Point-of-care determination of neonatal bilirubin with the blood gas analyzer RapidLab 1265.

BACKGROUND: The aim of the study was to evaluate the comparability of the new neonatal bilirubin method on the RapidLab 1265 blood gas analyzer. This point-of-care testing (POCT) device has the option for the determination of neonatal bilirubin, making it potentially valuable for use in neonate intensive care units or in outpatient ambulances. METHODS: We paired 240 patient samples for intermethod comparisons between the new POCT method and the routine laboratory method (Vitros 350 chemistry system with BuBc slide). In parallel, a transcutaneous jaundice meter (JM-103) was applied to the newborns. Low birthweight and premature neonates were excluded from the trial. The turn-around-time (TAT) for the POCT method was also compared with the routine method, and the practicality of the new analyzer was evaluated for clinical purposes. RESULTS: Bilirubin measurements using the RapidLab 1265 are suitable for the application in newborns. For imprecision, coefficients of variation between 5.6% and 23% were found. The correlation between the Vitros 350 (x) and RapidLab 1265 (y) was y=1.0x-0.1 (r=0.91), with a mean bias of +0.1 mg/dL and a 95% limit of agreement of ±2.5 mg/dL. As in all POCT methods, the TAT was significantly lower than that of the core laboratory. CONCLUSIONS: In contrast to the JM-103, the results of the RapidLab 1265 correlated closely with the Vitros 350, although occasional results of both methods were more different than expected. In general, the RapidLab 1265 blood gas analyzer provides clinically useful bilirubin results using neonatal whole blood samples, although imprecision data are higher than for the laboratory method. The POCT device is suitable for neonatal intensive care units after thoroughly training the employees that will use the device.

HPA axis reactivity and lymphocyte glucocorticoid sensitivity in fibromyalgia syndrome and chronic pelvic pain.

OBJECTIVE: Chronic pelvic pain (CPP) and fibromyalgia syndrome (FMS) have been associated with hypothalamic-pituitary-adrenal (HPA) axis alterations, i.e., mild hypocortisolism and enhanced feedback sensitivity. We tested the hypothesis of reduced cortisol release in response to a psychosocial stressor and pharmacological stimulation. Furthermore, glucocorticoid (GC) sensitivity was evaluated. METHODS: Plasma total and salivary-free cortisol concentrations were measured in response to a standardized social laboratory stressor, the Trier Social Stress Test, and to adrenocorticotropin (ACTH)(1-24) stimulation. In the Trier Social Stress Test, we additionally measured ACTH. GC sensitivity was measured by dexamethasone inhibition of lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha production in whole blood. RESULTS: There were no HPA axis alterations in women with CPP (N = 18) in these tests. Patients with FMS (N = 17) showed lower total cortisol release in response to the social stressor and exogenous ACTH, but normal free cortisol and ACTH levels compared with controls (N = 24). GC sensitivity was similar in all groups. CONCLUSIONS: Our results suggest normal HPA responses to stress and ACTH stimulation in patients with CPP but reduced adrenal reactivity in patients with FMS, namely in total cortisol release. Free cortisol on the other hand was unaltered, possibly reflecting an adaptation to reduced circulating total cortisol.

Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study.

CONTEXT: Chronic fatigue syndrome (CFS) is an important public health problem. The causes of CFS are unknown and effective prevention strategies remain elusive. A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention. OBJECTIVE: To examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and nonfatigued control subjects. DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 43 cases with current CFS and 60 nonfatigued controls identified from a general population sample of 56 146 adult residents from Wichita, Kan. MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety, and posttraumatic stress disorder) by CFS status. RESULTS: The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety, and posttraumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology. CONCLUSIONS: This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS.

The low-dose dexamethasone suppression test in fibromyalgia.

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.

Cognitive dysfunction relates to subjective report of mental fatigue in patients with chronic fatigue syndrome.

Patients with chronic fatigue syndrome (CFS) frequently complain of cognitive dysfunction. However, evidence of cognitive impairment in CFS patients has been found in some, but not other, studies. This heterogeneity in findings may stem from the relative presence of mental fatigue in the patient populations examined. The present study assessed this possibility in a population-based sample of CFS patients. In all, 43 patients with CFS defined by the criteria of the 1994 research case definition using measurements recommended by the 2003 International CFS Study Group, and 53 age-, sex-, and race/ethnicity-matched nonfatigued subjects were included in the study. Mental fatigue was assessed using the mental fatigue subscale of the multidimensional fatigue inventory. Cognitive function was evaluated using an automated battery of computerized tests (Cambridge neuropsychological test automated battery (CANTAB)) that assessed psychomotor function, planning and problem-solving abilities, and memory and attentional performance. CFS patients with significant complaints of mental fatigue (score of mental fatigue 2 standard deviations above the mean of nonfatigued subjects) exhibited significant impairment in the spatial working memory and sustained attention (rapid visual information processing) tasks when compared to CFS patients with low complaints of mental fatigue and nonfatigued subjects. In CFS patients with significant mental fatigue, sustained attention performance was impaired only in the final stages of the test, indicating greater cognitive fatigability in these patients. CFS patients with low mental fatigue displayed performance comparable to nonfatigued subjects on all tests of the CANTAB battery. These findings show strong concordance between subjective complaints of mental fatigue and objective measurement of cognitive impairment in CFS patients and suggest that mental fatigue is an important component of CFS-related cognitive dysfunction.

Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS.

OBJECTIVE: Studies of primary and tertiary care patients suggest that maladaptive coping styles contribute to the pathogenesis and maintenance of chronic fatigue syndrome (CFS). We assessed coping styles in persons with unexplained fatigue and nonfatigued controls in a population-based study. METHODS: We enrolled 43 subjects meeting the 1994 Research Case Definition of CFS, matching them with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [we term them insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using standard rating scales. RESULTS: Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability. CONCLUSIONS: We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls.

Predicting posttraumatic stress symptoms from pretraumatic risk factors: a 2-year prospective follow-up study in firefighters.

OBJECTIVE: Most studies focusing on risk factors for posttraumatic stress disorder (PTSD) have used retrospective study designs. Only a small number of studies have prospectively examined risk factors in the immediate aftermath of trauma exposure in predicting PTSD symptoms. The purpose of this study was to identify predictive risk factors for posttraumatic stress symptoms and comorbid psychopathological symptoms present during the time before exposure to traumatic stress in a high-risk population. METHOD: Forty-three professional firefighters were assessed immediately after basic training (baseline) and at 6, 9, 12, and 24 months after entry into firefighter service. Subjects were screened for psychopathological symptoms, including symptoms of PTSD, depression, and anxiety. Subjects were also characterized with regard to personality traits such as self-efficacy, hostility, and alexithymia. Neuroendocrine activity was assessed by examination of awakening and diurnal salivary cortisol profiles and 24-hour urinary catecholamine excretion. Multiple linear regression analysis was used to analyze posttraumatic stress symptoms at 24-month follow-up as a function of pretraumatic characteristics. RESULTS: A high level of hostility and a low level of self-efficacy at baseline accounted for 42% of the variance in posttraumatic stress symptoms after 2 years. Subjects who had both risk factors at baseline showed a significant increase in measures of PTSD symptoms, depression, anxiety, general psychological morbidity, global symptom severity, and alexithymia during the 2-year period. Biological characteristics were not predictive of the development of psychopathological symptoms. CONCLUSIONS: These results suggest that specific personality traits may constitute markers of vulnerability to the development of psychopathological symptoms after trauma exposure. Early identification of preexisting risk factors is needed to provide effective prevention and intervention for individuals who are at risk of developing trauma-related disorders.

Chronic fatigue syndrome--a clinically empirical approach to its definition and study.

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria. METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms). RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm. CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.

Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome.

OBJECTIVES: Validated or standardized self-report questionnaires used in research studies and clinical evaluation of chronic fatigue syndrome (CFS) generally focus on the assessment of fatigue. There are relatively few published questionnaires that evaluate case defining and other accompanying symptoms in CFS. This paper introduces the self-report CDC CFS Symptom Inventory and analyzes its psychometric properties. METHODS: One hundred sixty-four subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas were enrolled. Evaluation included a physical examination, a standardized psychiatric interview, three previously validated self-report questionnaires measuring fatigue and illness impact (Medical Outcomes Survey Short-Form-36 [MOS SF-36], Multidimensional Fatigue Inventory [MFI], Chalder Fatigue Scale), and the CDC CFS Symptom Inventory. Based on theoretical assumptions and statistical analyses, we developed several different Symptom Inventory scores and evaluated them on their ability to differentiate between participants with CFS and non-fatigued controls. RESULTS: The Symptom Inventory had good internal consistency and excellent convergent validity. A Total score (all symptoms), Case Definition score (CFS case defining symptoms) and Short Form score (6 symptoms with minimal correlation) differentiated CFS cases from controls. Furthermore, both the Case Definition and Short Form scores distinguished people with CFS from fatigued subjects who did not meet criteria for CFS. CONCLUSION: The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed. Further research is needed to confirm and replicate the current findings in a normative population.

Regional prevalence of fatiguing illnesses in the United States before and after the terrorist attacks of September 11, 2001.

OBJECTIVE: Stress or emotional traumas are considered risk factors for unexplained fatiguing illnesses. From July to December 2001, the Centers for Disease Control and Prevention conducted a multigeographical pilot study to test the feasibility of a survey to estimate the prevalence of fatiguing illnesses in the United States. We used data obtained during this survey to estimate the effect of the coincidentally occurring terrorist attacks of September 11, 2001, on the regional prevalence of fatiguing illnesses. METHODS: Identified by random-digit dialing, 2,728 households in eight regional strata were interviewed, and 7,317 respondents were screened for severe fatigue of at least 1 month duration. Identified fatigued people of age 18 to 69 years (N = 440) and a sample of nonfatigued people of the same age range (N = 444) were interviewed in detail concerning fatigue, other symptoms, and medical and psychiatric histories. RESULTS: Weighted prevalence estimates based on interviews performed after the attacks were significantly lower compared with estimates based on interviews performed before the attacks (prolonged fatigue: 5,450 vs. 1,530/100,000, p =.010; chronic fatigue: 18,510 vs. 10,070/100,000, p =.002; chronic fatigue syndrome-like illness: 2,510 vs. 960/100,000, p =.014). CONCLUSION: Our findings suggest decreased regional prevalence of fatiguing illnesses in the aftermath of the terrorist attacks. The causes of this effect are unknown but might involve acute psychological and physiological adaptations that modify the perception or manifestation of fatigue. Future studies should be specifically designed to scrutinize the relationship between stress and fatiguing illnesses and the mediating mechanisms of such a relationship.

HPA axis reactivity in chronic pelvic pain: association with depression.

OBJECTIVES: Chronic pelvic pain (CPP) is a frequent gynecological complaint. The pathophysiology of CPP is not fully understood. The aim of this study was to determine whether the presence of depressive symptoms is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in CPP. METHODS: We measured neuroendocrine responses to a standardized social stress test and to a standard adrenocorticotropin (ACTH)(1-24) stimulation test in 18 patients with CPP, stratified based on the presence of high versus low self-reported depressive symptoms, compared with 24 controls. RESULTS: Women with CPP and low depression exhibited enhanced ACTH responses to psychosocial stress compared with women with CPP and high depression, whereas there were no differences in cortisol responses. In the ACTH(1-24) stimulation test, CPP patients with high depression demonstrated enhanced cortisol responses. CONCLUSION: These results suggest a relationship between self-reported depression and reactivity of the HPA axis in patients with CPP.

Efficient synthesis of [3H]-sanglifehrin A via selective oxidation/reduction of alcohols at C31 and C35.

[Reaction: see text]. Sanglifehrin A is a novel complex natural product showing strong immunosuppressive activity and remarkably high affinity for cyclophilin A. To assess its pharmacokinetic properties in vivo, an efficient synthetic route was developed to introduce a tritium label in position C35 of sangliferin A via an oxidation/reduction strategy. The synthetic approach is particularly attractive, because the C35-oxo intermediate 7 is available in good yield on large scale and the reducing agent, lithium tri-sec-butylborotritide, is readily available. An attempt to apply a similar strategy to the alcohol in position C31 led primarily to C31-epi-hydroxy sanglifehrin A under a variety of conditions.

Silver nanowires as surface plasmon resonators.

We report on chemically prepared silver nanowires (diameters around 100 nm) sustaining surface plasmon modes with wavelengths shortened to about half the value of the exciting light. As we find by scattered light spectroscopy and near-field optical microscopy, the nonradiating character of these modes together with minimized damping due to the well developed wire crystal structure gives rise to large values of surface plasmon propagation length and nanowire end face reflectivity of about 10 microm and 25%, respectively. We demonstrate that these properties allow us to apply the nanowires as efficient surface plasmon Fabry-Perot resonators.

The role of early adverse experience and adulthood stress in the prediction of neuroendocrine stress reactivity in women: a multiple regression analysis.

Sensitization of stress-responsive neurobiological systems as a possible consequence of early adverse experience has been implicated in the pathophysiology of mood and anxiety disorders. In addition to early adversities, adulthood stressors are also known to precipitate the manifestation of these disorders. The present study sought to evaluate the relative role of early adverse experience vs. stress experiences in adulthood in the prediction of neuroendocrine stress reactivity in women. A total of 49 women (normal volunteers, depressed patients, and women with a history of early abuse) underwent a battery of interviews and completed dimensional rating scales on stress experiences and psychopathology, and were subsequently exposed to a standardized psychosocial laboratory stressor. Outcome measures were plasma adrenocorticotropin (ACTH) and cortisol responses to the stress test. Multiple linear regression analyses were performed to identify the impact of demographic variables, childhood abuse, adulthood trauma, major life events in the past year, and daily hassles in the past month, as well as psychopathology on hormonal stress responsiveness. Peak ACTH responses to psychosocial stress were predicted by a history of childhood abuse, the number of separate abuse events, the number of adulthood traumas, and the severity of depression. Similar predictors were identified for peak cortisol responses. Although abused women reported more severe negative life events in adulthood than controls, life events did not affect neuroendocrine reactivity. The regression model explained 35% of the variance of ACTH responses. The interaction of childhood abuse and adulthood trauma was the most powerful predictor of ACTH responsiveness. Our findings suggest that a history of childhood abuse per se is related to increased neuroendocrine stress reactivity, which is further enhanced when additional trauma is experienced in adulthood.

Sanglifehrin-cyclophilin interaction: degradation work, synthetic macrocyclic analogues, X-ray crystal structure, and binding data.

Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC(50) = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C(26)=C(27) exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC(50) = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 A of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.