMID: 24565953
Osteoarthritis; Rule of Halves; Primary care
8.  Risk stratification of pT1-3N0 patients after radical cystectomy for adjuvant chemotherapy counselling 
British Journal of Cancer  2012;107(11):1826-1832.
In pT1-T3N0 urothelial carcinoma of the bladder (UCB) patients, multi-modal therapy is inconsistently recommended. The aim of the study was to develop a prognostic tool to help decision-making regarding adjuvant therapy.
We included 2145 patients with pT1-3N0 UCB after radical cystectomy (RC), naive of neoadjuvant or adjuvant therapy. The cohort was randomly split into development cohort based on the US patients (n=1067) and validation cohort based on the Europe patients (n=1078). Predictive accuracy was quantified using the concordance index.
With a median follow-up of 45 months, 5-year recurrence-free and cancer-specific survival estimates were 68% and 73%, respectively. pT-stage, ge, lymphovascular invasion, and positive margin were significantly associated with both disease recurrence and cancer-specific mortality (P-values⩽0.005). The accuracies of the multivariable models at 2, 5, and 7 years for predicting disease recurrence were 67.4%, 65%, and 64.4%, respectively. Accuracies at 2, 5, and 7 years for predicting cancer-specific mortality were 69.3%, 66.4%, and 65.5%, respectively. We developed competing-risk, conditional probability nomograms. External validation revealed minor overestimation.
Despite RC, a significant number of patients with pT1-3N0 UCB experience disease recurrence and ultimately die of UCB. We developed and externally validated competing-risk, conditional probability post-RC nomograms for prediction of disease recurrence and cancer-specific mortality.
PMCID: PMC3504939  PMID: 23169335
bladder cancer; radical cystectomy; T1-3 N0; prediction; nomogram; chemotherapy
9.  Genetically defining the mechanism of Puma- and Bim-induced apoptosis 
Cell Death and Differentiation  2011;19(4):642-649.
Using genetically modified mouse models, we report here that p53 upregulated modulator of apoptosis (Puma) and Bcl-2 interacting mediator of cell death (Bim), two pro-apoptotic members of the B-cell lymphoma protein-2 (Bcl-2) family of proteins, cooperate in causing bone marrow and gastrointestinal tract toxicity in response to chemo and radiation therapy. Deletion of both Puma and Bim provides long-term survival without evidence of increased tumor susceptibility following a lethal challenge of carboplatin and ionizing radiation. Consistent with these in vivo findings, studies of primary mast cells demonstrated that the loss of Puma and Bim confers complete protection from cytokine starvation and DNA damage, similar to that observed for Bax/Bak double knockout cells. Biochemical analyses demonstrated an essential role for either Puma or Bim to activate Bax, thereby leading to mitochondrial outer membrane permeability, cytochrome c release and apoptosis. Treatment of cytokine-deprived cells with ABT-737, a BH3 mimetic, demonstrated that Puma is sufficient to activate Bax even in the absence of all other known direct activators, including Bim, Bid and p53. Collectively, our results identify Puma and Bim as key mediators of DNA damage-induced bone marrow failure and provide mechanistic insight into how BH3-only proteins trigger cell death.
PMCID: PMC3307979  PMID: 22015606
Puma; Bim; apoptosis; myelosuppression; ABT-737
10.  Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 
Cell Death and Differentiation  2011;19(1):107-120.
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including ‘apoptosis', ‘necrosis' and ‘mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
PMCID: PMC3252826  PMID: 21760595
autophagy; mitochondrial membrane permeabilization; necroptosis; parthanatos; TNFR1; TP53
11.  Caspase-2: the orphan caspase 
Cell Death and Differentiation  2011;19(1):51-57.
Despite an abundance of literature on the role of caspase-2 in apoptosis, there exists much controversy about this protease making it difficult to place caspase-2 correctly in the apoptotic cascade, and hence its role in apoptosis remains unclear. The identification of the PIDDosome as a signaling platform for caspase-2 activation prompted intense investigation into the true role of this orphan caspase. What has emerged is the idea that caspase-2 may not be mandatory for apoptosis and that activation of this caspase in response to some forms of stress has other effects on the cell such as regulation of cell cycle progression. This idea is particularly relevent to the discovery that caspase-2 may act as a tumor suppressor. Here, we discuss the proposed mechanisms through which caspase-2 signals, in particular those involving PIDD, and their impact on cellular fate.
PMCID: PMC3252831  PMID: 22075987
caspase-2; apoptosis; PIDD; PIDDosome; cell cycle
12.  Use of sophisticated intra-operative monitoring in resuscitation of unexpected cardiovascular collapse during general anaesthesia 
The diagnosis of intraoperative anaphylaxis is important but can be difficult as the symptoms can be varying and dependent on patient factors.
We describe an acute, unexpected and life threatening cardiovascular (CV) collapse, presumed to be due to an acute anaphylactic reaction secondary to gelatin administration, following induction of general anaesthesia (GA), in an ASA 3 patient scheduled for axillo-bifemoral bypass.
The management of the profound cardiovascular (CV) collapse was greatly assisted by sophisticated haemodynamic, depth of anaesthesia and cerebral oximetry monitoring.1 As far as we are aware this is the first such case where the full haemodynamic, depth of anaesthesia and cerebral oxygenation changes during CV collapse, presumed due to an acute anaphylactic reaction under GA have been fully documented.
The use of advanced monitoring intraoperatively proved extremely useful in guiding the resuscitation of a life threatening allergic reaction under general anaesthesia.
PMCID: PMC3604686  PMID: 23336989
General anaesthesia; Analphylaxis; Haemodynamic monitoring; Cerebral oximetry; Depth of anaesthesia monitoring
14.  Structural correlates for lexical efficiency and number of languages in non-native speakers of English 
Neuropsychologia  2012;50(7):1347-1352.
► We dissociate structural correlates for two different non-native language skills. ► Number of languages spoken was associated with the posterior supramarginal gyrus. ► The efficiency of word use was associated with the left pars opercularis.
We used structural magnetic resonance imaging (MRI) and voxel based morphometry (VBM) to investigate whether the efficiency of word processing in the non-native language (lexical efficiency) and the number of non-native languages spoken (2+ versus 1) were related to local differences in the brain structure of bilingual and multilingual speakers. We dissociate two different correlates for non-native language processing. Firstly, multilinguals who spoke 2 or more non-native languages had higher grey matter density in the right posterior supramarginal gyrus compared to bilinguals who only spoke one non-native language. This is interpreted in relation to previous studies that have shown that grey matter density in this region is related to the number of words learnt in bilinguals relative to monolinguals and in monolingual adolescents with high versus low vocabulary. Our second result was that, in bilinguals, grey matter density in the left pars opercularis was positively related to lexical efficiency in second language use, as measured by the speed and accuracy of lexical decisions and the number of words produced in a timed verbal fluency task. Grey matter in the same region was also negatively related to the age at which the second language was acquired. This is interpreted in terms of previous findings that associated the left pars opercularis with phonetic expertise in the native language.
PMCID: PMC3382713  PMID: 22401989
Language; Efficiency; Lexical; MRI; Bilingual
15.  Preferential control of induced regulatory T cell homeostasis via a Bim/Bcl-2 axis 
Cell Death & Disease  2012;3(2):e270-.
Apoptosis has an essential role in controlling T cell homeostasis, especially during the contraction phase of an immune response. However, its contribution to the balance between effector and regulatory populations remains unclear. We found that Rag1−/− hosts repopulated with Bim−/− conventional CD4+ T cells (Tconv) resulted in a larger induced regulatory T cell (iTreg) population than mice given wild-type (WT) Tconv. This appears to be due to an increased survival advantage of iTregs compared with activated Tconv in the absence of Bim. Downregulation of Bcl-2 expression and upregulation of Bim expression were more dramatic in WT iTregs than activated Tconv in the absence of IL-2 in vitro. The iTregs generated following Tconv reconstitution of Rag1−/− hosts exhibited lower Bcl-2 expression and higher Bim/Bcl-2 ratio than Tconv, which indicates that iTregs were in an apoptosis-prone state in vivo. A significant proportion of the peripheral iTreg pool exhibits low Bcl-2 expression indicating increased sensitivity to apoptosis, which may be a general characteristic of certain Treg subpopulations. In summary, our data suggest that iTregs and Tconv differ in their sensitivity to apoptotic stimuli due to their altered ratio of Bim/Bcl-2 expression. Modulating the apoptosis pathway may provide novel therapeutic approaches to alter the balance between effector T cells and Tregs.
PMCID: PMC3288351  PMID: 22318539
iTreg; apoptosis; Bim; Bcl-2
16.  Welcome to Oncogenesis 
Oncogenesis  2012;1(2):e2-.
PMCID: PMC3412633  PMID: 23552519
17.  Infection in conflict wounded 
Although mechanisms of modern military wounding may be distinct from those of ancient conflicts, the infectious sequelae of ballistic trauma and the evolving microbial flora of war wounds remain a considerable burden on both the injured combatant and their deployed medical systems. Battlefield surgeons of ancient times favoured suppuration in war wounding and as such Galenic encouragement of pus formation would hinder progress in wound care for centuries. Napoleonic surgeons eventually abandoned this mantra, embracing radical surgical intervention, primarily by amputation, to prevent infection. Later, microscopy enabled identification of microorganisms and characterization of wound flora. Concurrent advances in sanitation and evacuation enabled improved outcomes and establishment of modern military medical systems. Advances in medical doctrine and technology afford those injured in current conflicts with increasing survivability through rapid evacuation, sophisticated resuscitation and timely surgical intervention. Infectious complications in those that do survive, however, are a major concern. Addressing antibiotic use, nosocomial transmission and infectious sequelae are a current clinical management and research priority and will remain so in an era characterized by a massive burden of combat extremity injury. This paper provides a review of infection in combat wounding from a historical setting through to the modern evidence base.
PMCID: PMC3013428  PMID: 21149356
war; wound; infection; trauma; antibiotic; nosocomial
18.  Deep Brain Stimulation of the Periaqueductal Grey (PAG) Induces Vasodilation in Humans 
Hypertension  2011;57(5):e24-e25.
PMCID: PMC3092071  PMID: 21403090
19.  Host immunity to repeated rabies virus infection in big brown bats 
The Journal of General Virology  2010;91(Pt 9):2360-2366.
Bats are natural reservoirs for the majority of lyssaviruses globally, and are unique among mammals in having exceptional sociality and longevity. Given these facets, and the recognized status of bats as reservoirs for rabies viruses (RABVs) in the Americas, individual bats may experience repeated exposure to RABV during their lifetime. Nevertheless, little information exists with regard to within-host infection dynamics and the role of immunological memory that may result from abortive RABV infection in bats. In this study, a cohort of big brown bats (Eptesicus fuscus) was infected intramuscularly in the left and right masseter muscles with varying doses [10−0.1–104.9 median mouse intracerebral lethal doses (MICLD50)] of an E. fuscus RABV variant isolated from a naturally infected big brown bat. Surviving bats were infected a second time at 175 days post-(primary) infection with a dose (103.9–104.9 MICLD50) of the same RABV variant. Surviving bats were infected a third time at either 175 or 305 days post-(secondary) infection with a dose (104.9 MICLD50) of the same RABV variant. When correcting for dose, similar mortality was observed following primary and secondary infection, but reduced mortality was observed following the third and last RABV challenge, despite infection with a high viral dose. Inducible RABV-neutralizing antibody titres post-infection were ephemeral among infected individuals, and dropped below levels of detection in several bats between subsequent infections. These results suggest that long-term repeated infection of bats may confer significant immunological memory and reduced susceptibility to RABV infection.
PMCID: PMC3052523  PMID: 20519458
22.  Alcohol exposure and outcomes in trauma patients 
To determine the injury patterns, complications, and mortality after alcohol consumption in trauma patients.
The Trauma Registry at an American College of Surgeons (ACS) level I center was queried for all patients with a toxicology screen admitted between 1st January 2002 and 31st December 2005. Alcohol-positive (AP) patients were matched to control patients who had a completely negative screen (AN) using age, gender, mechanism, Injury Severity Score (ISS), head Abbreviated Injury Scale (AIS), chest AIS, abdominal AIS, and extremity AIS. Injuries and outcomes were compared between the groups.
As many as 5,317 patients had toxicology data, of which 471 (8.9%) had a positive alcohol screen (AP). A total of 386 AP patients were then matched to 386 control (AN) patients. The AP group had a significantly higher mortality than the AN group overall (23 vs. 13%; p < 0.001), and by ISS stratification: ISS < 16 (6 vs. 0.4%; p < 0.001), ISS 16–25 (53 vs. 28%; p = 0.01), and ISS > 25 (90 vs. 67%; p = 0.01). AP patients had a higher incidence of admission systolic blood pressure < 90 (18 vs. 10%; p < 0.001) and Glasgow Coma Scale (GCS) score ≤ 8 (25 vs. 17%; p = 0.002). AN patients had a significantly higher incidence of hemopneumothorax (11 vs. 7%; p = 0.03), while AP patients had a higher incidence of cardiac arrest (8 vs. 3%; p = 0.004). There was no difference in intensive care unit (ICU) and hospital length of stay.
In a mixed population of trauma patients, an AP screen is associated with an increased incidence of admission hypotension and depressed GCS score. In this case-matched study, alcohol exposure appeared to increase mortality after injury.
PMCID: PMC3150794  PMID: 21837258
Alcohol; Injury; Trauma; Complications; Mortality
23.  Longitudinal assessment of fibrinogen in relation to subclinical cardiovascular disease: the CARDIA study 
To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons.
A population-based, prospective, observational study of black and white men and women (Coronary Artery Risk Development in Young Adults [CARDIA]). Fibrinogen levels were measured at year 7 (ages 25–37, n = 2969), and again at year 20 (ages 38–50, n = 2832). Measures of subclinical atherosclerosis (coronary artery calcification [CAC] and carotid intimal-medial thickness [CIMT]) were recorded at year 20.
Over the 13-year study interval (1992–1993 to 2005–2006), fibrinogen rose from a mean of 3.32 to 4.05 g L−1. After adjusting for age, gender and race, fibrinogen was positively associated with greater incidence of CAC and increased CIMT cross-sectionally as well as after 13 years of follow-up (all P-trend < 0.001). After further adjustment for field center, BMI, smoking, education, systolic blood pressure, diabetes, antihypertensive medication use, total and HDL cholesterol, and CRP, significant positive relationships between fibrinogen and incidence of CAC remained for the total cohort longitudinally (P-trend = 0.037), but not cross-sectionally (P-trend = 0.147).
This 13-year study demonstrates that higher levels of fibrinogen during young adulthood are positively associated with incidence of CAC and increased CIMT in middle-age, but the strength of the association declines with increasing age.
PMCID: PMC2856753  PMID: 20025644
atherosclerosis; carotid thickening; coronary calcification; fibrinogen
24.  Depersonalisation/derealisation symptoms in vestibular disease 
Depersonalisation is a subjective experience of unreality and detachment from the self often accompanied by derealisation; the experience of the external world appearing to be strange or unreal. Feelings of unreality can be evoked by disorienting vestibular stimulation.
To identify the prevalence of depersonalisation/derealisation symptoms in patients with peripheral vestibular disease and experimentally to induce these symptoms by vestibular stimulation.
121 healthy subjects and 50 patients with peripheral vestibular disease participated in the study. For comparison with the patients a subgroup of 50 age matched healthy subjects was delineated. All completed (1) an in‐house health screening questionnaire; (2) the General Health Questionnaire (GHQ‐12); (3) the 28‐item depersonalisation/derealisation inventory of Cox and Swinson (2002). Experimental verification of “vestibular induced” depersonalisation/derealisation was assessed in 20 patients and 20 controls during caloric irrigation of the labyrinths.
The frequency and severity of symptoms in vestibular patients was significantly higher than in controls. In controls the most common experiences were of “déjà vu” and “difficulty in concentrating/attending”. In contrast, apart from dizziness, patients most frequently reported derealisation symptoms of “feel as if walking on shifting ground”, “body feels strange/not being in control of self”, and “feel ‘spacey' or ‘spaced out'”. Items permitted discrimination between healthy subjects and vestibular patients in 92% of the cases. Apart from dizziness, caloric stimulation induced depersonalisation/derealisation symptoms which healthy subjects denied ever experiencing before, while patients reported that the symptoms were similar to those encountered during their disease.
Depersonalisation/derealisation symptoms are both different in quality and more frequent under conditions of non‐physiological vestibular stimulation. In vestibular disease, frequent experiences of derealisation may occur because distorted vestibular signals mismatch with the other sensory input to create an incoherent frame of spatial reference which makes the patient feel he or she is detached or separated from the world.
PMCID: PMC2077438  PMID: 16464901
depersonalisation; derealisation; dissociation; vestibular; dizziness
25.  Neonatal hypothermia detection by ThermoSpot in Indian urban slum dwellings 
To look at the performance of ThermoSpot liquid crystal thermometry in detecting neonatal hypothermia.
A comparison was made between skin temperatures taken by ThermoSpot and axillary temperatures taken by digital electric thermometry. Non‐medically trained local volunteers performed daily paired recordings on infants on days 1, 2, 3, 4, 5, 6, and 7 of life.
This is a non‐hospital based study set in the homes of neonates in an underprivileged urban slum community in the developing world.
Inclusion criteria: babies born at home. Exclusion criteria: hospital admission; parental refusal.
The ThermoSpot was stuck to the neonate's abdomen over the liver area on day 1 and removed on day 7.
Main outcome measures
Fixed test properties of ThermoSpot.
Over 180 paired observations, the fixed test properties of ThermoSpot in the detection of hypothermia were: sensitivity 88%; specificity 97%; positive likelihood ratio 29; negative likelihood ratio 0.13.
ThermoSpot performed well when used by non‐medically trained volunteers for the detection of neonatal hypothermia in the homes of an urban slum community.
PMCID: PMC2672686  PMID: 16159955
hypothermia; liquid crystal thermometry; ThermoSpot; temperature

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