Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone.

BACKGROUND: The incidence of left ventricular hypertrophy (LVH) in primary aldosteronism (PA) is higher than in essential hypertension. LVH is an independent cardiovascular risk factor. Treatment of PA with mineralocorticoid receptor blockers (MRBs) improves LVH. Previous studies included relatively small groups, low incidence of LVH and used high MRB dose. We tested the hypothesis that long-term regression of LVH in PA/low-renin hypertension may be achieved with low-dose MRB. METHODS: Forty-eight patients (male/female 28/20, age 61.4 years, range 47-84) had PA (low renin, high aldosterone and high aldosterone/renin ratio, n=24) or low-renin hypertension (low renin, normal aldosterone and high aldosterone/renin ratio, n=24). All had either LVH or concentric remodelling. All had an echocardiogram both at baseline and at 1 year after the initiation of spironolactone. A subgroup of 29 patients had an echocardiogram at baseline, 1 year (range 0.5-1.5) and 3 years (range 1.8-7). RESULTS: At baseline, spironolactone was commenced in all patients. The dose was 33.3±13.7 and 29.0±11.7 mg/day at 1 year and 3 years, respectively. A total of 73% of the patients received ≤37.5 mg/day. Introduction of spironolactone enabled the reduction of other antihypertensive medications (from 2.6±1.2 to 1.5±1.0 at 1 year). At 1 year, systolic and diastolic blood pressure decreased (149.3±14.1 to 126.2±12.0 mmHg, P<0.001, and 88.2±9.8 to 78.3±7.1 mmHg, P<0.001, respectively). At baseline, LVH was present in 39 of the 48 (81%) patients, and concentric remodelling, i.e. increased relative wall thickness (RWT) with a normal left ventricular mass index (LVMI), in 36 (75%). At 1 year, LVMI decreased in 44 of the 48 (92%) patients (142.9±25.4 versus 117.7±20.4 g/m2, P<0.001). LVH normalized in 16 of the 39 (41%) patients. RWT normalized in 36% of the patients. The changes in blood pressure and LVMI did not correlate. At 3 years, LVH decreased further and normalized in 57% of the patients. CONCLUSIONS: In patients with PA/low-renin hypertension, long-term regression of LVH may be achieved with low-dose MRB.

Cytokine secretion and markers of inflammation in relation to acidosis among chronic hemodialysis patients.

BACKGROUND: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels. METHODS: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 ± 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured. RESULTS: Acidosis versus no acidosis (serum HCO3 ­ 21.5 ± 0.2 vs. 24.9 ± 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 ± 0.11 vs. 1.71 ± 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH. CONCLUSIONS: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10.

Caffeine alters cytokine secretion by PBMC induced by colon cancer cells.

BACKGROUND: Studies have shown that caffeine might be capable to prevent colon cancer development. This activity is linked in part to its anti-inflammatory properties mediated through modulation of immune responses. It was the aim of the study to evaluate the role of caffeine in the immune balance between peripheral blood mononuclear cells (PBMC) and those of HT-29 and RKO human colon cancer lines. METHODS: Cytokine production was evaluated following incubation of the two types of cancer cells without and with three concentrations of caffeine. RESULTS: A concentration-dependent inhibition of TNFα and IFNγ secretion by PBMC was observed only after their stimulation by cancer cells. Reduction of the anti-inflammatory IL-1ra and IL-10 production was observed using higher caffeine concentrations only. CONCLUSION: We presume that by changing the equilibrium between pro- and anti-inflammatory cytokines in favor of anti-inflammation, caffeine may reduce the inflammatory process with a consequent suppression of colorectal cancer progress.

Nephrolithiasis: evaluation and management.

Nephrolithiasis is a major cause of morbidity involving the urinary tract. The prevalence of this disease in the United States has increased from 3.8% in the 1970s to 5.2% in the 1990s. There were nearly two million physician-office visits for nephrolithiasis in the year 2000, with estimated annual costs totaling $2 billion. New information has become available on the clinical presentation, epidemiologic risk factors, evaluative approach, and outcome of various therapeutic strategies. In this report, we will review the epidemiology and mechanisms of kidney-stone formation and outline management aimed at preventing recurrences. Improved awareness and education in both the general population and among health-care providers about these modifiable risk factors has the potential to improve general health and decrease morbidity and mortality secondary to renal-stone disease.

On the combined effect of statins and lycopene on cytokine production by human peripheral blood cells.

Since both statins and lycopene exert immunomodulatory activities following incubation with human peripheral blood mononuclear cells (PBMC), the present work was designed to examine whether they may induce a synergistic or antagonistic effect on cytokine production while applied together. Peripheral blood mononuclear cells isolated from 15 healthy subjects were incubated for 24 h as follows: (1) without and with 0.125 or 0.25 microM lycopene, (2) without and with 10 or 50 mM pravastatin or simvastatin, and (3) with lycopene and with one of the statins together at the respective doses. The production of the following cytokines was assessed: interleukin (IL)-1beta, IL-1ra, IL-2, and IL-10, as well as tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma). The results showed that lycopene and simvastatin applied together reduced TNFalpha and IFNgamma secretion, and abolished the increased production of the proinflammatory cytokine IL-1gamma caused by incubation with simvastatin only, an observation suggesting that simultaneous administration of both substances may reduce inflammatory responses.

In vitro effect of lycopene on cytokine production by human peripheral blood mononuclear cells.

There is evidence indicating that regular consumption of tomato products is associated with favorable immunomodulatory effects. In addition, tomato extracts have been shown to possess antioxidant, anticarcinogenic and antithrombotic activity in vitro. Since tomatoes are rich in carotenoids and particularly in lycopene--the pigment responsible for the red color of tomatoes--the present work was designed to examine the in vitro effect of lycopene on cytokine production by peripheral blood mononuclear cells (PBMC) from 15 healthy subjects. First, 2 x 10(6) PBMC suspended in 1 ml of conditioned medium were incubated over a period of 24 and 48 hours without or with the following concentrations of lycopene: 0.25, 0.5, 1.0, 2.0 and 4.0 microM. The production of the subsequent cytokines was evaluated: IL-1beta, IL-1ra, IL-2, IL-6 and IL-10, as well as TNFalpha and IFNgamma. Lycopene induced a dose-dependent increase in IL1beta, and TNFalpha production and a decrease in IL-2, IL-10 and IFNgamma secretion, whereas that of IL-6 and IL-1ra was not affected. It is concluded that understanding the role of lycopene in modulation of the immune system may promote decisions as for dietary supplementation of lycopene for reducing the risk of certain diseases.

Hydrophobic but not hydrophilic statins enhance phagocytosis and decrease apoptosis of human peripheral blood cells in vitro.

The engulfing ability of phagocyting cells is related to the fluidity of the cell membrane that in turn depends on its chemical composition. Changes in membranal lipid content may increase or decrease membranal fluidity with a subsequent enhanced or impaired phagocytosis, respectively. Statins are recognized as potent inhibitors of cholesterol synthesis and therefore, are successfully administered to patients with hypercholesterolemia. Since it is considered that cholesterol affects cell function via changes in membrane composition, the present study was designed to examine the in vitro effect of three hydrophobic statins--atorvastatin, lovastatin and simvastatin, and a hydrophilic one--pravastatin, on the engulfing capacity, phagocytic index and apoptosis of peripheral blood phagocytes from healthy volunteers. Peripheral white blood cells obtained from 20 healthy normocholesterolemic individuals were incubated for 2h with 10 and 50 microM of the four statins and phagocytosis of fluorescent latex particles was detected by flow cytometry. Apoptosis was examined using annexin V and propidium iodide staining. An increase in the percentage of phagocyting cells was observed after incubation with 50 microM of lovastatin and simvastatin. On the other hand, all three hydrophobic statins induced a dose-dependent increase in the phagocytic index. The hydrophilic pravastatin did not affect phagocytosis, phagocytic index and apoptosis. All three hydrophobic statins at 50 microM exerted a slight, but significant decrease of apoptosis. The results suggest that the effect of hydrophobic statins on the engulfing capacity of human peripheral blood phagocytes and apoptosis is dependent on their dosage and physiochemical properties. This observation is an additional contribution to the statins' pleiotropic effect.

[Contained rupture of the aorta as a cause of prolonged abdominal pain].

Abdominal pain is a frequent complaint. In this report, a woman who presented with abdominal pain was found to have a contained rupture of the abdominal aorta that extended into the retroperitoneum. The diagnosis was difficult due to the multiple manifestations in the clinical presentation. Rupture of the aorta is more frequent in patients who suffer from an aortic aneurysm. The patient described, however, did not have an aneurysm, as illustrated by the abdominal CT scan and surgical findings. Therefore, abdominal or back pain may be caused by a rupture of the aorta, even in the absence of an aortic aneurysm.

Functional hypersplenism in mice induced by adoptive transfer of syngeneic spleen cells.

Investigation of peripheral blood cell count alterations in cases with hypersplenism, and an understanding of the relationship between splenic function and hematopoietic cell production require suitable experimental animal models. Previously described methods are either traumatic or require surgical intervention. We suggest a relatively simple method for achievement of a state mimicking hypersplenism in mice by intraperitoneal inoculation of syngeneic spleen cells. Mice were inoculated intraperitoneally with 3 x 10(7) splenocytes suspended in 0.3 ml phosphate buffered saline (PBS). After 2 months, the inoculated animals showed a progressive decrease in the peripheral white blood cell (WBC) counts and hyperplastic bone marrow that persisted until the experimental end point (7 months). Five days after inoculation of splenocytes stained with carboxy-fluorescein diacetate succinimidyl ester (CFSE), the majority of the stained cells was present in the peritoneal cavity (33%) and in the liver (13%), whereas the percentage of stained cells in the peripheral blood and the spleen cell suspension was negligible. The mitogen response of the peripheral blood mononuclear cells (PBMC) from treated mice to concanavalin A (Con A) remained unaltered. Splenocyte-inoculated mice that were further splenectomized did not show leukocytosis after splenectomy, as was observed in animals in which the spleen was removed without any pretreatment. The lack of any signs of discomfort in animals from the study group, in comparison with the visibly ill appearance and even death of mice in which hypersplenism was achieved by repeated injections of methylcellulose (MC), which served as controls, favors the convenience of the method.

Constrictive pericarditis: A reminder of a not so rare disease.

Constrictive pericarditis is a rare condition characterized by clinical signs of right heart failure subsequent to loss of pericardial compliance. The etiology of constrictive pericarditis has changed during the last decades in developed countries. While, in the past, tuberculosis and idiopathic pericardial constriction were the prevalent causes of the disease, cardiac surgery has become one of the main reasons for its development in recent years. However, cases defined as idiopathic constrictive pericarditis are still observed. In addition to the classical chronic and subacute forms, new presentations, such as effusive-constrictive, localized, transient, occult, and constrictive pericarditis with normal pericardial thickness, have been described. Although conservative treatment may alleviate the patient's symptoms, pericardiectomy remains the only definitive treatment for the disease. It is worth noting that the sooner the diagnosis of pericardial constriction is established, the better the outcome is. The pathophysiological features, clinical findings, diagnostic tools, and therapeutic approach to constrictive pericarditis are detailed in this review.

[Nephrotic syndrome as a first manifestation of familial Mediterranean fever].

AA amyloidosis may be a complication of Familial Mediterranean Fever (FMF). This is a case history of a female patient who did not have the classic symptoms of FMF, which usually precede the renal manifestation. The patient was admitted with edema of both legs, and the nephrotic syndrome was discovered, leading to the diagnosis of AA amyloidosis on kidney biopsy. Genetic testing uncovered the homozygous M694V type mutation, the most common mutation of FMF, which renders the patients prone to amyloidosis. This case represents the phenotype II of FMF, which presents with amyloidosis without prior classic attacks of FMF. Since effective prevention of the development of amyloidosis is available, genetic testing should be considered in order to identify mutations which carry high risk for the development of amyloidosis. This is also relevant in asymptomatic individuals with family history of FMF.

Phagocytic capacity and apoptosis of peripheral blood cells from patients with iron deficiency anemia.

Following clinical observations that patients with iron deficiency anemia (IDA) are more susceptible to infections than non-anemic individuals, the phagocytic capacity and number of apoptotic peripheral white blood cells (PWBC) from patients with IDA were examined. PWBC from 15 patients with IDA and from 18 healthy donors were incubated with various doses of iron. Phagocytosis was examined using latex particles and apoptosis was evaluated by a flow cytometric assay using propidium iodide staining. The percentage of phagocyting polymorphonuclear cells was lower in IDA patients compared to that of the controls. However, there was no difference in the percentage of phagocyting monocytes from individuals of both groups. The number of latex beads engulfed by each polymorphonuclear or monocyte was lower in IDA patients. Incubation with 100 microg% of iron did not affect the phagocytic ability of both cell types in IDA patients, but increased that of control cells. Incubation with 300 microg% of iron caused an increase in the phagocytic capacity of patients' cells and a decrease in that function in cells from controls. Higher dose (500 microg%) induced suppression of phagocytosis in cells from both groups. There was no difference in the number of apoptotic cells from individuals of both groups. Apoptosis of polymorphonuclears, but not mononuclear cells from both controls and IDA patients showed a linear dependency on the iron concentration in the medium. It is possible that the impaired phagocytic capacity of the PBWC found in patients with IDA contribute to the increased susceptibility to infections observed in these individuals.

Early development of severe constrictive pericarditis after coronary bypass grafting.

A 61-year-old patient developed severe constrictive pericarditis with exertional dyspnea, 3 weeks after coronary bypass surgery. The diagnosis was confirmed by echocardigraphy and computed tomography examination. Despite the short duration of the disease, the pericardium showed a thickness of about 1 cm. Because initial treatment with steroids, diuretics and antiinflammatory drugs was of no avail, the patient underwent pericardiectomy, with a satisfactory outcome. The relatively rapid progress of constriction and the marked thickness of the pericardium that developed after a short period of time are emphasized.

The effect of sodium bicarbonate on cytokine secretion in CKD patients with metabolic acidosis.

The incidence of acidosis increases with the progression of chronic kidney disease (CKD). Correction of acidosis by sodium bicarbonate may slow CKD deterioration. Inflammation, which is common in CKD, may be related to acidosis. Whether the slower rate of GFR decline following the correction of acidosis is related to changes in inflammatory markers is unknown. The current study examined whether correcting CKD-acidosis affected inflammatory cytokines secretion. Thirteen patients with CKD 4-5 and acidosis were tested for cytokines secretion from peripheral-blood mononuclear cells at baseline and after one month of oral sodium bicarbonate. Following treatment with sodium bicarbonate there was no change in weight, blood pressure, serum creatinine, albumin, sodium, calcium, phosphate, PTH, hemoglobin and CRP. Serum urea decreased (134±10-116±8 mg/dl, P=0.002), potassium decreased (5.1±0.4-4.8±0.1 mequiv./l, P=0.064), pH increased (7.29±0.01-7.33±0.01, P=0.008), and serum bicarbonate increased (18.6±0.4 mequiv./l to 21.3±0.3 mequiv./l, P=0.001). The secretion of the anti-inflammatory cytokine IL-10 decreased (2.75±0.25 ng/ml to 2.29±0.21 ng/ml, P=0.041). There was no significant change in the secretion of the other pro-inflammatory and anti-inflammatory cytokines, including IL-1ß, IL-2, IL-6, TNFα, IFNγ, IL-1ra. Thus, correcting acidosis in CKD with bicarbonate decreases IL-10 secretion. Its significance needs to be further investigated.

Factor(s) released from irradiated B-CLL cells induce apoptosis in leukemic lymphocytes.

Photon irradiation of peripheral blood lymphocytes from 25 patients with untreated B-chronic lymphocytic leukemia (B-CLL) induced an increase in apoptotic response by 270%. No significant increase in apoptosis was observed after irradiation of peripheral blood mononuclear cells from 15 healthy volunteers. Supernatants (sups) derived from irradiated leukemic cells incubated with non-irradiated autologous cells induced a 75% enhancement in number of apoptotic cells, as compared with sups from non-irradiated CLL cells. The level of tumor necrosis factor alpha, a cytokine known to prevent apoptosis, was reduced in the sups of irradiated CLL cells in comparison to that of non-irradiated lymphocytes. The interleukin (IL)-10 level, an IL reported to induce apoptosis, was similar in the sups of irradiated and non-irradiated lymphocytes from B-CLL patients. No change in IL-2 levels was observed. The significance of these findings and the role of factor(s) in the sups of irradiated leukemic lymphocytes as inducers of apoptosis are discussed.

Ultrastructural features of bone marrow cells from patients with acquired sideroblastic anemia.

The ultrastructural findings of the bone marrow cells from 15 patients with acquired sideroblastic anemia are presented. The red cell precursors from all patients showed the presence of electron-dense material in the mitochondria, representing most probably iron deposits. A great number of these mitochondria were completely destroyed. The erythropoietic precursors from one of the patients showed markedly elongated mitochondria that measured up to 3 microm. In addition numerous cytoplasmic vacuoles were observed. The red cell precursors from 60% of the patients showed signs of dyserythropoiesis, such as incomplete nuclear division and nuclear distortion. The polymorphonuclears from 47% of the patients presented nuclear abnormalities expressed as nuclear bridges, appendices, and blebs. In addition, phagocytosis of red blood cells was observed. The results of the study underline the advantages of the transmission electron microscope examination in visualization of intricate alterations in hematopoietic cells that cannot be detected with a light microscope.

Phagocytosis--the mighty weapon of the silent warriors.

Professional phagocytes, comprising polymorphonuclear neutrophils and monocyte/macrophage cells, play an important role in the host defense. Any defect in their function exposes the organism to microbial intruders terminating in fatal diseases. The functional responses of the phagocytes to bacterial and fungal infections include chemotaxis, actin assembly, migration, adhesion, aggregation, phagocytosis, degranulation, and reactive oxygen species production. Superoxide generation by phagocytic NADPH oxidase is an imperative step toward bacterial killing. Phagocytes participate in inflammatory reactions and exert tumoricidal activity. They are supported by serum factors such as immunoglobulins, cytokines, complement, the acute phase reactant C-reactive protein, production of antibacterial proteins, and others. In addition to their principal task to eliminate bacteria, they are engaged in removing damaged, senescent, and apoptotic cells. Engulfed cell debris, large particles such as latex beads, fat, and oil droplets, are examples of phagocytic activity illustrated in the present review with transmission and scanning electron microscope micrographs. Numerous factors, such as diseases and stressful conditions, affect the engulfing activity of the professional phagocytes. Our experience regarding the impaired phagocytic capacity of cells in patients with diabetes and chronic renal failure is discussed. The results obtained in our laboratory from experiments detecting the effect of strenuous physical exercise, hypothermia, fasting, and abdominal photon irradiation on the phagocytic capacity of human polymorphonuclear neutrophils and rat peritoneal macrophages are hereby summarized and the reports on those subjects in the recent literature are reviewed. A variety of assays are applied for quantifying phagocytosis. Flow cytometry based on incubation of phagocytic cells with fluorescent conjugated particles and measuring the amount of fluorescence as an indicator of the engulfing capacity of the cells is a useful method. A direct visualization of the ingested particles using light or electron microscopy is a valuable tool for estimation of phagocytic function. In our hands, the use of semithin sections of embedded phagocytes following their incubation with latex particles provided satisfactory results for measuring the total number of phagocytic cells, as well as the internalizing capacity of each individual cell. Microbiological assays, the nitroblue tetrazolium test, quantitation of antibody- and antigen-mediated phagocytosis, as well as methods reviewed in detail in other reports are additional applications for determination of this intricate process.

In vitro immune response of human peripheral blood cells to vitamins C and E.

Since oxygen free radicals exert a noxious effect on cell functions, the purpose of the study was to examine the influence of the antioxidant vitamins C and E on the phagocytic capacity, apoptotic death, production of TNFalpha and IL-10 by human peripheral blood cells. In addition, an attempt to find a correlation between the effect of these vitamins on apoptosis and DNA synthesis was carried out. Peripheral white blood cells obtained from 27 healthy volunteers were incubated for 24 hr without and with vitamins C and E at doses extrapolated from clinical practice. Incubation of cells with vit. C caused a significant increase in the number of latex particles internalized by each individual polymorphonuclear cell, but not by monocytes. Both vitamins did not change the number of cells capable for phagocytosis. By the method of propidium iodide staining for detection of apoptosis, incubation of the cells with 0.2 mg/mL vit. C for 24 hrs caused a 39% increase in the percentage of apoptotic cells, as compared to those kept at the same incubation conditions without vitamin. 0.125 mg/mL of vit. E did not affect the percentage of apoptotic cells. On the other hand, applying the caspase-3 method for apoptosis detection, vitamins C and E did not affect the caspase-3 activity. Both vitamins caused an inhibition of 3H-TdR incorporation, which was dose-dependent for vit. C. Concentrations of the vitamins lower than those mentioned above did not alter DNA synthesis. While TNFalpha production was not affected by both vitamins, the spontaneous secretion of IL-10 was dose-dependently reduced by vit. C but remained unaltered following incubation with vit. E. The results, although observed in vitro, might be of importance when those vitamins are administered to healthy subjects.

Cat bite in an old patient: is it a simple injury?

An 84-year-old woman bitten by her domestic cat developed a severe wound infection caused by Pasteurella multocida. Although she was treated with antibiotics according to the bacterial sensitivity, the infection progressed to sepsis and became complicated by transient renal failure caused by interstitial nephritis. The need in the emergency department for a thorough examination of patients with domestic animal-inflicted injuries, the indication for surgical debridement, and the isolation of the offender by early obtained cultures are considered. The administration of the properly chosen antibiotics and prophylactic vaccination against rabies and tetanus are discussed.

[Sarcoidosis--an uncommon cause of pancreatic mass].

Sarcoidosis is a multi-system granulomatous disease that mainly affects the lungs and the lymphatic system. Involvement of the digestive system is rare, while the presentation of a mass in the pancreas as the first sign of sarcoidosis in the digestive system is yet rarer. Very few cases have been reported in the literature. The presentation of a mass in the pancreas is indicative of malignancy or inflammation and thus makes the diagnosis of sarcoidosis very difficult. Often it is discovered only after surgical intervention. We present a case study in which the involvement of the pancreas, bile ducts and mesentery lymph nodes led to a Whipple operation. However, on biopsy, non-caseating granulomas were found with no signs of malignancy. In view of the difficulties in diagnosing sarcoidosis of the digestive system and pancreas, we present a review of the literature on the diagnosis and management of this form of sarcoidosis.