Role of the combination spironolactone-norgestimate-estrogen in Hirsute women with polycystic ovary syndrome.

OBJECTIVE: To compare the combination spironolactone-norgestimate-ethinyl estradiol in hirsutism with other protocols including the same dose of estrogen. STUDY DESIGN: In this open prospective study, 167 women with hirsutism due to polycystic ovary syndrome (PCOS) were randomly assigned to the following treatment protocols: Group A (n = 72): spironolactone 100 mg-norgestimate 250 mcg-ethinyl estradiol 35 microg; Group B (n = 70): cyproterone acetate 12 mg-ethinyl estradiol 35 microg; Group C (n = 25): norgestimate 250 microg-ethinyl estradiol 35 microg. RESULTS: The decrease in the hirsutism score was higher in group A than in the other groups (p < 0.001) and comparable in groups B and C. The decrease in acne score, androgen and estradiol levels, and ovary volume was similar in groups A and B. C-reactive protein increase was similar in all groups, but the augmentation of fibrinogen (p = 0.04), triglycerides (p < 0.01), monocyte count (p = 0.04), platelet number (p < 0.001) and mean volume (p = 0.01) was more pronounced in group B than in group A. Low-density lipoprotein/high-density lipoprotein cholesterol ratio decreased in groups A and C. CONCLUSION: Spironolactone-norgestimate-ethinyl estradiol is an effective and well-tolerated combination for the treatment of hirsutism in PCOS, with a favorable influence on lipids and indices of low-grade inflammation.

Evaluation of bone density in girls with precocious and early puberty during treatment with GnRH agonist.

BACKGROUND: Major changes in bone status occur during puberty. Most longitudinal studies have shown no impairment in bone mineral density (BMD) in girls with precocious (PP) and early puberty (EP) during and after GnRH agonist therapy. METHODS: In the present study we evaluated BMD, bone strength (BS) and bone metabolism in 26 girls with PP and with EP before and during treatment with GnRH agonist. BMD was measured by dual energy X-ray absorptiometry and BS was measured using the quantitative high frequency ultrasound technique at baseline, after 6 and 12 months from onset of therapy. Variables were compared with age- and sex-matched values of the same population. Biochemical markers of bone turnover were measured at the same intervals. RESULTS: Mean lumbar spine (LS) and femoral neck (FN) BMD were significantly lower at baseline (LS: p < 0.0001, FN: p < 0.0017) compared with age-matched reference values. Bone strength was significantly lower at the radius (p < 0.0001) and normal at the tibia. A non-significant increase in BMD and a significant increase in BS were observed throughout the first year of therapy with GnRH agonist. Serum bone specific alkaline phosphatase measurements were normal at baseline and remained stable. Urinary deoxypyridinoline\creatinine measurements were significantly higher (p < 0.0001) at baseline and decreased significantly (p < 0.001) during treatment. CONCLUSIONS: Girls with central idiopathic PP and EP have lower BMD and BS for chronological age and increased bone resorption markers. These parameters show a trend of normalization during the first year of therapy with GnRH agonist.

To lock or not to lock patients'rooms: the key to autonomy?

Many patients with schizophrenia experience prominent negative symptoms. Functional impairment often results in patients who remain in their rooms for most of the day. It has thus become common practice in many psychiatric wards to lock patients' rooms during much of the morning and afternoon hours to encourage participation in ward activities and treatment modalities. Within the context of a quality control evaluation, two self-report surveys were conducted among patients (N=20) and staff members (N=9) in Beer Yaakov, Israel: the first survey was given when the rooms were locked at certain times, and the second survey was given after the rooms had been unlocked for one week. Patients and staff members expressed differing views both before and after the week-long open-door policy (patients enjoyed the policy, whereas many staff did not). Behavior during the period of the open-door policy varied among patients. The authors discuss the ethical grounds of locking doors and whether it is a best practice in keeping with rehabilitation interests.

PATE gene clusters code for multiple, secreted TFP/Ly-6/uPAR proteins that are expressed in reproductive and neuron-rich tissues and possess neuromodulatory activity.

We report here syntenic loci in humans and mice incorporating gene clusters coding for secreted proteins each comprising 10 cysteine residues. These conform to three-fingered protein/Ly-6/urokinase-type plasminogen activator receptor (uPAR) domains that shape three-fingered proteins (TFPs). The founding gene is PATE, expressed primarily in prostate and less in testis. We have identified additional human PATE-like genes (PATE-M, PATE-DJ, and PATE-B) that co-localize with the PATE locus, code for novel secreted PATE-like proteins, and show selective expression in prostate and/or testis. Anti-PATE-B-specific antibodies demonstrated the presence of PATE-B in the region of the sperm acrosome and at high levels on malignant prostatic epithelial cells. The syntenic mouse Pate-like locus encompasses 14 active genes coding for secreted proteins, which are all, except for Pate-P and Pate-Q, expressed primarily in prostate and/or testis. Pate-P and Pate-Q are expressed solely in placental tissue. Castration up-regulates prostate expression of mouse Pate-B and Pate-E, whereas testosterone ablates this induced expression. The sequence similarity between TFP/Ly-6/uPAR proteins that modulate activity of nicotinic acetylcholine receptors and the PATE (Pate)-like proteins stimulated us to see whether these proteins possess analogous activity. Pharmacological studies showed significant modulation of the nicotinic acetylcholines by the PATE-B, Pate-C, and Pate-P proteins. In concert with these findings, certain PATE (Pate)-like genes were extensively expressed in neuron-rich tissues. Taken together, our findings indicate that in addition to participation of the PATE (Pate)-like genes in functions related to fertility and reproduction, some of them likely act as important modulators of neural transmission.

Follicular variant of papillary thyroid carcinoma: clinical-pathological characterization and long-term follow-up.

PURPOSE: Questions arise concerning the behavior and prognosis of the follicular variant of papillary thyroid carcinoma. PATIENTS AND METHODS: Between 1990 and 2003, 92 patients with follicular variant of papillary carcinoma (group A) were enrolled in a long-term study and compared with control groups of follicular thyroid carcinoma (group B, 40 cases) and pure papillary thyroid carcinoma (group C, 99 subjects). RESULTS: Gender (female/male), age, and follow-up duration (years, mean+/-standard error) in groups B, A, and C were 36/4, 43+/-3, 11+/-1.1; 79/13, 46+/-2, 9.5+/-0.7; and 82/17, 44+/-1, 10+/-0.6, respectively. At the time of diagnosis, the rates of extensive extra thyroidal local spread, bilateral lesions, and vascular invasion were higher in group A than in group C. The rate of metastasis tumors was higher in group A than in group C and was comparable in groups A and B. Complete remission was reported in 95% of group B patients, 98% of group C individuals, and in only 77% of group A subjects. Persistent stable lesions and progressive disease rates in groups B, A, and C were 2.5% and 2.5%, 15% and 8%, and 0% and 2%, respectively. The survival rates at the end of the study were 100% in all cohorts, but the cumulative dose of administered radioiodine in group A was higher than in group C and was comparable to that given in group B. Metastases dedifferentiation was observed only in the group A (three patients). DISCUSSION: Follicular variant of papillary thyroid carcinoma may be more aggressive than previously considered and should be clearly distinguished from the two other forms of well-differentiated thyroid carcinoma.

Video testimony of long-term hospitalized psychiatrically ill Holocaust survivors.

OBJECTIVE: Many Holocaust survivors who have both psychotic disorders and residual symptoms of posttraumatic stress disorder (PTSD) remain chronically hospitalized in psychiatric institutions. This study investigated the clinical benefits of a therapeutic process facilitating a detailed videotaped account of traumatic experience (testimony method) in elderly long-term hospitalized Holocaust survivors. METHOD: Twenty-four schizophrenia patients (mean age=72.2 years) who were chronically hospitalized in Israeli state psychiatric hospitals underwent assessment by blind rating with a battery of psychiatric rating scales before and 4 months after extensive videotaped interview. The rating scales included the Positive and Negative Syndrome Scale; Clinical Global Impression (CGI); Mini-Mental State Examination (MMSE); Clinician-Administered PTSD Scale, Form 2; and Structured Interview for Disorders of Extreme Stress. Full pre- and postinterview data were available for 21 patients. RESULTS: Thirty-eight percent of the patients met the criteria for PTSD at the first interview, compared with only 19% at the second interview. The patients had significant reductions in functional impairment and in the severity and intensity of all posttraumatic symptom clusters (intrusion, avoidance, hyperarousal); the avoidance cluster showed the most reduction. Eleven subjects had an improvement of 30% or more in total posttraumatic severity score. No differences in Positive and Negative Syndrome Scale, MMSE, Structured Interview for Disorders of Extreme Stress, and CGI total scores were noted postinterview or between the two preinterview evaluation batteries in the comparison group. Female patients had a higher prevalence of PTSD symptoms. Total Clinician-Administered PTSD Scale, Form 2, scores and total Positive and Negative Syndrome Scale scores were inversely correlated both at baseline and at follow-up. CONCLUSIONS: Study observations suggest clinical benefits of the testimony method in the alleviation of many posttraumatic symptoms, but not psychosis, in a cohort of psychiatrically ill Holocaust survivors, despite an interval of as many as 60 years since the traumatic events. The findings have implications for care and rehabilitation of patients many years after acute traumatic events.

The MUC1 SEA module is a self-cleaving domain.

MUC1, a glycoprotein overexpressed by a variety of human adenocarcinomas, is a type I transmembrane protein (MUC1/TM) that soon after its synthesis undergoes proteolytic cleavage in its extracellular domain. This cleavage generates two subunits, alpha and beta, that specifically recognize each other and bind together in a strong noncovalent interaction. Proteolysis occurs within the SEA module, a 120-amino acid domain that is highly conserved in a number of heavily glycosylated mucin-like proteins. Post-translational cleavage of the SEA module occurs at a site similar to that in MUC1 in the glycoproteins IgHepta and MUC3. However, as in the case of other proteins containing the cleaved SEA module, the mechanism of MUC1 proteolysis has not been elucidated. Alternative splicing generates two transmembrane MUC1 isoforms, designated MUC1/Y and MUC1/X. We demonstrated here that MUC1/X, whose extracellular domain is comprised solely of the SEA module in addition to 30 MUC1 N-terminal amino acids, undergoes proteolytic cleavage at the same site as the MUC1/TM protein. In contrast, the MUC1/Y isoform, composed of an N-terminally truncated SEA module, is not cleaved. Cysteine or threonine mutations of the MUC1/X serine residue (Ser-63) immediately C-terminal to the cleavage site generated cleaved proteins, whereas mutation of the Ser-63 residue of MUC1/X to any other of 17 amino acids did not result in cleavage. In vitro incubation of highly purified precursor MUC1/X protein resulted in self-cleavage. Furthermore, addition of hydroxylamine, a strong nucleophile, markedly enhanced cleavage. Both these features are signature characteristics of self-cleaving proteins, and we concluded that MUC1 undergoes autoproteolysis mediated by an N --> O-acyl rearrangement at the cleavage site followed by hydrolytic resolution of the unstable ester and concomitant cleavage. It is likely that all cleaved SEA module-containing proteins follow a similar route.

TH1/TH2 cytokine secretion of first degree relatives of T1DM patients.

Th1/Th2 cytokine imbalance has been demonstrated in Type 1 diabetes (T1DM) patients. We characterized the peak levels, secretory pattern and total cytokine production of the Th1 cytokines (IL-2 and IFN gamma) and Th2 cytokines (IL-4 and IL-10), by stimulated peripheral blood mononuclear cells of twenty six first-degree relatives of T1DM patients, and eleven matched controls. At enrollment, first degree relatives demonstrated a significant increase in peak and overall secretion of IL-2; P<0.01 and P<0.005 respectively and IL-4 cytokine; P<0.05 and P<0.01 respectively, as compared to normal controls. Their mean IFN gamma secretion increased significantly, P<0.05, after one year while their higher IL-2 and IL-4 secretion remained unchanged. Ab-negative and Ab-positive relatives demonstrated a similar cytokine secretion pattern. Four relatives all Ab positive, developed diabetes: Peak IL-4 levels were low in three and markedly decreased within one year in one of these relatives, while peak IL-2 and IFN gamma levels were elevated in all of them. These data demonstrate that secretion of both Th1 and Th2 cytokines is increased in first-degree relatives of T1DM patients independently of their diabetes-associated autoantibodies. The presence of low IL-4 and elevated IL-2 and IFN gamma levels in autoAb positive relatives is associated with progression to overt disease.

Treatment preference and tolerability with alendronate once weekly over a 3-month period: an Israeli multi-center study.

BACKGROUND AND AIMS: Osteoporosis is a chronic condition requiring long-term treatment, for which compliance is not easy to achieve. 70 mg of alendronate once weekly (alendronate OW) provides equivalent efficacy to treatment with 10 mg of alendronate once a day (alendronate OD); however, there are relatively few data regarding patient and physician preferences for once-weekly vs daily dosing. The aim of this study was to measure compliance, convenience, tolerance and relative preference of alendronate OW treatment among post-menopausal women with osteoporosis and physician satisfaction, compared with previous treatment with alendronate OD. METHODS: This open-label, prospective multi-center trial was conducted at 14 hospitals and 150 primary-care community clinics in Israel. Post-menopausal osteoporotic women (n = 3710), who had been treated for at least 1 month with alendronate OD during the preceding year, were treated with alendronate OW for 12 weeks. Convenience, satisfaction, tolerance and relative preference of alendronate OW during the trial, compared with past experience with alendronate OD, were recorded. RESULTS: Overall, 96% of the patients preferred the alendronate OW regimen to the 10-mg daily dosage. Nearly all (98%) the patients who completed 12 weeks of treatment, including 77% of patients who had previously discontinued daily treatment due to intolerance, were willing to continue the alendronate OW regimen. Patient-reported compliance with dosing instructions was over 98%. Alendronate OW was well tolerated; only 2.8% of patients discontinued, due to adverse events. Physicians were highly satisfied with the once-weekly dosing regimen, and recommended continued treatment with alendronate OW for 99% of the patients. CONCLUSIONS: The majority of post-menopausal women with osteoporosis, including those who were previously intolerant to alendronate OD, preferred alendronate OW to the once-daily dosing regimen. It is important to consider patient preference when selecting the appropriate treatment for osteoporosis.

A novel protein derived from the MUC1 gene by alternative splicing and frameshifting.

Genes that have been designated the name "MUC" code for proteins comprising mucin domains. These proteins may be involved in barrier and protective functions. The first such gene to be characterized and sequenced is the MUC1 gene. Here we report a novel small protein derived from the MUC1 gene by alternative splicing that does not contain the hallmark of mucin proteins, the mucin domain. This protein termed MUC1/ZD retains the same N-terminal MUC1 sequences as all of the other known MUC1 protein isoforms. The common N-terminal sequences comprise the signal peptide and a subsequent stretch of 30 amino acids. In contrast, the MUC1/ZD C-terminal 43 amino acids are novel and result from a reading frameshift engendered by a splicing event that forms MUC1/ZD. The expression of MUC1/ZD at the protein level in human tissues is demonstrated by Western blotting, immunohistochemistry, immunoprecipitation, and an ELISA. Utilization was made of affinity-purified MUC1/ZD-specific polyclonal antibodies as well as two different monoclonal antibodies that are monospecific for the MUC1/ZD protein. The MUC1/ZD protein is expressed in tissues as an oligomeric complex composed of monomers linked by disulfide bonds contributed by MUC1/ZD cysteine residues. MUC1/ZD protein expression did not parallel that of the tandem-repeat array-containing MUC1 protein. Results presented here demonstrate for the first time the expression of a novel MUC1 protein isoform MUC1/ZD, which is generated by an alternative splicing event that both deletes the tandem-repeat array and leads to a C-terminal reading frameshift.

Low stimulated IL-4 secretion in PBMC from patients with chronic idiopathic urticaria.

An imbalance between the Th1 and Th2 arms of the cellular immune system has been reported in several autoimmune diseases but not in chronic idiopathic urticaria (CIU). Peak, total secretion and secretory pattern of the Th1 cytokines (IFNgamma and IL-2) and Th2 cytokines (IL-4 and IL-10) were determined in resting and stimulated peripheral blood mononuclear cells (PBMC) from nineteen CIU patients, six acute urticaria patients and twelve controls. Stimulated IL-4 secretion was significantly reduced in CIU patients as indicated by their five- and three-fold lower peak levels and total IL-4 secretion, respectively. The IL-4 secretory pattern overtime was also markedly different in patients and controls. The late secretion of IFNgamma at 144 h was also reduced in CIU patients. These aberrations were not detectable in AU patients. Secretion of IL-2 was lower in CIU and AU patients as compared to controls while IL-10 secretion was comparable in the three groups. Our data demonstrate for the first time a predominantly reduced IL-4 secretion in CIU patients. This is associated with reduced secretion of both IL-2 and IFNgamma. These findings indicate a generalized down-regulation of both Th1 and Th2 cytokines' secretion in CIU.

DSM-IV self-report and subjective evaluation by psychiatrists in Israel.

BACKGROUND: Psychiatric disorder, with the range of both subsyndromal and syndromal manifestation, is an important, yet often unrecognized and unacknowledged, problem among physicians. It is a subject that remains understudied, particularly among psychiatrists. The purpose of this study was to explore the subjective perception of mental illness among members of the psychiatric profession. METHOD: Psychiatrists attending an educational symposium completed, anonymously, a self-evaluation questionnaire in which they were asked to self-diagnose the presence of DSM-IV disorders. RESULTS: 110 responses were received (response rate: 52.1%); 90% of respondents indicated the presence of at least one syndrome or trait. The most common disorders on axis I and axis II were "mood disorder" and "narcissistic traits" respectively, with the least common being "psychotic disorder" and "schizotypal traits." Female psychiatrists reported more impairment, particularly among axis I disorders. The reported number of axis I and II conditions decreased with subjects' age. CONCLUSIONS: Manifestations of psychiatric conditions including the range of subthreshold phenomena, as self-diagnosed according to DSM-IV criteria, appear to be prominently reported, albeit with low severity, in a subjective manner by psychiatrists. Our findings may be of importance in encouraging the implementation of special programs in training and ongoing occupational support.

Monitoring response to osteoporosis therapy with alendronate by a multisite ultrasound device: a prospective study.

BACKGROUND: Osteoporotic fractures are a major health problem among postmenopausal women. A significant proportion of subjects with low bone density are currently undiagnosed. Peripheral devices can be used for osteoporosis diagnosis, but their role in long-term monitoring of skeletal changes is unclear. The current study evaluated the ability of quantitative ultrasound (QUS) measurements to follow osteoporotic subjects treated with alendronate. METHODS: QUS measurements were done with Sunlight Omnisense (Omnisense, Sunlight Medical Ltd., Tel Aviv, Israel), which determines the bone speed of sound (SOS) in several skeletal sites. Postmenopausal women with T-scores of -2 or less at one site were recruited and treated with alendronate for at least 1 yr. Follow-up was done with QUS and dual-energy X-ray absorptiometry (DXA) (Lunar DPX scanner, Madison, WI, USA) measurements. RESULTS: After 12 mo, bone mineral density (BMD) increased significantly at the lumbar spine (LS) (0.34 +/- 0.08 T-score, p = 0.0001 with 95% CI [0.19, 0.49]) and QUS at the tibia (TIB) (0.21 +/- 0.09 T-score, p = 0.02 with 95% CI [0.03, 0.39]). After 12 mo, a significant increase in mean T-scores was demonstrated in all sites assessed according to baseline T-score of -2 or less. CONCLUSIONS: Peripheral QUS measurement may be considered for follow-up on skeletal changes in response to alendronate treatment.

Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients.

BACKGROUND: The hyperprolactinemia induced by conventional antipsychotics often leads to osteoporosis. The commonly used atypical antipsychotics risperidone and olanzapine vary in their hyperprolactinemic properties. Therefore, we compared hormone profiles and bone properties in female premenopausal schizophrenia patients treated with either risperidone or olanzapine. METHOD: In a cross-sectional study, consecutive premenopausal, female, DSM-IV schizophrenia patients who were treated with either risperidone (N = 12) or olanzapine (N = 14) for at least 2 years were included. Dual energy X-ray absorptiometry evaluated bone mineral density, and multisite quantitative ultrasound measured bone speed of sound. In addition, profiles of urinary excretion of deoxypyridinoline and circulating levels of hormones and lipids were assessed. RESULTS: Serum prolactin levels were higher in the risperidone-treated group as compared with the olanzapine subjects (123 +/- 144 and 25.9 +/- 25.7, p <.05). Whereas bone mineral density was similar in the treatment groups, bone speed of sound was lower in the risperidone group as compared with the olanzapine-treated group. Expressed as age-adjusted Z score, bone speed of sound at the radius was -0.31 and 0.58, respectively, p <.05, and at the phalanx, -1.41 and 0.04, respectively, p <.05. The bone speed of sound in the risperidone-treated patients inversely correlated with urinary deoxypyridinoline excretion (r = 0.73, p <.05). CONCLUSION: Risperidone treatment, as opposed to olanzapine, for female premenopausal schizophrenia results in hyperprolactinemia and clinically relevant decrease in bone mineral density. The calculated relative risk for fragility fracture of women treated with risperidone as compared to those treated with olanzapine is 1.78 when bone speed of sound was measured at the phalanx and 1.23 when measured at the radius.

Discordant effect of body mass index on bone mineral density and speed of sound.

BACKGROUND: Increased BMI may affect the determination of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) and speed of sound (SOS) measured across bones. Preliminary data suggest that axial SOS is less affected by soft tissue. The purpose of this study is to evaluate the effect of body mass index (BMI) on BMD and SOS measured along bones. METHODS: We compared axial BMD determined by DXA with SOS along the phalanx, radius and tibia in 22 overweight (BMI > 27 kg/m2), and 11 lean (BMI = 21 kg/m2) postmenopausal women. Serum bone specific alkaline phosphatase and urinary deoxypyridinoline excretion determined bone turnover. RESULTS: Mean femoral neck--but not lumbar spine BMD was higher in the overweight--as compared with the lean group (0.70 +/- 0.82, -0.99 +/- 0.52, P < 0.00001). Femoral neck BMD in the overweight--but not in the lean group highly correlated with BMI (R = 0.68. P < 0.0001). Mean SOS at all measurement sites was similar in both groups and did not correlate with BMI. Bone turnover was similar in the two study groups. CONCLUSIONS: The high BMI of postmenopausal women may result in spuriously high BMD. SOS measured along bones may be a more appropriate means for evaluating bones of overweight women.

Effect of acute psychotic stress in nondiabetic subjects on beta-cell function and insulin sensitivity.

OBJECTIVE: To determine the effect of acute psychotic stress on glucose homeostasis in nondiabetic subjects. RESEARCH DESIGN AND METHODS: Beta-cell function and insulin sensitivity were determined by the homeostasis model assessment in 39 nondiabetic patients with acute psychotic stress reaction admitted to a psychiatric ward. The clinical global impression (CGI) score was used to evaluate the level of psychological stress. Patients were assessed on admission, after 2 weeks, before discharge, and 6 months after discharge. RESULTS: The mean CGI score decreased significantly with time: 5.3 +/- 0.8 and 1.6 +/- 0.7 on admission and predischarge, respectively (P < 0.001). This was associated with a significant reciprocal increase of mean beta-cell function from 96.8 +/- 33.2 to 134.4 +/- 60% at admission and postdischarge, respectively (P < 0.003), and a decrease of mean insulin sensitivity from 101.7 +/- 36 to 77.1 +/- 34.8% (P < 0.001). In contrast, mean glucose and HbA(1c) levels did not change significantly. Subgroup analysis demonstrated that patients with the highest stress score on admission (> or =6) had significantly higher glucose (P = 0.01) and insulin levels (P = 0.04) than patients with lower score (<6). Furthermore, insulin sensitivity and CGI score on admission were inversely correlated (r = -0.38, P < 0.02). In these patients, no correlation was found between beta-cell function or insulin sensitivity and BMI. CONCLUSIONS: These data indicate that beta-cell function and insulin sensitivity are inversely correlated with acute psychotic stress.

Constitutive up-regulated activity of MAP kinase is associated with down-regulated early p21Ras pathway in lymphocytes of SLE patients.

Aberrant expression of the p21Ras proto-oncogene has been reported in lymphoid cells of SLE patients. We previously showed that the expression of the p21Ras stimulatory element, hSOS1, is reduced in PBMC from SLE patients with non-active disease. However, the significance of this finding regarding the regulation and function of the p21Ras pathway and its correlation to disease activity remained unclear. The expression, regulation and function of the p21Ras pathway were determined in 23 ambulatory SLE patients with active and non-active disease and eleven controls. Levels of p21Ras stimulatory element hSOS1 but not p21Ras and its inhibitory element p120GAP were significantly decreased in SLE patients. Early p21Ras signalling was down-regulated in SLE patients with active disease as indicated by the decreased membrane/cytoplasmic (M/C) ratios of the p21Ras regulatory elements hSOS1 and p120GAP and by the non-responsiveness of these ratios to cellular stimulation. Anchorage of p21Ras to the cellular membrane was also significantly decreased in these patients. In contrast, the late p21Ras signalling was up-regulated in SLE patients as indicated by the significantly higher constitutive activity of the p21Ras down stream key regulator enzyme MAP Kinase. Taken together, our data demonstrate for the first time a disease associated functional defect in p21Ras signalling in lymphocytes of SLE patients.

Evidence for aberrant regulation of the p21Ras pathway in PBMCs of patients with chronic idiopathic urticaria.

BACKGROUND: Recent data suggest that a subpopulation of patients with chronic urticaria has an autoimmune disorder. Aberrant expression and regulation of the p21Ras pathway has been reported in lymphoid cells in a variety of systemic autoimmune diseases but not in chronic idiopathic urticaria (CIU). OBJECTIVES: The aim of this study was to examine the expression, regulation, and function of the p21Ras pathway in patients with CIU. METHODS: Twenty-four patients with CIU and 14 control subjects were enrolled. All patients and 9 control subjects were intradermally injected with autologous serum. PBMCs were isolated, and the p21Ras and its regulatory proteins were studied. RESULTS: We found increased expression of the p21ras proto-oncogene in patients with CIU. This was associated with a low expression of the p21Ras stimulatory element human son of sevenless (hSOS1) but normally expressed p21Ras inhibitory element p120GTPase-activating protein. The basal nonstimulated membrane/cytoplasmic ratio of hSOS1, which indicates the p21Ras pathway activity, was higher in patients compared with that seen in control subjects. Moreover, after stimulation, both patients and control subjects decreased their hSOS1 membrane/cytoplasmic ratio. The magnitude of this decrease was much higher in patients than in control subjects: 14- and approximately 2-fold, respectively. The basal and stimulated activities of the p21Ras downstream key regulatory enzyme mitogen-activated protein kinase were comparable in patients and control subjects, as was their in vitro mitogen-stimulated lymphocyte proliferation. CONCLUSION: Our data demonstrate for the first time an aberrant signaling through the p21Ras pathway in lymphocytes of patients with CIU. This finding further supports the autoimmune basis of this disease.