HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism.

The mechanism by which HIV-1 induces CD4(+) T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4(+) T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism.

The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos.

The most obvious segments of the vertebrate embryo are the trunk mesodermal somites which give rise to the segmented vertebral column and the skeletal muscles of the body. Mechanistic insights into vertebrate somitogenesis have recently been gained from observations of rhythmic expression of the avian hairy-related gene (c-hairy1) in chick presomitic mesoderm (PSM), suggesting the existence of a molecular clock linked to somite segmentation ([1]; reviewed in [2]). Here, we show that lunatic Fringe (IFng), a vertebrate homolog of the Drosophila Fringe gene, is also expressed rhythmically in PSM. The PSM expression of IFng was observed as coordinated pulses of mRNA resembling the expression of c-hairy1. We show that c-hairy1 and IFng expression in the PSM are coincident, indicating that both genes are responding to the same segmentation clock. The genes were found to differ in their regulation, however; in contrast to c-hairy1, IFng mRNA oscillations required continued protein synthesis, suggesting that IFng could be acting downstream of c-hairy1 in the clock mechanism. In Drosophila, Fringe has been shown to play a role in modulating Notch-Delta signalling [3,4], a pathway which in vertebrates has been implicated in defining somite boundaries [5-9]. These observations place the segmentation clock upstream of the Notch-Delta pathway during vertebrate somitogenesis.

Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.

Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 +/- 8.7 vs. 148.4 +/- 20.3 nmol/L; P less than 0.01) and low 24-h urinary free cortisol excretion (122.7 +/- 8.9 vs. 203.1 +/- 10.7 nmol/24 h; P less than 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 +/- 26.4 vs. 225.4 +/- 34.5 pmol/L.min, P less than 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 +/- 0.6 vs. 7.7 +/- 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.

Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings.

The syndrome of chronic fatigue, feverishness, diffuse pains, and other constitutional complaints, often precipitated by an acute infectious illness and aggravated by physical and emotional stressors, has a lengthy history in the medical literature. The Centers for Disease Control (CDC) recently formulated a case definition, renaming the illness "chronic fatigue syndrome." Nevertheless, there remain few biological data that can validate the existence of this syndrome as distinct from a wide variety of other, largely psychiatric disorders, and little understanding of its pathogenesis. In the present study, basal plasma and cerebrospinal fluid levels of the monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) were determined in 19 patients meeting CDC research case criteria for chronic fatigue syndrome and in 17 normal individuals. Patients with chronic fatigue syndrome showed a significant reduction in basal plasma levels of MHPG and a significant increase in basal plasma levels of 5-HIAA. Although the functional significance of these findings has not been definitively elucidated, they are compatible with the clinical presentation of a syndrome associated with chronic lethargy and fatigue, and with evidence of persistent immune stimulation, and lend support to the idea that chronic fatigue syndrome represents a clinical entity with potential biological specificity.

Attention and short-term memory in chronic fatigue syndrome patients: an event-related potential analysis.

We recorded event-related brain potentials (ERPs) from 13 patients with chronic fatigue syndrome (CFS) and 13 matched normal controls. To assess attentional and memory deficits in CFS patients, we used a short-term memory task in which events occurred in different spatial locations and the patients made a rapid-response (RT) when a letter in a relevant location matched a letter in the prememorized set (Attention paradigm). Time-on-task effects on the ERP and behavioral measures were assessed over the 2 1/4-hour duration of this task. Both groups also performed a visual Oddball paradigm, with an RT, before and after the Attention paradigm. The patients' RTs were much more variable and, in nine of 13 cases, slower than the mean RT of the controls in both paradigms. The patients' memory performance was not significantly different from that of the controls and there were no group differences in the overall amplitude, latency, or scalp distribution of the N1, P2, N2, or P300 components of the ERP in either paradigm. The ERP and performance data from both paradigms suggest that perceptual, attentional, and short-term memory processes were unaffected in CFS patients and that the differences were limited to response-related processes.

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression.

We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until they were unable to maintain half maximal force. MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal. The mean amplitudes of MEPs recorded within the first few minutes after the last exercise sets in all three groups were approximately half their mean pre-exercise MEP amplitudes. This postexercise MEP depression was similar in all groups. We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.

Bone and liver images in medullary carcinoma of the thyroid gland: concise communication.

Thirty-four patients with surgically documented medullary carcinoma of the thyroid (MCT) and elevated serum calcitonin levels had Tc-99m phosphate bone and/or Tc-99m sulfur colloid liver images for suspected metastases. Liver images demonstrated metastatic lesions in nine of 32 patients (28%). Bone images were positive for metastases in eight of 30 patients (27%). Four of these eight abnormal bone studies detected only skeletal lesions, two demonstrated only extraosseous metastases, and two showed both kinds. Of 18 patients with both radionuclide bone studies and skeletal radiographs, four demonstrated skeletal metastases, and lesions were recognized on both examinations. This study demonstrates that radionuclide bone and liver images frequently detect metastatic lesions in patients with MCT and elevated serum calcitonin levels, and that some nonskeletal metastases in patients with this tumor display an unusual affinity for bone-seeking radiotracers.

Abnormalities in response to vasopressin infusion in chronic fatigue syndrome.

Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.

Parathyroid transplantation: fate of a long-term allograft in man.

Previously our group reported clinical, histological, and biochemical evidence of parathyroid allograft survival in a patient transplanted sequentially with renal and parathyroid tissues from the same donor. After 30 months of function, both grafts were concomitantly rrjected. The prolonged parathyroid allograft survival described in certain experimental animals has been attributed to the tissue's being "immunologically privileged." Our current clinical observations do not support this hypothesis.

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls.

Two hundred and twenty-five subjects, including normal volunteers and patients with previously documented seasonal affective disorder (SAD), chronic fatigue syndrome (CFS), Cushing's syndrome, Addison's disease and obsessive-compulsive disorder (OCD), completed a self-rated inventory of reported sensitivity to various chemical exposures. Patients with CFS, Addison's disease and SAD self-reported more sensitivity to chemical exposures than normal controls. In addition, women reported more sensitivity than men. This report suggests that chemical sensitivity may be a relevant area to explore in certain medical and psychiatric populations. A possible relationship between reported chemical sensitivity and hypothalamic-pituitary-adrenal (HPA)-axis functioning is discussed.

Lack of seasonal variation of symptoms in patients with chronic fatigue syndrome.

Several of the symptoms involved in chronic fatigue syndrome (CFS) such as fatigue, hypersomnia, hyperphagia, weight gain, and mood show seasonal variations in the general population. The aim of this study was to investigate whether patients with CFS experience seasonal fluctuations in these symptoms as well. Seasonal variation of symptoms was assessed in a group of 41 patients with CFS and 41 controls closely matched for age, gender, and city of residence. Participants were recruited across the US and were asked to complete the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Profile of Mood States (POMS). CFS patients showed significantly lower scores on multiple SPAQ-derived measures as compared with controls. These included seasonal variation in energy, mood, appetite, weight, and sleep length. Patients also reported a significantly reduced sensitivity toward sunny, dry, and long days than controls. No association was noted between intensity of seasonal changes and severity of depressive symptoms. Patients with CFS exhibit an abnormally reduced seasonal variation in mood and behavior and would not be expected to benefit from light therapy.

Analysis of neuropsychological functioning in patients with chronic fatigue syndrome.

Memory impairment dominates the cognitive complaints of patients with chronic fatigue syndrome (CFS). Twenty CFS patients were available for studies with a clinical and experimental battery composed of memory and cognitive tests. The results on objective testing indicated that the CFS patients had some mild memory impairment, but only on tasks requiring conceptually driven encoding and retrieval processes. There were no associations between the nature of the precipitating illness, self ratings of fatigue, physical findings, or laboratory determination and objective memory performance or self report of memory functioning. These generally negative results indicate that memory impairment in CFS patients is typically mild and involves memory processes that participate in conceptualising information.

Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock.

The segmented aspect of the vertebrate body plan first arises through the sequential formation of somites. The periodicity of somitogenesis is thought to be regulated by a molecular oscillator, the segmentation clock, which functions in presomitic mesoderm cells. This oscillator controls the periodic expression of 'cyclic genes', which are all related to the Notch pathway. The mechanism underlying this oscillator is not understood. Here we show that the protein product of the cyclic gene lunatic fringe (Lfng), which encodes a glycosyltransferase that can modify Notch activity, oscillates in the chick presomitic mesoderm. Overexpressing Lfng in the paraxial mesoderm abolishes the expression of cyclic genes including endogenous Lfng and leads to defects in segmentation. This effect on cyclic genes phenocopies inhibition of Notch signalling in the presomitic mesoderm. We therefore propose that Lfng establishes a negative feedback loop that implements periodic inhibition of Notch, which in turn controls the rhythmic expression of cyclic genes in the chick presomitic mesoderm. This feedback loop provides a molecular basis for the oscillator underlying the avian segmentation clock.

Lymphocyte phenotype and function in the chronic fatigue syndrome.

Lymphocytes of 18 patients meeting the Centers for Disease Control (CDC) case definition for the chronic fatigue syndrome (CFS), 10 similar, chronically fatigued patients not fully conforming to the CDC case definition, and 17 matched, healthy individuals were studied to determine the presence of abnormalities of peripheral cell phenotype and function. Extensive phenotypic analyses of B- and T-cell subsets, natural killer (NK) cells, and macrophages were performed using single-, dual-, and three-color flow cytometry. Compared to controls, in CFS patients the percentage of CD4 T cells and CD4,CD45RA, or naive T cells, was reduced. The CD4,CD45RO, or memory T-cell, subset was numerically normal but expressed increased levels of adhesion markers (CD29, CD54, and CD58). CFS patient lymphocytes showed reduced proliferative responses to phytohemagglutinin, concanavalin A, and staphylococcal enterotoxin B. Lymphocytes from fatigue patients not meeting the CDC definition showed similar abnormalities. These data indicate that peripheral T cells manifest an increased state of differentiation in CFS and related conditions. This may arise as a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.

Allergy and the chronic fatigue syndrome.

The chronic fatigue syndrome is a heterogeneous disorder characterized by easy fatigability, feverishness, diffuse pains, and depression. Many patients also report inhalant, food, or drug allergies. This article reviews the clinical features of the syndrome and hypotheses of its pathogenesis, especially those regarding the Epstein-Barr virus and cellular immune mechanisms. Also summarized are recent studies of the validity of atopic complaints in the syndrome. The results of epicutaneous skin testing demonstrated a high correlation with history in 24 patients. Atopy coexists with the chronic fatigue syndrome in greater than 50% of patients.

Review: Medullary carcinoma of the thyroid: radiographic features of a unique tumor.

Medullary carcinoma of the thyroid is a unique neoplasm characterized by consistent production of a hormonal marker, calcitonin, calcification of both primary and metastatic foci, and association with other endocrine neoplasms. It accounts for 3.5%--10% of all thyroid malignancies. First described by Hazard et al. [1] in 1959, this neoplasm has become the focus of increasing clinical and experimental investigation. It occurs both sporadically and in families. When familial, it is seen as a component of the multiple endocrine neoplasia type II (MEN-II) syndromes. Interest in medullary carcinoma of the thyroid far exceeds that warranted by its infrequent occurrence. Over 200 articles dealing with this tumor have appeared in the medical literature in the last 10 years. This may be attributed to the number of distinctive properties of the tumor: the familial occurrence when associated with endocrinopathies, the propensity to produce amyloid, and the great synthetic capability for the biogenic amines calcitonin, serotonin, histaminase, and prostaglandins. Of greatest importance is the value of calcitonin radioimmunoassay for detecting patients with the tumor even though it may be evident clinically. Fifty-three patients with surgically and biochemically proven medullary carcinoma were evaluated and followed at Duke University Medical Center from 1968 to 1981. Ten patients with sporadic tumor, 37 with MEN type IIa, and six with MEN type IIb prompted this review. They will be used to illustrate the varied and sometimes characteristic radiographic manifestations of medullary carcinoma of the thyroid. This tumor has a spectrum of radiographic features in multiple organs that, when familial, facilitate its recognition and treatment.

Chronic fatigue syndrome: lack of association with hepatitis C virus infection.

Chronic fatigue syndrome (CFS) is a debilitating heterogeneous disorder lacking consistent, objective physical or laboratory abnormalities. Among the hypothetical etiologies for CFS are chronic viral infections. The present controlled seroprevalence study found that, among typical CFS patients, evidence of hepatitis C virus (HCV) infection is uncommon. Only one of 36 patients and none of 14 controls were anti-HCV positive. The positive patient had persistent aminotransferase elevations and prior posttransfusion hepatitis. Thus HCV infection is not a common feature of CFS and should not be routinely sought.