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Glaucoma is characterized by retinal ganglion cell (RGC) neurodegeneration. Elevated intraocular pressure (IOP) is a major risk factor however, mechanisms independent of IOP play a role in RGC pathology. Both antibodies and CD4 T-cells as well as microbiota take part in the pathogenesis of both glaucoma and rheumatoid arteritis (RA).Heat shock proteins (HSPs) which originate in bacteria cross-react with RCG epitopes and were involved in rat model of retinal injury. Enhanced expression of HSPs in the retina was associated with glaucoma-like neuropathology and previous studies have also suggested a pathogenic role for HSPs in RA. In view of these data we suggest that glaucoma should be included in the spectrum of autoimmune diseases and that proven medications for RA should be adopted as an innovative IOP -independent therapeutic strategy for glaucoma.

While a specific role for nitric oxide (NO) in inducing the hemodynamic alterations of pregnancy is somewhat controversial, it is widely accepted that excess NO is generated during pregnancy. l-Arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate l-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as the specific arginine transporter for endothelial NO synthase. The present study was designed to test the hypothesis that, during pregnancy, when arginine consumption by the fetus is significantly increased, compensatory changes in maternal arginine uptake affect the endothelium. Uptake of radiolabeled arginine (l-[3H]arginine) by freshly harvested maternal aortic rings from pregnant rats decreased by 65 and 30% in mid- and late pregnancy, respectively, compared with those obtained from virgin animals. This decrease was associated with a significant increase in endothelial protein nitration (the footprint of peroxynitrite generation), as shown by both Western blotting and immunohistochemistry utilizing anti-nitrotyrosine antibodies, reflecting endothelial damage. Northern blot analysis revealed that steady-state aortic CAT-1 mRNA levels did not change throughout pregnancy, whereas CAT-1 protein abundance was significantly increased, peaking at mid-pregnancy. Protein content of protein kinase C (PKC)-α, which was previously shown to decrease CAT-1 activity, increased significantly in the pregnant animals and was associated with a significant increase in CAT-1 phosphorylation. Intraperitoneal injection of α-tocopherol, a PKC-α inhibitor, prevented the decrease in arginine transport and attenuated protein nitration. In conclusion, aortic arginine uptake is reduced during pregnancy, through posttranslational modulation of CAT-1 protein, presumably via upregulation of PKC-α. The aforementioned findings are associated with an increase in protein nitration and, therefore, in selected individuals, may lead to the development of certain forms of endothelial dysfunction, like preeclampsia.

Background: The decrease in glomerular filtration rate (GFR), which is characteristic of obstructive uropathy, was suggested to be associated with attenuated nitric oxide (NO) generation. Since availability of L-arginine, the sole precursor for NO, governs NO synthesis, we aimed to determine the role of glomerular arginine transport in rats subjected to 24 h of bilateral ureteral ligation (BUO). Methods: Glomerular arginine transport was measured by uptake of radiolabeled arginine ([3H]-L-arginine), cationic amino acid transporters (CAT)-1 and -2 and arginases I and II mRNA expression were determined using reverse transcription-polymerase chain reaction. CAT-1, arginase I, and arginase II protein contents were evaluated by Western blotting. Results:L-Arginine transport by freshly harvested glomeruli from BUO rats was significantly augmented than in controls. The aforementioned findings were associated with a significant increase in glomerular CAT-1 mRNA expression, while CAT-2 mRNA was unchanged. Western blotting demonstrated a significant increase in CAT-1 abundance in BUO. Expression of both glomerular arginase I and II mRNA and protein content were significantly elevated in BUO. Conclusions: BUO induces an increase in glomerular arginine transport via upregulation of CAT-1, probably due to increase in arginine utilization by a non-NO pathway.

It has become evident that increased nitric oxide (NO) generation may be associated with production of reactive oxygen species, such as peroxynitrite (ONOO-). Peroxynitrite has been postulated to be responsible for several of the cytotoxic effects previously ascribed to NO. Since cellular arginine uptake has been shown to modulate nitric oxide synthase activity, we were intrigued to study the effect of ONOO- on arginine traffic in renal mesangial cells.Arginine uptake, CAT-1 and CAT-2 mRNA expression by northern blotting analysis, and CAT-1 protein content using western blotting were determined in mesangial cells pre-treated with peroxynitrite (0.1 and 0.5 mM) for 2 h.Peroxynitrite induced a significant increase in arginine uptake and CAT-2 mRNA expression compared with untreated cells. In contrast, CAT-1 mRNA expression and protein abundance were diminished.In rat mesangial cells, peroxynitrite augments arginine uptake via augmentation of CAT-2 while decreasing CAT-1 expression.

Endothelial cell dysfunction (ECD) is a common feature of chronic renal failure (CRF). Defective nitric oxide (NO) generation due to decreased endothelial NO synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino-acid transporter-1 (CAT-1) acts as the specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in CRF. We studied glomerular and aortic arginine uptake, CAT-1, and CAT-2 messenger ribonucleic acid (mRNA) expression, and CAT-1 protein in: (a) rats 6 weeks following 5/6 nephrectomy (CRF), (b) sham-operated animals, and (c) rats with CRF treated orally with either atorvastatin or arginine in drinking water (modalities which have been shown to enhance eNOS activity and improve endothelial function). Both glomerular and aortic arginine transport were significantly decreased in CRF. Treatment with either arginine or atorvastatin abolished the decrease in arginine uptake in CRF rats. Using reverse transcriptase-polymerase chain reaction and Northern blotting, we found a significant increase in glomerular and aortic CAT-1 mRNA expression in CRF. Western blotting revealed that CAT-1 protein was decreased in CRF, but remained intact following arginine and atorvastatin administration. Renal and systemic arginine uptake is attenuated in CRF, through modulation of CAT-1 protein. These findings provide a possible novel mechanism to eNOS inactivation and endothelial dysfunction in uremia.

Augmented arginine uptake, through modulation of cationic amino acid transporter-1, increases GFR in diabetic rats. Background It is suggested that either arginine or its metabolites, nitric oxide and polyamines play a role in the renal hemodynamic alterations observed in the early stages of diabetes. Yet, the regulation of arginine transport in diabetic kidneys has never been studied. Methods Arginine uptake was determined in glomeruli harvested from control rats; diabetic rats (2weeks following an intraperitoneal injection of streptozotocin, 60mg/kg body weight); rats, 4days following left nephrectomy (a nondiabetic model of hyperfiltration); diabetes + lysine (0.5% in the drinking water to attenuate arginine uptake); and control + lysine. Results Glomerular arginine transport was significantly increased in diabetic rats, but remained unchanged following uninephrectomy. Lysine abolished the increase in arginine uptake in diabetic rats but had no effect in controls. The increase in creatinine clearance observed in diabetes was completely abolished by lysine. Using reverse transcription-polymerase chain reaction (RT-PCR), Northern blotting, and immunohistochemistry, we found a significant increase in glomerular cationic amino acid transporter-1 (CAT-1) expression in diabetic animals, which was unaffected by lysine. When human endothelial cells were incubated with arginine end products no effect on arginine transport was observed. However, only in the presence of 0.5mmol/L sodium nitroprusside (SNP) an augmented steady-state CAT-1 mRNA was demonstrated by RT-PCR. Conclusion In a rat model of early diabetes, glomerular arginine uptake is elevated through modulation of CAT-1 expression, thus, contributing to the pathogenesis of hyperfiltration. Increased nitric oxide formation may play a role in this process.

The fat soluble vitamin D3 metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)], and its nuclear receptor play an important role in regulating immune responses. While 1,25(OH)(2)D(3 )is known to inhibit transcription of cytokine genes that are required for Th1 differentiation or are products of differentiated Th1 cells, its role in regulating differentiation of Th2 cells is less clear. In this study, we show that 1,25(OH)(2)D(3) has anti-inflammatory effects in an in vivo Th2-dependent asthma model. In addition, we demonstrate that 1,25(OH)(2)D(3 )down-regulates the cytoskeleton rearrangement required for promoting integrin-mediated adhesion of naive and effector CD4(+) T cells. Finally, 1,25(OH)(2)D(3 )inhibits chemokine-induced migration of naive cells and their homing to the lymph nodes. Thus, in addition to its regulation of cytokine transcription, 1,25(OH)(2)D(3 )regulates migration of cells and thus controls the skewing of various Th subsets in the secondary lymphoid organs and inhibits Th function at sites of inflammation.

We present a 75-year-old patient with recurrent palpable purpura and multiorgan involvement by leukocytoclastic vasculitis caused by mixed-type cryoglobulinemia. The disease spanned 40 years, with many flare-ups, each associated with thrombocytopenia, and finally culminated in widespread involvement of not only the skin and the kidneys but also the lungs and spleen. Despite extensive investigation, no association with hepatitis C virus or with any malignant or connective tissue disorder was found.

Summary Background Penicillin allergy poses a major problem in the management of infectious diseases. Objective We estimated the costs and usage of antibiotic treatment of ‘penicillin-allergic’ patients in comparison to non-allergic patients in a tertiary care hospital. Materials and methods The study was based on the records of 118 randomly chosen in-hospital patients labelled as being ‘allergic to penicillin’ and who were treated with antibiotics. The antibiotic selection and cost of the patients with alleged penicillin allergy were compared to 118 matched patients without an antibiotic allergy (controls). Results During in-hospital treatment, the mean antibiotic cost for penicillin-allergic patients was 63% higher than the cost for the controls. In addition, there was a 38% higher cost of the recommended anti-microbial treatment regimen to be followed upon discharge by the former compared to the latter. Conclusions Penicillin-allergic patients were more likely to receive broader spectrum antibiotics compared to the non-allergic ones. Since many of the patients who are labelled as being ‘allergic to penicillin’ are, in fact, not allergic to it, inaccurate reporting of penicillin allergies may have costly economic and epidemiologic repercussions in addition to more toxic effects which can occur when choosing alternative drugs in case of penicillin allergy.

l-Arginine transport is augmented through up-regulation of tubular CAT-2 mRNA in ischemic acute renal failure in rats. Background Ischemic acute renal failure (iARF) is associated with increased nitric oxide (NO) production during the reperfusion period, as endothelial nitric oxide synthase (eNOS) is maximally activated, and renal tubular inducible NOS (iNOS) is stimulated. Increased NO production leads to augmented tubular injury, probably through the formation of peroxynitrite. l-Arginine (l-Arg), the only precursor for NO, is transported into cells by cationic amino acid transporters, CAT-1 and CAT-2. We hypothesized that the increased NO production observed in iARF may result from increased l-Arg uptake, which would be reflected in the augmented expression of l-Arg transporter(s). Methods Ischemic acute renal failure was induced in rats by right nephrectomy + left renal artery clamping for 60 minutes. l-Arg uptake was examined in freshly harvested glomeruli and tubuli from control, sham operated, and animals subjected to 15, 30, and 60 minutes, and 24 hours of reperfusion, following 60 minutes of ischemia. Using RT-PCR, renal tissues were examined further for the expression of iNOS, CAT-1, CAT-2, arginase I and arginase II. Results Tubular expression of iNOS mRNA was initiated by ischemia, continued to increase after 60 minutes of reperfusion, and decreased after 24 hours. l-Arg transport into glomeruli was similar in all experimental groups. l-Arg uptake into tubuli was markedly augmented following the 60-minute reperfusion, while it moderately increased after 24 hours of reperfusion. This was accompanied by a parallel, preferential increase in tubular CAT-2 mRNA expression at 60 minutes of reperfusion. CAT-1 mRNA expression was unchanged, as detected by RT-PCR. In addition, the expression of arginase II and arginase I mRNA was attenuated by 30 minutes and one hour of reperfusion, and returned to baseline values after 24 hours of reperfusion. Conclusions Ischemic ARF is associated with augmented tubular CAT-2 mRNA expression, which leads to enhanced l-Arg transport and increased NO production. This may contribute to the renal injury exhibited in iARF.

Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Thus, the continuous recirculation of mature lymphocytes is crucial for the development of primary immune response to foreign Ags. We have previously shown that low levels of IFN-γ inhibit homing of B cells to the secondary lymphoid organs. In this study, we demonstrate that similarly low doses of IFN-γ down-regulate integrin-mediated adhesion and migration of naive T and Th2 cells, and have a profound effect on the in vivo homing of naive T cells to the lymph nodes. Moreover, we show that these low doses of IFN-γ have anti-inflammatory effects in an in vivo asthma model. Thus, in contrast to the proinflammatory effects of IFN-γ at relatively high concentrations, low dose IFN-γ appears to exert global suppressory effects on T cell trafficking and may have clinical application as an anti-inflammatory agent.

In order to fully mature and participate in the humoral immune response, immature B cells must first migrate into specific areas in the spleen where they differentiate into mature cells. However, before their maturation in the spleen, immature B cells must be excluded from non-splenic secondary lymphoid organs where any antigen encounter would lead to the death of the cells because of the negative selection process. We have recently shown that immature B cells can actively exclude themselves from antigen-enriched sites by down-regulating their integrin-mediated adhesion in a process mediated by interferon-gamma (IFN-gamma). In this study, we followed the pathway by which IFN-gamma regulates the homing of B cells. We show here that the inhibitory signal of IFN-gamma is transmitted through the IFN-gamma receptor whose engagement leads to the activation of PI3K. This PI3K activation subsequently leads to the inhibition of PKCalpha phosphorylation and cytoskeleton rearrangement required for promoting integrin-mediated adhesion and migration of B cells.

The mechanism by which immature B cells are sequestered from encountering foreign antigens present in lymph nodes or sites of inflammation, before their final maturation in the spleen, has not been elucidated. We show here that immature B cells fail to home to the lymph nodes. These cells can actively exclude themselves from antigen-enriched sites by downregulating their integrin-mediated adhesion to the extracellular matrix protein, fibronectin. This inhibition is mediated by interferon γ secretion. Perturbation of interferon γ activity in vivo leads to the homing of immature B cells to the lymph nodes. This is the first example of autocrine regulation of immune cell migration to sites of foreign antigen presentation.

To compare the effect of various oestrogen and oestrogen/progestin preparations on bone density over a 2-year follow-up period in early postmenopausal women.A retrospective study on 315 women followed in a menopause clinic.Antero-posterior lumbar spine bone densitometry was performed at baseline and between 18 and 24 months (mean 22 months) after initiation of hormone therapy. Participants were divided into six groups: women taking conjugated equine oestrogen (CEE) (n = 30); CEE plus sequential monthly medroxyprogesterone acetate (MPA) (n = 52); CEE plus sequential bimonthly MPA (n = 51); oral estradiol plus sequential monthly norethisterone acetate (n = 52); transdermal estradiol plus sequential monthly MPA (n = 30). A control group (n = 100) was composed of nonusers of hormones.Hormone users, as a whole (n = 215), increased their bone mineral density (BMD) by 2.9% (4.8) as compared to the controls who lost 3.5% (3.4; P0. 001). There were similar gains in BMD amongst the five study groups. Calcium supplementation was associated with better results in all women: users of hormones and calcium had a gain in BMD of 4.5% (4.8) compared to only 1.5% (4.5) in those on hormones but without calcium (P0.001); amongst the controls, women using calcium lost 1.4% (2. 4), whilst nonusers of calcium lost 3.7% (2.4; P0.001). A dose-response curve was found between basal BMD and the effect of hormone therapy: women with osteoporosis (T-score75%) demonstrated the largest increase in BMD - 6.3% (4.6), osteopenia (T-score 75-85%) was associated with a gain of 3.2% (5.6), low-borderline values (T-score 86-100%) gave a modest increase of 1.3% (4.3), and those with more than average BMD values (T-score100%) actually lost bone despite hormone treatment [-2.1% (4.1)].All hormone regimens had a similar bone conserving effect. Basal BMD value may serve as a predictor for the success of treatment. Calcium supplementation should be recommended in all postmenopausal women.

Background: The immunomodulatory activity of macrophages was shown to be a crucial mechanism in the pathogenesis of asthma. Methods: Induced sputum (IS) and methacholine challenge (MC) were carried out in 21 atopic subjects. Suppressive activity (SA) of sputum macrophages (SMO) was investigated on autologous peripheral lymphocytes (APL) proliferation in 12 of these patients and compared to the MC. Results: In 10 of the 21 patients, the FEV1 was >80%; five of these had a nonreactive MC. Eosinophils and metachromatic cells correlated well (r=0.6442; P=0.0029), but not with the MC. The SA of SMO correlated (P=0.0152) with the MC: SMO enhanced APL proliferation in five patients with a positive MC, while SMO showed SA in five with a negative MC. Only two patients with suppressive SMO had a positive MC. Cytokine profiles from five patients showed that two patients with a negative MC had interleukin (IL)-1α and β, IL-6, and transforming growth factor (TGF)-β transcripts, while two patients with a positive MC transcripted IL-4 and IL-5. One patient with a borderline MC transcripted IL-5, but not IL-4. Conclusions: These data support the theory that patients with reduced suppressive bronchial macrophages display clinical bronchial hyperreactivity.

Hypothyroidism, which is a common disorder among postmenopausal women, may be associated with higher than average bone mineral content. Contrarily, treatment with L-thyroxine may cause a significant bone loss. The aim of our study was to evaluate the effects of hormone-replacement therapy (HRT) on bone density in women with subclinical hypothyroidism treated with L-thyroxine. A total of 73 postmenopausal women with thyroid-stimulating hormone (TSH) levels5 mU/l and normal free thyroxine values, who never used HRT or L-thyroxine, were divided into three groups according to the treatment given during a 3-year follow-up period: 34 women received only HRT; 20 women received HRT and L-thyroxine, and the remaining 19 women received neither medications. A euthyroid control group included 41 postmenopausal women with TSH levels between 0.5 and 1.5 mU/l, who were using HRT since the initial visit. Lumbar spine bone density measurements were performed at baseline and study termination. Taken as a whole, the hypothyroid women had a non-significant higher baseline bone mineral density (BMD) as compared to the euthyroid controls (1.068 +/- 0.19 g/cm2 vs. 1.024 +/- 0.15). After 3 years, both the euthyroid and hypothyroid women on HRT only had an increase in BMD (0.032 +/- 0.04 g/cm2 and 0.028 +/- 0.05 g/cm2, respectively; p0.001 for both, compared to baseline). Hypothyroid women using no medication had a decrease of 0.034 +/- 0.07 g/cm2 in BMD, and those receiving both HRT and L-thyroxine lost the most: 0.04 +/- 0.08 g/cm2 (p0.05 for both, compared to baseline). The addition of L-thyroxine thus prevented the beneficial effect of HRT on BMD. Thyroid hormone replacement is recommended only when overt symptoms of hormone deficiency occur. In such cases, a single bone-conserving treatment with HRT may not suffice.

Predicting mortality is important in treatment planning and professional duty towards patients and their families.To evaluate the predictive value regarding patients' survival once the diagnosis of "general deterioration" replaces an ICD-9 diagnosis upon re-admission.In this retrospective cohort case-control study, we screened the records of patients re-admitted at least three times during the past 2 years. For each patient's death during the third hospitalization, we matched (for age and gender) a patient who survived the third hospitalization. We evaluated 14 parameters potentially accountable for increased risk of mortality, e.g., length of stay at each admission, interval to re-admission, etc. We applied a multifactorial analysis using logistic regression to predict the risk of mortality during the third hospitalization as potentially affected by the aforementioned parameters.The study included 81 study patients and 81 controls. Of the 14 parameters potentially explaining an increased risk of mortality during the third hospitalization, several were found to be statistically significant. The most significant was the diagnostic switch from a specific ICD-9 diagnosis on first admission to the non-specific diagnosis of "general deterioration" at the second hospitalization. In such cases, the risk of death during the third hospitalization was increased by 5300% (odds ratio = 54, P = 0.008). The increased risk of mortality was not restricted to patients with malignancy as their background diagnosis.At re-admission a switch from disease-specific diagnosis to the obscure diagnosis "general deterioration" increases the subsequent risk of mortality.

Metachromatic cells are increased in the airways of asthmatic patients. We obtained metachromatic cells from asthmatic airways using an induced sputum technique. The histamine release following ConA, anti-IgE and anti-IgE + IL3 from those cells were evaluated before and following the addition of cromoline Na and nedocromil Na. Metachromatic cells had a higher rate of spontaneous histamine release when compared to peripheral basophils. Cromoline Na and nedocromil Na inhibited histamine release from triggered metachromatic cells but not from peripheral basophils. It is concluded that airway metachromatic cells from asthmatics behave differently than peripheral basophils.

This study assessed the usefulness of the oral captopril test in the prediction of renal impairment among elderly patients with congestive heart failure (CHF). Forty-seven patients agedor = 65 years with CHF (EF40%) participated in a prospective nonrandomized series. Blood samples for plasma renin activity (PRA) were drawn before and 60 minutes after 50 mg of oral captopril. Twenty-four hours later, captopril was administered (up to 75 mg/day over a 4 day period), and renal laboratory and clinical assessment were performed at baseline and for a 9 day period. In 7 of 47 patients (14.9%), deterioration of renal function was observed. During the captopril test, the PRA increased significantly after 1 hour in almost all patients and the mean blood pressure decreased from 99.2 +/- 14.6 mmHg to 92.2 +/- 13.7 mmHg (p0.001). All patients whose baseline PRA level was1.9 ng/ml/hr and whose stimulated PRA was3.2 ng/ml/hr maintained a stable renal function throughout the study period. Significant statistical correlation (p0.05) was found between the initial PRA, the changes in PRA or mean blood pressure during the captopril test, and the change in plasma creatinine and creatinine clearance in the entire group, and was even more evident in a subgroup of patients with an ejection fractionor = 30%. All these correlations were not statistically significant in the patients with an ejection fraction30%. It is thus concluded that measurement of pretreatment PRA levels might be a useful laboratory tool for predicting the renal safety of captopril use in patients with CHF whose EFor = 30%.

This study was undertaken to examine whether clinical factors predict reinfarction within 1 year of a first acute myocardial infarction (AMI) and to quantify the subsequent influence of reinfarction on long-term mortality. Data from 3,695 patients with a first AMI included in the Secondary Prevention Reinfarction Israeli Nifedipine Trial Registry were analyzed. The 1 -year reinfarction incidence was 6.0% (220 of 3,695) and in-hospital mortality during reinfarction was 31%. Patients with reinfarction were older (63.0 vs 60.8 years) at entry. The independent clinical predictors for 1-year reinfarction were (adjusted relative odds): peripheral vascular disease (2.12), anterior location of the first AMI (1.62), angina before the first AMI (1.53), congestive heart failure on admission (1.34), diabetes (1.33), systemic hypertension (1.28) and age increment (1.13). One-year reinfarction rate increased from 4.0% in patients with 0 or 1 risk factor to 23.3% in patients with 5 to 6 risk factors (p

Objective. To determine the value of measurement of serum soluble tumor necrosis factor receptor (sTNFR), compared with established parameters such as anti–double-stranded DNA, in monitoring systemic lupus erythematosus (SLE) disease activity, and to determine whether serum sTNFR are bioactive and can effectively inhibit TNF bioactivity. Methods. Fifty-three consecutive ambulatory or hospitalized SLE patients and 140 consecutive healthy subjects were enrolled in a prospective cohort study. Serum levels of sTNFR were measured by a unique 2-sided capture enzyme-linked immunosorbent assay using mouse monoclonal antibodies and rabbit antisera against the sTNFR. Results. The mean ± SD concentrations of both the p55 (type I) and p75 (type II) soluble receptors were significantly higher in a group of 46 SLE patients than in controls: 1.89 ± 0.89 ng/ml versus 0.77 ± 0.19 ng/ml and 7.25 ± 3.89 ng/ml versus 3.02 ± 0.57 ng/ml, respectively (P < 0.0001 for both). The incidence and the extent of the increase among the healthy subjects and these patients (as well as in 7 additional patients on whom sequential studies were performed) correlated with disease activity more than did the occurrence of serum anti-DNA antibodies (correlation coefficients with disease activity 0.81 and 0.85 for p55 and p75 sTNFR, respectively, and 0.51 for anti-DNA antibodies). The increase in sTNFR levels seems to reflect, largely, enhanced formation, and only to a minor extent, reduced clearance due to impairment of renal function. Sera of the SLE patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF, and this was shown to result entirely from their higher sTNFR receptor concentration. Conclusion. An increase in serum levels of sTNFR may become a useful marker for SLE activity since it shows a stronger correlation than do any other laboratory or clinical parameters employed presently in the daily clinical setting. At the concentrations attained in the serum of SLE patients, sTNFR effectively inhibit the bioactivity of TNF and may thus be a significant determinant of the intensity of the manifestations of SLE.

Tumor necrosis factor (TNF-alpha) acts as a growth stimulatory factor on leukemic B lymphocytes from many patients with chronic lymphocytic leukemia (CLL). Because TNF induces production of interleukin-6 (IL-6), which has been shown to be a growth factor for myeloma and other transformed B cells, we examined the possibility that IL-6 mediates the growth-stimulatory effect of TNF on B-CLL cells. In fact, we found that IL-6 is an inhibitor of B-CLL growth. The addition of recombinant human IL-6 markedly decreased the TNF-induced B-CLL growth, and this decrease was even greater when soluble IL-6 receptor, known to act as IL-6 agonist, was added with recombinant IL-6. Conversely, neutralizing monoclonal antibodies to IL-6 and to the IL-6 receptor potentiated the growth stimulation of TNF on B-CLL cells, in line with the possibility that IL-6 functions as a negative feedback regulator of an autocrine TNF action on these B-leukemic cells. Evidence is presented that production of IL-6 by monocytes and B cells of CLL patients is low, suggesting that administration of IL-6 may be beneficial in CLL to reduce the eventual growth stimulation by TNF and, possibly, also the deficiency in platelets and Ig production in this disease.

Thyroid disorders, especially subclinical hypothyroidism, are common in middle-aged women. Our study was aimed at examining possible associations between menopause and serum levels of thyr...

Using technetium scans, this study was aimed at examining possible changes in left ventricular function related to the natural process of cessation of ovarian estrogen production. Fourteen healthy postmenopausal women, divided into two groups according to the time-lapse from menopause (A3 years; B5 years), underwent a technetium heart scan. The two groups did not differ in heart rate, blood pressure, double product, systemic vascular resistance and cardiac index. The mean end-systolic volume in group A was 14.9 and 25.7 ml/m2 in group B (p = 0.003). The mean pressure/volume ratio was significantly higher in group A than in group B (8.6 vs. 4.7 mm Hg/ml/m2, p = 0.02). Peak ejection rate and peak filling rate were also significantly greater in group A compared to group B (3.3 vs. 2.8 end-diastolic volumes/s, p = 0.02; 2.8 vs. 2.1 end-diastolic volumes/s, p = 0.001, respectively). Our findings suggest that women at an early phase of menopause have a higher degree of myocardial contractility than women of a similar age whose menopause is of longer duration.

This study was aimed to evaluate the effects of tropicamide 0.5% eye drops on cardiovascular parameters during exercise testing. The study group included 154 healthy subjects (mean age: 44.7 +/- 8 years). The subjects were divided into three groups according to the size of the pupils at the onset of exercise: A: pupils not dilated (n = 27), B: pupils partially dilated (n = 90) and C: pupils widely dilated (n = 37). They were compared to 66 healthy controls (age 43.8 +/- 8) who did not receive the drops. Rest and exercise parameters were affected in groups A and B, while the results of group C resembled those of the controls: (a) resting heart rate -66.7, 66.6, 70.9 and 69.3, respectively (p = 0.03); (b) heart rate at 50 and 100 W - 104, 107, 110 and 111 (p = 0.01) and 131, 131, 137, 139, respectively (p = 0.01); and (c) peak systolic blood pressure - 192, 186, 183, 175; respectively (p = 0.004). Reanalyzing the data by scoring of visual impairment gave identical results. As a whole, the study group achieved higher work loads than the controls (126 vs. 119 W; p = 0.03). We conclude that the instillation of ocular tropicamide has definite effects on cardiovascular parameters, both at rest and during exercise. Mainly, patients showed a lower heart rate at the initial levels of exercise. However, at symptom-limited level, tropicamide does not influence a patient's ability to achieve the target heart rate, and stress testing results are not altered by the drug.

Captopril and aspirin have been claimed to adversely affect renal function. This study was designed to evaluate the safety of concomitant administration of both drugs in patients with moderate to severe congestive heart failure (CHF). The study group consisted of 10 patients with a mean age of 77.6 +/- 4.4 years and a mean New York Heart Association functional class of 2.6 +/- 0.5. Captopril was administered in a rapidly escalating dose regimen over a 4-day period to a maximum dose of 75 mg/day. Aspirin 0.25 g/day was added from day 5 on. Renal plasma flow (RPF) was measured by iodohippurate scan and the creatinine clearance test (Ccr) was used as an index of glomerular filtration rate (GFR). Both Ccr and RPF remained unchanged throughout the study period; 48.9 +/- 16; 48.2 +/- 16.5; 49.4 +/- 16, and 222 +/- 67, 241 +/- 97, 237 +/- 88 ml/min, for days 0, 4, 9, respectively. Only 1 patient developed a significant decrease in Ccr following the administration of captopril. This patient had a further decrease when aspirin was added. The decrease in Ccr was accompanied by a marked reduction in filtration fraction and in mean arterial pressure. Our data suggest that the administration of aspirin to elderly patients with moderate CHF treated with captopril is relatively safe and is not associated with further deterioration in renal function.

We evaluated the safety of enalapril administration in 20 very old (76 +/- 7 years) patients with rapidly progressive congestive heart failure (deteriorating from New York Heart Association class 2 to class 4 on admission). They were all given increasing doses of enalapril regardless of concomitant diuretic therapy and state of hydration. Renal function deteriorated in four patients (group A) and remained unchanged in 16 (group B). The mean pretreatment serum creatinine level in group A was significantly higher than that in group B (2.4 vs 1.3 mg/dl, p less than 0.001). No patient with a serum creatinine level less than 1.9 mg/dl on admission had further impairment of renal function. Groups A and B did not differ by age, concomitant diseases (including hypertension and diabetes mellitus), or medications (including diuretics) or by in-hospital serum electrolyte concentrations and blood pressure. Renal damage was noted during the initial four days of the study and was reversible following discontinuation of enalapril. Our data suggest that enalapril can be safely administered to very old patients with rapidly progressive congestive heart failure provided that the initial serum creatinine level is below 1.9 mg/dl. In patients with a higher serum creatinine level, careful monitoring and prompt discontinuation of enalapril administration can prevent irreversible renal damage.

In twenty-seven patients with venography-documented Budd-Chiari syndrome (BCS), underlying diseases included polycythemia vera (nine patients), membranous occlusion of the inferior vena cava (three), and cirrhosis (two). In only nine patients did the syndrome occur in the absence of any predisposing factor. All patients with a membranous web were relatively young (mean age 29 years) and were born in Morocco. With regard to prognosis, three groups could be delineated. Eight patients formed a rapidly progressive group, with mean survival from first symptom of only 4.3 weeks, and were characterized mainly by their relatively advanced age and minimal enlargement of the spleen.

Peroxisome proliferator-activated receptor (PPAR) agonists were shown to inhibit atherosclerosis through augmentation of endothelial nitric oxide synthase (eNOS) activity. In addition, rosiglitazone exerts a beneficial effect in chronic renal failure (CRF). Since l-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings was studied in control animals, rats, 6 wk following 5/6 nephrectomy (CRF) and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKCα and phosphorylated CAT-1 increased significantly in CRF, effects that were prevented by rosiglitazone. PKCα phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of phorbol-12-myristate-13-acetate to rosiglitazone-treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to carbamyl-choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKCα. These findings are associated with restoration of eNO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia.

A 75 year-old comatous patient was admitted after ingestion of 200 mg oxazepam. Skin blisters, attributed to oxazepam toxicity, appeared on the left forearm the following day and regressed spontaneously nine days later.

Self-contained underwater breathing apparatus (scuba) diving has grown in popularity, with millions of divers enjoying the sport worldwide. This activity presents unique physical and physiological challenges to the respiratory system, raising numerous concerns about individuals with asthma who choose to dive. Asthma had traditionally been a contraindication to recreational diving, although this caveat has been ignored by large numbers of such patients. Herein we review the currently available literature to provide evidence-based evaluation of the risks associated with diving that are posed to asthmatics. Although there is some indication that asthmatics may be at an increased risk of pulmonary barotrauma, the risk seems to be small. Thus, under the right circumstances, patients with asthma can safely participate in recreational diving without any apparent increased risk of an asthma-related event. Decisions on whether or not diving is hazardous must be made on an individual basis and be founded upon an informed decision shared by both patient and physician.

The Raloxifene Use for The Heart (RUTH) trial [1] s one of the few recent ambitious trials trying to find successful therapeutic approach to primary prevenion of common menopause-related and gender-related iseases. In short, some 10,000 women above the age of 5 years (mean age 67.5 years), with coronary artery isease (CAD) or at high risk for CAD, participated n this double-blind, raloxifene versus placebo, multiational study; they were followed for a median period f 5.6 years. The study was completed by about 80% f the women, 70% of whom took at least 70% of their ssigned medications. While there was no difference between the two study rms in regard with the cardiac primary outcomes, a 6% risk reduction for invasive breast cancer, a 33% eduction for all breast cancers, and a 35% reduction n clinical vertebral fractures were documented with aloxifene. In contrast, there was a 49% increase in atal stroke and a 44% increase in venous thromboemolism in the active study arm. Thus, the beneficial strogenic (bone protection) and anti-estrogenic (breast

Endothelial cell dysfunction (ECD) is a common feature of hypercholesterolemia. Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as a specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in hypercholesterolemia. We studied aortic arginine uptake, CAT-1 and CAT-2 mRNA expression, and CAT-1, and PKC alpha protein in: (a) control, untreated animals (CTL), (b) rats fed with 4% cholesterol+1% cholate and 2% corn oil for 6 weeks (CHOL) and (c) rats with hypercholesterolemia treated orally with either atorvastatin (CHOL+ATORVA, 20mg/kg BW/day) or arginine 1% (CHOL+ARG) in the drinking water (modalities which have been shown to enhance CAT-1 activity and improve endothelial function). Serum cholesterol levels significantly increased in cholesterol fed animals, an increase which was blocked by atorvastatin (CTL: 66.8+/-15, CHOL: 133.9+/-22, CHOL+ARG: 128.2+/-20, CHOL+ATORVA: 77+/-15 mg/dl). Arginine transport was significantly decreased in CHOL. Treatment with neither arginine nor atorvastatin had an effect. Using RT-PCR, we found no change in aortic CAT-1 and CAT-2 mRNA expression in CHOL as well as following arginine or atorvastatin administration. The abundance of CAT-1 protein was significantly augmented in cholesterol fed rats and was not affected by arginine or atorvastatin. PKC alpha protein content, which was previously shown to regulate CAT-1 activity, increased significantly in CHOL and was neither affected by atorvastatin nor arginine. In conclusion, aortic arginine uptake is attenuated in hypercholesterolemia, through post-translational modulation of CAT-1 protein, possibly via upregulation of PKC alpha.

Background: Eosinophilia accompanies a large number of diseases and conditions, but information is lacking about the clinical characteristics of patients who are hospitalized due to this abnormality. Our aim was to determine the clinical profile and most informative diagnostic tests in patients hospitalized in a tertiary hospital because of hypereosinophilia. Methods: A retrospective review was done of the medical records of all patients hospitalized in a large urban medical center due to hypereosinophilia. All relevant clinical, laboratory, and imaging data were analyzed. Results: A total of 100 patients were included in the study (58 males and 42 females, mean age 55.2±29 years). The blood eosinophil blood count was 4107±7254/μl (mean±SD) and this usually persisted for a few months. The cause of the eosinophilia was asthma or other atopic disease in 13% of the cases, allergic drug reaction in 6%, eosinophilic pneumonia in 10%, neoplastic diseases in 10%, idiopathic hypereosinophilic syndrome in 8%, Churg–Strauss Syndrome in 4%, infections in 10%, allergic fungal disease in 2%, and skin diseases in 3%; the cause remained unknown in 34% of cases. Conclusion: Guidelines are suggested for the investigation of patients with eosinophilia, including the level of the eosinophilia associated with specific diseases and the most informative diagnostic tests. © 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Immature B cells are targeted to specific areas in the spleen, where a fraction of these cells receive signals that induce them to mature and participate in the immune response. In this study, we show that the C-C chemokine receptor 2 (CCR2) is transcribed in immature B cells, while its message is dramatically down-regulated at the mature stage. CCR2-deficient cells exhibit up-regulation of chemokine-induced actin polymerization, migration, and homing to the lymph nodes of immature B cells. In addition, we demonstrate that control of homing by CCR2 is mediated by its ligand, CCL2/JE, which is secreted by B cells and down-regulates the stromal derived factor-1 (SDF-1) signaling cascade. Thus, this study describes an additional, previously uncharacterized, role for CCR2 and its ligand as negative regulators of the homing of immature B cells.

It is now accepted that allicin, the main biologically active compound in garlic, exhibits antioxidant activity. The present study was designed to test the hypothesis that the antioxidant activity of garlic can be partially attributed to the inhibition of nitric oxide (NO) production by cytokine-induced NO synthase (iNOS). Cardiac myocytes cultured from neonatal Wistar rats were stimulated by lipopolysaccharide (LPS) and incubated for 24 h with various concentrations of allicin. This resulted in marked inhibition of nitrite production. Interestingly, a low concentration of allicin (10 microM) was significantly more potent in abrogating the effect of LPS on nitrite production than a higher concentration (40 microM). Allicin decreased steady-state iNOS mRNA levels, and this effect was maximal when a lower concentration was used (10 microM compared with 40 microM). In order to explore additional effects of allicin on NO generation that might counteract the effect on iNOS, we assessed the effects of higher allicin concentrations on arginine transport. Allicin inhibited the uptake of 1 mM extracellular arginine in a concentration-dependent manner. The expression of the two arginine transporters that are expressed in cardiac myocytes [CAT-1 (cationic amino acid transporter-1) and CAT-2] was studied using reverse transcription-PCR. A concentration of 200 microM allicin abolished the expression of CAT-2 mRNA, 100 microM significantly attenuated it, whereas 50 microM had no effect. Allicin had no effect on steady-state CAT-1 mRNA levels. Our results suggest that allicin inhibits iNOS activity through two different mechanisms: at lower concentrations it decreases iNOS mRNA levels, whereas at higher concentrations it inhibits arginine transport through down-regulation of CAT-2 mRNA.

Tetrahydrobiopterin (BH4) has been shown to be required for dimerization and acquisition of nitric oxide (NO) generating capacity by nitric oxide synthase (NOS). In the present study we have investigated the hypothesis that BH4 may affect NOS activity through a novel mechanism-namely, modulating arginine transport in rat cardiac myocytes. Cardiac myocytes have been previously shown to express cationic amino acid transport proteins (y+ system) CAT-1 and CAT-2. Increasing extracellular BH4 concentrations up to 0.5 mmol/L augments arginine transport in 1 mmol/L arginine media (no BH4, 558 +/- 42 fmol arginine/microg protein/min; 0.1 mmol/L BH4, 580 +/- 11 fmol arginine/microg protein/min; 0.5 mmol/L BH4, 944 +/- 71* fmol arginine/microg protein/min; 1.0 mmol/L BH4, 983+/-84* fmol arginine/microg protein/min, n = 4; *: P.05 vs no BH4). Treating the cells with lipopolysaccharide (LPS) (10 microg/mL) significantly augmented arginine transport only in the presence of BH4 (no BH4, 600 +/- 33 fmol arginine/microg protein/min; 0.1 mmol/L BH4, 691 +/- 29*dagger fmol arginine/microg protein/min; 0.5 mmol/L BH4, 1123 +/- 32*dagger fmol arginine/microg protein/min; 1.0 mmol/L BH4, 1296 +/- 42*dagger fmol arginine/microg protein/min, n = 4; *: P.01 vs no BH4, dagger: P.05 vs no LPS). The administration of biopterin, sodium nitroprusside (NO donor), 2,4-diamino-6-hydroxy-pyrimidine (inhibitor of BH4 synthesis), and sepiapterin (the precursor of de novo synthesis of BH4) to unstimulated cells had no effect on arginine uptake values. Using reverse trancriptase-polymerase chain reaction, we next studied the steady state levels for CAT-1 and CAT-2 mRNA. Incubation with BH4 significantly increased CAT-2 mRNA expression in a concentration-dependent manner in 0.1, 0.5, and 1 mmol/L BH4, respectively. Northern blotting analysis further confirmed this observation. We also found that in the presence of BH4 in these concentrations, CAT-1 mRNA expression was abolished. We suggest that BH4 augments intracellular arginine availability by modulating CAT-2 mRNA expression and suggest that its presence is required for the LPS effect on trans-membrane arginine traffic.

Eighteen postmenopausal women were examined by Doppler echocardiography before initiation of HRT (T1), then after ten weeks (T2) and one year (T3). This study group was compared with another in which HRT was not used. Flow velocity integral, which correlates with SV, and MA, an indicator of cardiac contractility, were calculated. In the study group, PFV was 107 ± IS cm/s at T1 and increased significantly at T2 and T3. Ejection time, which was prolonged at T2 compared to T1, returned to its basal value at T3. Flow velocity integral increased at T2, but this change was only partially sustained at T3. Mean acceleration maintained its increase throughout T2 to T3. None of the Doppler parameters showed a significant change in the controls from T1 to T3. Our results suggest that the peripheral hemodynamic effects of HRT, such as vasodilatation, are transient, whereas the central effects (increased inotropism) are long-lasting. (Chest 1992; 102:1496-98)

Currently, estrogen replacement therapy is widely used as a specific treatment for hypoestrogenic associated conditions such as vasomotor instability, genitourinary atrophy and osteoporosis. These conditions affect a substantial number of postmenopausal women.1 The favorable effects of estrogen replacement therapy on cardiac morbidity and mortality in postmenopausal women have usually been attributed to an improved lipid profile. 2–4 It is now accepted that other mechanisms, such as the direct effect of estrogens on coronary vasculature and atherosclerotic plaque, may also have an important role in cardioprotection.3–5 Using Doppler echocardiography we recently demonstrated a significant increase in aortic flow velocity and acceleration after 10 weeks of hormone replacement therapy.6 These findings led us to investigate whether menopause and the related decrease in estrogen levels were associated with changes in Doppler-derived parameters of aortic flow.

The total and differential leukocyte count of 4 groups of patients, admitted to the hospital because of acute gastroenteritis was evaluated. The 4 groups included: (a) 131 adult patients with positive stool culture for shigella; (b) 23 children (age less than 15 years) with positive stool culture for shigella; (c) 52 adult patients with positive stool culture for salmonella; (d) 43 adult patients with negative stool culture for bacterial pathogens. The total leukocyte count did not contribute to the differential diagnosis between shigella gastroenteritis and gastroenteritis of other etiology. However, the absolute band count was significantly higher in adults with shigella gastroenteritis. Moreover, a band to total neutrophil ratio further increased the diagnosis specificity. The differential leukocyte count can contribute to early diagnosis of shigellosis in adult patients.

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

Cholinergic urticaria (CU) is a common variant of the physically induced types of urticaria. It accounts for about 30% of all cases of the physically induced types of urticaria and for nearly 7% of all the types of chronic urticaria? The hallmarks of the disease are pruritic wheals, which are distinctive, monomorphic, and punctate; 2 to 3 mm in size; and surrounded by a bright rash. 1, 2 Usually, the rash appears on the upper trunk, face, and arms 5 to 15 minutes after a trigger event and lasts 20 to 30 minutes. Several external physical triggers, all of which raise the body core temperature, are known to induce this phenomenon? The cause of CU is unknown, but high serum histamine levels have been detected during attacks. 3 To the best of our knowledge, familial cases have not been previously described. Herein we present four families characterized by CU since early adulthood and manifested in male family members only.

Nonsteroidal antiinflammatory drugs (NSAIDs) have arterial vasospastic properties. The authors report a stroke that occurred within minutes following an intramuscular injection of diclofenac. A sixty-one-year-old man, a heavy smoker, was admitted for an acute onset of mild hemiparesis thirty minutes after a single intramuscular injection of diclofenac. The neurologic deficit was resolved at one month of follow-up. The authors suggest a temporal causal relationship between the cerebrovascular event and the injection of diclofenac. The mechanism of stroke might be related to a synergistic vasospastic property shared by the use of an NSAID and heavy smoking.

The purpose of this study was to examine the impact of intensive home-care surveillance on morbidity rates of elderly patients with severe congestive heart failure. Forty-two patients aged 78 +/- 8 years who had severe congestive heart failure (New York Heart Association functional classes III through IV, mean ejection fraction 27% +/- 6%), were examined at least once a week at home by internists from the district hospital and by a trained paramedical team. The year before entry to the home-care program was compared to the first year of home surveillance. The mean total hospitalization (hosp) rate was reduced from 3.2 +/- 1.5 hosp/yr to 1.2 +/- 1.6 hosp/yr and duration from 26 +/- 14 days/yr to 6 +/- 7 days/yr (p < 0.001 for both). Cardiovascular admissions decreased from 2.9 +/- 1.5 hosp/yr to 0.8 +/- 1.1 hosp/yr and duration from 23 +/- 13 days/yr to 4 +/- 4 days/yr (p < 0.001). The vital status (ability to perform daily activities, expressed in a 1 to 4 scale) was improved from 1.4 +/- 0.9 to 2.3 +/- 0.7 (p < 0.001). In conclusion, an intensive home-care program was associated with a marked decrease in the need for hospitalization and improved the functional status of elderly patients with severe congestive heart failure. Such a service might also have a cost-effective advantage and a major impact on health expenditure.

1. The increased urinary excretion of porphyrins as well as of their precursors was studied in a patient with hereditary coproporphyria during two acute attacks in which symptoms differed markedly in character and severity. 2. The increase in urinary coproporphyrin was similar in the ‘mild’ and in the ‘severe’ attack, indicating a lack of correlation between coproporphyrin level and clinical symptoms. 3. Aminolaevulinic acid, porphobilinogen and uroporphyrin exhibited significantly higher values during the ‘severe’ attack than during the ‘mild’ attack. During the severe attack these three compounds were increased 18-, 14- and 46-fold, respectively, compared with increases of 3-, 3- and 8-fold, respectively, during the mild attack. 4. The striking rise in the formation of uroporphyrin was reflected in the plasma porphyrin profile, which revealed predominance of uroporphyrin. In accordance with this finding, an increase in erythrocyte porphobilinogen deaminase of 130% was recorded. 5. The fluorescence emission spectra of saline-diluted plasma (excitation of 405 nm) showed a distinct peak at 618 nm during the ‘severe’ episode and a small peak during the ‘mild’ attack, pointing to the possibility of diagnosing an attack simply by following the fluorometric screen of plasma. 6. The ‘severe’ attack of coproporphyria was treated with daily infusions of haem arginate, 3 mg/kg, every day for 4 days, at the end of which period a dramatic clinical response was observed. The relief of symptoms was found to be clearly related to the moderate decrease in uroporphyrin excretion observed rather than to the steep decline in the precursors.