Immune dysfunction in patients with obstructive jaundice, mediators and implications for treatments

Patients with obstructive jaundice have an increased perioperative complication rate. Sepsis, bleeding, wound problems, renal and liver malfunction are all seen in these patients. Assessment of immune function has been an active research area in these patients. This review will examine various aspects of immune functions in obstructive jaundice, discuss the recent research results and controversies and then go on to discuss the relevant mediators of immune function and some possible implications for treatment.     

Inflammatory mechanisms in Alzheimer's disease: implications for therapy

OBJECTIVE: The purpose of this article is to review evidence that inflammatory and immune mechanisms are important in the pathophysiology of Alzheimer's disease and to suggest new treatment strategies. METHOD: The authors review the English-language literature of the last 10 years pertaining to the pathophysiology of Alzheimer's disease. RESULTS: There is ample evidence supporting the hypothesis that inflammatory and immune mechanisms are involved in tissue destruction in Alzheimer's disease. Acute phase proteins are elevated in the serum and are deposited in amyloid plaques, activated microglial cells that stain for inflammatory cytokines accumulate around senile plaques, and complement components including the membrane attack complex are present around dystrophic neurites and neurofibrillary tangles. CONCLUSIONS: Clinical trials of anti-inflammatory/immunosuppressive drugs are necessary to determine whether alteration of these inflammatory mechanisms can slow the progression of Alzheimer's disease.     

Clustering of sleep electroencephalographic patterns in patients with the fibromyalgia syndrome

Several electroencephalographic (EEG) abnormalities have been observed during sleep in patients suffering from the fibromyalgia syndrome (FMS). In this study, 12 patients with fibromyalgia and 14 control subjects had two polysomnographic recordings obtained at home. Data from the second night were subjected to blinded manual scoring as well as signal processing using linked or 'step-wise clustering for pattern recognition. In this procedure, a common learning set was generated using the spectral information in three 2 min EEG samples from each of the sleep stages selected from five patients with FMS and five controls. In this way, 17 characteristic EEG classes were defined. All 2 s EEG segments from the whole night from all subjects were then assigned to one of these classes. Five of the classes (dominated by 0.5-4.5 Hz activity) were more frequent in the control group, whereas three other classes (dominated by 8-11 Hz activity) were prevalent in the patient group. This trend was consistent in all sleep stages, although most striking in non-rapid eye movement (NREM) sleep. The predominance of these classes in the patient group may correspond to the alpha-EEG sleep anomaly previously reported in subjects with FMS. More importantly, as the EEG power in the lowest frequency range (prevalent in controls) probably is a marker for restorative sleep, the findings may reflect important aspects of sleep disturbances n subjects suffering from FMS, thereby contributing to some of the daytime symptoms in these patients.     

Antipolymer antibody reactivity in a subset of patients with fibromyalgia correlates with severity

Postmenopausal hormone replacement therapy (HRT) has favorable effects on the serum lipid profile, and it also decreases the risk of cardiovascular diseases. The apolipoprotein E genotype has influence on serum levels of lipids and lipoproteins; apoE allele epsilon4 (apoE4) is associated with high total and LDL cholesterol levels. Genotype also influences the lipid responses to treatment with diet and statins, but the effect of HRT in different apoE genotypes is unknown. We studied the effects of HRT on the concentrations of serum lipids in apoE4-positive early postmenopausal women (genotypes 3/4 and 4/4) compared with apoE4-negative women (genotypes 2/3 and 3/3) in a population-based, prospective 5-year study. In all, 232 early postmenopausal women were randomized into 2 treatment groups: an HRT group (n=116), which received a sequential combination of 2 mg estradiol valerate (E2Val) from day 1 to 21 and 1 mg cyproterone acetate (CPA) from day 12 to 21 (Climen), and a placebo group (n=116), which received 500 mg/d calcium lactate. Serum concentrations of total, LDL, and HDL cholesterol and triglycerides were measured at baseline and after 2 and 5 years of treatment. A total of 154 women completed the final analysis. During the follow-up period, serum total cholesterol and LDL cholesterol concentrations decreased in the HRT group in apoE4-negative women (8.1% and 17.1%, respectively; P<0.001) but did not change in the HRT group in apoE4-positive women or in the placebo group. Serum HDL cholesterol concentrations decreased in the placebo group (apoE4-negative, 3.9%, P=0.015; apoE4-positive, 8.1%, P=0.004) but did not change significantly in the HRT group. Serum triglyceride levels tended to increase in both study groups and genotypes (15.1% to 36.2%, P<0.038 to 0.001), but no differences were observed between the study groups or genotypes, respectively. Our finding was that in postmenopausal Finnish women LDL cholesterol levels in apoE4-negative subjects respond more favorably to HRT than those in apoE4-positive subjects. This finding has potential importance in postmenopausal women with hypercholesterolemia, if confirmed in other studies.     

Ocular findings in patients with neutrophil dysfunction

Of 32 patients (19 females and 13 males, ranging in age from 2 to 44 years), nine had ocular problems related to neutrophil dysfunction. Four patients had blepharokeratoconjunctivitis and pannus formation. In one of these, severe visual loss secondary to corneal thinning and scarring occurred. Five patients had inactive chorioretinal scars without visual loss. Although some of the other 23 patients had minor ocular abnormalities, we could not demonstrate that they were related to the neutrophil dysfunction. However, none of the control subjects (20 patients with systemic lupus erythematosus and 20 randomly selected eye clinic patients) had lesions resembling those of the patients with neutrophil dysfunction. Fisher's exact test (one-tailed) gave the following values: P less than .03 for keratitis; P less than .01 for chorioretinal scars; and P less than .001 for keratitis and chorioretinal scars. Abnormal neutrophil function probably interferes with the control of normal eyelid flora and predisposes the eye to the development of marginal keratitis. Eyelid hygiene and topical administration of antibiotics and corticosteroids during inflammatory episodes may prevent the progression of corneal vascularization. The chorioretinal scars do not appear to be progressive.     

Depressed fibromyalgia patients are equipped with an emphatic competence dependent self-esteem

Employing a recently developed questionnaire we studied the self-esteem structure of 61 female fibromyalgia (FM) patients by comparing them with i) 40 healthy psychology students and ii) 37 patients suffering from rheumatoid arthritis. Depressed FM patients (n=36) had a high need to gain self-esteem through competence and others' approval combined with a low basic sense of self-esteem. In this regard they differed significantly from the healthy controls who had a more equal amount of the two types of self-esteem. These patients had also a more demanding and "hard-driving" self-esteem structure than either control group and exhibited a lower self-assertiveness and less emotional candour than the healthy controls. The non-depressed FM patients did not display this self-esteem pattern. In conclusion, FM patients are probably not a homogeneous group. Furthermore, we suggest that an emphatic competence-dependent self-esteem is one vulnerability factor which, in proper genetic and environmental conditions, increases susceptibility to fibromyalgia and depression.     

"Chronic Lyme disease" as the incorrect diagnosis in patients with fibromyalgia

OBJECTIVE: To evaluate a large number of patients referred with persistent symptoms thought to represent chronic Lyme disease. METHODS: We retrospectively reviewed the charts of nearly 800 patients referred with persisting nonspecific musculoskeletal and/or neurologic symptoms thought to represent chronic Lyme disease. RESULTS: Seventy-seven patients were found to have fibromyalgia, not ongoing Lyme disease, as the explanation of their chronic symptoms. Many had received multiple courses of antibiotic therapy for symptoms of fibromyalgia mistakenly attributed to chronic Lyme disease. No patient reported permanent and/or total resolution of fibromyalgia symptoms following antibiotic therapy. Appropriate therapy for fibromyalgia in those who remained compliant, however, was often effective in improving some if not all of the chronic symptoms. CONCLUSION: Fibromyalgia is a treatable and potentially curable disorder, and should be considered in the evaluation of patients with "refractory Lyme disease."     

Sensory cells determine afferent terminal morphology in cross-innervated electroreceptor organs: implications for hair cells

Type I and type II hair cells of the vestibular system are innervated by afferents that form calyceal and bouton terminals, respectively. These cannot be experimentally cross-innervated in the inner ear to determine how they influence each other. However, analogous organs are accessible for transplantation and cross-innervation in the brown ghost electric fish. These fish possess three types of electroreceptor organs. Of these, the sensory receptors of the type I tuberous organ are S-100- and parvalbumin-positive with a calbindin-positive afferent that forms a large calyx around the organ. Neither the sensory receptors nor the afferents of the ampullary organs label with these antibodies, and the afferent branches form a single large bouton beneath each receptor cell. In controls, when cut ampullary afferents reinnervate transplanted ampullary organs, they have characteristic calbindin-negative terminals with large boutons. When type I tuberous afferents reinnervate ampullary organs, receptor cells remain S-100- and parvalbumin-negative, and the tuberous afferents still express calbindin. The nerve terminals, however, make large ampullary-like boutons on the receptor cells. These results suggest that (1) afferent terminal morphology is dictated by the receptor organ; (2) expression of calbindin by the afferent is not suppressed by innervation of the incorrect end organ; (3) ampullary organs generate ampullary receptor cells although innervated by tuberous afferents; and (4) ampullary receptor cells can be trophically supported by tuberous afferents.     

Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain

OBJECTIVE: We suggested fibromyalgia (FM) is a disorder associated with an altered functioning of the stress-response system. This was concluded from hyperreactive pituitary adrenocorticotropic hormone (ACTH) release in response to corticotropin-releasing hormone (CRH) and to insulin induced hypoglycemia in patients with FM. In this study, we tested the validity and specificity of this observation compared to another painful condition, low back pain. METHODS: We recruited 40 patients with primary FM (F:M 36:4), 28 patients (25:3) with chronic noninflammatory low back pain (LBP), and 14 (12:2) healthy, sedentary controls. A standard 100 microg CRH challenge test was performed with measurement of ACTH and cortisol levels at 9 time points. They were also subjected to an overnight dexamethasone suppression test, followed by injection of synthetic ACTH1-24. At 9 AM, the patients divided in 2 groups, received either 0.025 or 0.100 microg ACTH/kg body weight to test for adrenocortical sensitivity. Basal adrenocortical function was assessed mainly by measurement of 24 h urinary excretion of free cortisol. RESULTS: Compared to the controls, the patients with FM displayed a hyperreactive ACTH release in response to CRH challenge (ANOVA interaction effect p = 0.001). The mean ACTH response of the patients with low back pain appeared enhanced also, but to a significantly lesser extent (p = 0.02 at maximum level) than observed in the patients with FM. The cortisol response was the same in the 3 groups. Following dexamethasone intake there were 2 and 4 nonsuppressors in the FM and LBP groups, respectively. The very low and low dose of exogenous ACTH1-24 evoked a dose and time dependent cortisol response, which, however, was not significantly different between the 3 groups. The 24 h urinary free cortisol levels were significantly lower (p = 0.02) than controls in both patient groups; patients with FM also displayed significantly lower (p < 0.05) basal total plasma cortisol than controls. CONCLUSION: The present data validate and substantiate our preliminary evidence for a dysregulation of the HPA axis in patients with FM, marked by mild hypocortisolemia, hyperreactivity of pituitary ACTH release to CRH, and glucocorticoid feedback resistance. Patients with LBP also display hypocortisolemia, but only a tendency toward the disrupted HPA features observed in the patients with FM. We propose that a reduced containment of the stress-response system by corticosteroid hormones is associated with the symptoms of FM.     

Oesophageal dysfunction in male patients with angina-like pain

The value of betamethasone valerate by inhalation in the prophylactic therapy of severe childhood asthma has been established. To determine whether the efficacy of this drug is due to a local or a systemic action a double-blind crossover study of 28 days' treatment with oral betamethasone valerate and 28 days' treatment with inhaled steroid was carried out in 10 asthmatic children. Daily doses used were 1 mg orally and 800 mug by inhalation. Nine patients had fewer symptoms, higher peak expiratory flow rates, and a lower bronchodilator requirement on inhaled than on oral therapy. Exercise-induced bronchoconstriction was diminished on inhaled therapy. Five children requested early termination of the oral therapy period because of unacceptable symptoms. Nine parents stated a preference for the period of inhaled therapy. It is concluded that betamethasone valerate is highly effective by inhalation but that a comparable oral dose has no appreciable clinical effect.     

Cardiovascular surgery in the patients with liver dysfunction

Under the current situations we have increasing opportunities to manage the patients with posthepatitis and/or congestive liver dysfunction. In order to prevent postoperative hepatic failure we described perioperative management for those patients. For this purpose, the major point is the selection of appropriate operative methods which reduce operative invasions and have sure efficacy. In order to decide operative methods, we have to grasp the functional reserve of dysfunctional liver. We have no effective methods to estimate the functional reserve, but our data suggested that serum cholinesterase level at the preoperative states might demonstrate prognostic significance. The others are managements of postoperative cardiopulmonary distress and infection. It goes without saying that preoperative improvement of anemia and poor nutrition.     

Atrial pacing in patients with sinus node dysfunction

Sinus nod recovery time (SNRT) at paced atrial rates of 100 (SNRT100) and 120 (SNRT120) beats/min, atrial effective refractory periods at spontaneous heart rates (AERP) and at paced rates of 100 (AERP100) and 120 (AERP120) beats/min, and premature atrial stimulation were among the studies in evaluating 33 patients with symptomatic sinus node disease and 42 normal subjects. Although mean SNRT100 and SNRT120 were statistically significantly greater in patients than in control subjects, there was a significant overlap between patient and control groups, and SNRT100 or SNRT120 was associated with a 30.3 per cent false-negative and 5 per cent false-positive incidence. Correction for heart rate (SNRT-spontaneous cycle length) failed to improve the sensitivity or specificity of this test. There was no significant difference in mean AERP, AERP100 or AERP120, or in sinoatrial conduction time in patients compared with control subjects. Analyses of curves derived from plots of test and return cycles showed abnormal curves in only five of the 24 patients studied by progressively premature atrial stimulation. Two of these five patients showed normal zone I and II phenomena followed by a progressive linear increase in the return cycle that was thought to be due to abnormal refractoriness of the perinodal fibers.     

Basic pathogenic mechanisms operating in experimental models of acute anterior uveitis

BACKGROUND: Determining how representative the known structures are of the proteins encoded by a complete genome is important for assessing to what extent our current picture of protein stability and folding is overly influenced by biases in the structure databank (PDB). It is also important for improving database-based methods of structure prediction and genome annotation. RESULTS: The known structures are compared to the proteins encoded by eight complete microbial genomes in terms of simple statistics such as sequence length, composition and secondary structure. The known structures are represented by a collection of nonhomologous domains from the PDB and a smaller list of 'biophysical proteins' on which folding experiments have concentrated. The proteins encoded by the genomes are considered as a whole and divided into various regions, such as known-structure homologue, low complexity (nonglobular), transmembrane or linker. Various tests are performed to assess the significance of the reported differences, in both a practical and a statistical sense. CONCLUSIONS: The proteins encoded by the genomes are significantly different from those in the PDB. Their sequence lengths, which follow an extreme value distribution, are longer than the PDB proteins and much longer than the biophysical proteins. Their composition differs from the PDB proteins in having more Lys, Ile, Asn and Gln and less Cys and Trp. This is true overall and especially for the regions corresponding to soluble proteins of as yet unknown fold. Secondary-structure prediction on these uncharacterized regions indicates that they contain on average more helical structure than the PDB; differences about this mean are small, with yeast having slightly more sheet structure and Haemophilus influenzae and Helicobacter pylori more helical structure. Further information is available through the GeneCensus system at http://bioinfo.mbb.yale.edu/genome.     

Orthostatic sympathetic derangement in subjects with fibromyalgia

OBJECTIVE: To assess the sympathetic-parasympathetic balance in individuals with fibromyalgia (FM), and its response to orthostatic stress, by power spectral analysis of heart rate variability. METHODS: We studied 19 women with FM and 19 age matched controls. A high resolution electrocardiogram was obtained in supine and standing postures after achieving a stable heart rate. Spectral analysis of R-R intervals was done by the fast Fourier transform algorithm. RESULTS: Analyses of the different frequency components revealed significant difference between the 2 groups in the low frequency (0.050-0.150 Hz) band, which reflects modulation of the sympathetic nervous system. Controls displayed an increased power spectral density upon standing (+0.081 +/- 0.217 Hz); individuals with FM had a discordant response (-0.057 +/- 0.097 Hz) (p = 0.018). CONCLUSION: In FM, there is a deranged sympathetic response to orthostatic stress. This abnormality may have implications regarding the pathogenesis of FM.     

Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus

The anti-DNA response is a hallmark of systemic lupus erythematosus (SLE). The precise mechanisms leading to anti-DNA antibody (Ab) production remain to be studied. Nonetheless, it is becoming clear that anti-DNA Abs cause inflammatory lesions not only via deposition of circulating immune complexes (IC) consisting of anti-DNA Ab and antigens (Ags), but also via in situ IC formation by cationic anti-DNA Abs. It is intriguing that cationic anti-DNA Abs are encoded by a unique germline Vkappa gene, A30, which encodes an extraordinary cationic light chain, whereas somatic mutations did not induce a cationic shift of electrical charge in human lupus nephritis, suggesting that the usage of a specific germline gene may confer the cationic charge (or pathogenicity) on anti-DNA Abs and that somatic mutations induce the affinity maturation of Abs. Whether cationic anti-DNA Abs will develop depends at least partly on the presence or absence of the germline A30 gene, since patients who lack this gene in the germline Vkappa repertoire did not develop severe lupus nephritis. Receptor editing, a mechanism for changing the affinity of the B cell Ag receptor [surface immunoglobulin (Ig) receptor] to avoid self-reactivity actually seems defective in patients with SLE because normal B cells edited the A30 gene, whereas SLE B cells express A30 mRNA. Thus, along with the importance of somatic mutations, polymorphisms of Ig Vkappa locus, and genetic predisposition, the failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.     

Serum concentrations of apolipoproteins in patients with thyroid dysfunction

We measured serum concentrations of apolipoproteins (apo A-I, A-II, B, C-II, C-III and E) in patients with thyroid disease (hyperthyroidism; n = 44, hypothyroidism; n = 15) and in normal subjects (n = 89). We found that apoA-II, B and C-III concentrations revealed significant difference among three groups of the normal (apoA-II; 31.4 +/- 4.9 mg/dl, apoB; 85.8 +/- 16.3 mg/dl, apoCIII; 7.45 +/- 2.99 mg/dl), hyperthyroidism (apoA-II; 29.8 +/- 5.4, apoB; 63.4 +/- 18.9, apoC-III; 6.28 +/- 2.45) and hypothyroidism (apoA-II; 27.5 +/- 5.3, apoB; 108.0 +/- 30.9, apoC-III; 9.43 +/- 2.74). Thyroid hormones showed clear negative correlation to apoB (r = 0.70, p < 0.001). Furthermore, apoC-III was also found to be negatively correlated with thyroid hormone concentrations (r = 0.47, p < 0.001).     

Dobutamine-atropine stress echocardiography for risk stratification in patients with chronic left ventricular dysfunction

OBJECTIVE: To assess the prognostic value of sustained improvement, scar and inducible ischemia with or without viability in patients with chronic left ventricular dysfunction (LVD). BACKGROUND: Dobutamine-atropine stress echocardiography (DASE) accurately detects scar, reversible dysfunction and the extent of coronary artery disease in LVD. METHODS: Three hundred fifty consecutive patients (age 62+/-13 years, mean+/-SD, 215 men/135 women) with moderate to severe LVD (LVEF < 40%, mean 30+/-8%) underwent DASE and were followed for > or =18 months. Dobutamine-atropine stress echocardiographic findings were classified according to sustained improvement in all vascular territories, scar, inducible ischemia (worsening wall motion at peak dose only or biphasic responses) and their extent. RESULTS: Sustained improvement occurred in 83 patients (24%), scar alone in 99 (28%) and inducible ischemia in 168 (48%, with biphasic responses in 104). Ischemia was induced in all vascular territories in 26 patients. Patients with sustained improvement or scar alone were treated medically, whereas 46% (78/168) with inducible ischemia were revascularized (coronary bypass surgery, n = 67 or angioplasty, n = 11). There were 76 hard events including cardiac death in 59, nonfatal myocardial infarction in 11, and resuscitated sudden death in 6. Hard events were rare in sustained improvement (5%, 4/83), uncommon in scar (13%, 13/99) and common (p < 0.01) in medically treated patients with inducible ischemia (59%, 53/90). Cardiac deaths were especially common (p < 0.01) in patients with biphasic responses (55%, 28/51). Inducible ischemia independently predicted hard events (chi2 = 75.35, p < 0.001) along with reduced LVEF at peak dose (chi2 = 8.38, p = 0.004). Hard cardiac events were uncommon (8%, 6/78, p < 0.001) in patients with inducible ischemia who underwent early revascularization. CONCLUSIONS: Inducible ischemia during DASE was the major determinant of outcome in LVD and independent of clinical data and left ventricular function. Improved wall thickening alone and scar alone predicted good outcome. Survival of patients with inducible ischemia was better after revascularization.