In vitro induction of apoptotic cell death in chronic lymphocytic leukemia by two natural products: preliminary study.

PURPOSE: B cell chronic lymphocytic leukemia (B-CLL) is an neoplastic disorder characterized by alterations in the pathways of programmed cell death (apoptosis). Deregulation of apoptosis pathways also contributes to chemoresistance of B-CLL cells. Therefore, it is not surprising that induction and acceleration of apoptosis represent key point in novel B-CLL therapeutic protocols. The present study was designed to investigate the effects of two natural products, Immunarc forte and Korbazol on the in vitro survival of leukemic cells. METHODS: peripheral blood mononuclear cells (PBMC) from 20 B-CLL patients and 20 healthy donors were used for cytotoxicity studies. Cytotoxic activity of the tested products were assessed by the MTT colorimetric assay and the type of cell death was determined by flow cytometry. RESULTS: we found that Korbazol was selectively cytotoxic against B-CLL cells, but the cytotoxic activity of Immunarc forte was much weaker. Of note, synergy was shown between these two drugs, and this effect was also selective, without affecting the normal mononuclear cells. According to Annexin-V binding, Korbazol and Immunarc forte induced apoptotic type of cell death in B-CLL cells. Moreover, treatment with Korbazol, but not with Immunarc forte, decreased spontaneous apoptosis in cultured normal polymorphonuclear cells. CONCLUSION: our findings imply that Korbazol is as potential therapeutic agent that induces apoptosis of B-CLL cells. The resistance of normal mononuclear cells and anti-apoptotic effects on normal polymorphonuclear cells, as well as its ability to synergize with Immunarc forte, warrants further investigation and supports their therapeutic application in the treatment of B-CLL.

Endoplasmic reticulum stress associated with caspases-4 and -2 mediates korbazol-induced B-chronic lymphocytic leukemia cell apoptosis.

PURPOSE: B-cell chronic lymphocytic leukemia (B-CLL) is an incurable disease that rapidly develops drug resistance. Therefore there is a need for identifying new agents that will improve the therapeutic outcome. Korbazol is a natural product known to exert cytotoxic effect on the in vitro survival of leukemic cells. The aim of this study was to investigate the mechanism of korbazol-induced apoptosis in B-CLL leukemic cells. METHODS: peripheral blood mononuclear cells from 10 B-CLL patients were used for assessing the effect of caspase inhibitors and chelator of intracellular Ca(2)+. RESULTS: cell death rate induced by the tested compound was decreased with the caspase-3 inhibitor Ac-DEVD-CHO, and the inhibitors of caspase-2 (Z-VDVAD-FMK) and -4 (ZYVAD- FMK), but not with the caspase-9 inhibitor z-LEHD-FMK and caspase-8 inhibitor z-IETD-FMK. No significant release of cytochrome C (cyt C) from mitochondria to the cytosol of B-CLL cells treated with korbazol was observed. Moreover, chelating of intracellular Ca(2)+ with BAPTA-AM almost completely abolished the cytotoxic effect of korbazol. CONCLUSION: engagement of caspases-2 and -4 and mobilization of intracellular Ca(2)+ indicate involvement of endoplasmic reticulum (ER) stress in apoptosis induced by korbazol.

[Isolated systolic arterial hypertension in the elderly]. / Izolovana sistolna arterijska hipertenzija kod starnih osoba.

Isolated systolic hypertension is a common disorder in the elderly carrying a high risk of stroke and cardiovascular disease. Isolated systolic hypertension is usually defined as a systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure less than 95 mmHg. The arterial stiffening is the principal cause of increasing systolic pressure in advanced age. It is due to degeneration of the arterial wall and is associated with progressive arterial dilatation. Hypertension in elderly patients is also characterized by increase of peripheral vascular resistance. Due to the wide variability of blood pressure usually seen in old persons, the isolated systolic hypertension is not easy to recognize and final diagnosis requires a long period of observation. The ambulatory blood pressure monitoring proved to be helpful in distinguishing patients with true isolated systolic hypertension from subjects with exaggerated alarm reaction to the pressure measurement. Although the increased risk of cardiovascular and cerebrovascular mortality is well established for isolated systolic hypertension, there has been much debate whether available antihypertensive treatment can prevent or delay cardiovascular and cerebrovascular complications in this condition. During the last year several large new trials have been published, the so-called STOP-Hypertension, SHEP and MRC trials. All studies have demonstrated that the treatment of isolated systolic hypertension with diuretics or/and beta blockers (frequently used in combination) resulted in a significant reduction in the incidence of stroke and major cardiovascular events. New antihypertensive agents such as calcium channel blockers and angiotensin-converting enzyme inhibitors have also been shown to effectively lower systolic blood pressure in the elderly but the effects on long-term morbidity and mortality are still unknown.

Blood and plasma selenium levels and GSH-Px activities in patients with arterial hypertension and chronic heart disease.

The purpose of this study was to examine the relationship between arterial hypertension (HTN), chronic heart disease (CHD), and selenium (Se) status. Blood and plasma Se concentrations and Se-dependent GSH-Px activities were determined in 40 patients (HTN = 20; CHD = 20) and 17 healthy volunteers aged 41 to 66 years. Whole blood and plasma Se concentrations were significantly lower in the patients with HTN (19.1% and 26.3%, respectively) and CHD (33.1% and 29.4%, respectively) compared with the values obtained in the controls. The hypertensive patients had lower plasma Se-GSH-Px (26.7%), and those with CHD had both lower whole blood (19.5%) and plasma Se-GSH-Px activities (30.2%). A significant positive correlation between plasma Se-GSH-Px activity and ejection fraction (EF) was found in patients with CHD. There were significant correlations between plasma and whole blood Se concentration, plasma Se concentration and Se-GSH-Px activity, and whole blood Se and Se-GSH-Px activity. Our results showed that hypertensive patients and those with CHD had lower Se levels compared with controls. We conclude that low Se content might be a risk factor for development of HTN and CHD.

Unruptured congenital aneurysm of the right sinus of Valsalva. Dissecting into the interventricular septum.

We report the case of a congenital aneurysm of the right sinus of Valsalva dissecting into the interventricular septum in a 21-year-old man. This condition was diagnosed by echocardiography and magnetic resonance imaging. In particular, transthoracic and transesophageal color-coded Doppler echocardiography showed that there was no communication between the aneurysm and the surrounding heart chambers. The findings were confirmed by angiography. Heart enlargement and other symptoms and signs of heart failure indicated surgical repair of the lesion. Early postoperative dehiscence of the sutured orifice was accurately diagnosed with Doppler echocardiography and angiography. Reintervention was successful in filling and sealing the septal cavity. This case confirms the reported difficulties in the surgical correction of aneurysms of sinus of Valsalva lying within the interventricular septum.

[Isolated interrupted aortic arch]. / Izolovani prekid aortnog luka.

Interrupted aortic arch is rarely presented as an entirely isolated lesion (in childhood or young adult life) in a manner similar to classical coarctation and in association with obvious collateral circulation. We present a 24-year old male with arterial hypertension of the upper body part caused by interrupted aortic arch. In this patient the femoral pulses were reduced, collateral circulation was palpable intercostally. Echocardiography has provided information about the site of interruption of the aortic arch. Exact diagnosis was established by cineangiography which has displayed interruption of aortic arch just distally to the left truncus brachiocephalicus (type A) and extensive collateral circulation. At the same time other cardiac defects were excluded.

[Acute fatty liver in pregnancy]. / Akutna masna jetra u trudnoci.

Acute fatty liver in pregnancy (AFLP) is a rare disease with sudden onset in the third trimester of pregnancy characterized by jaundice, bleeding, liver failure and encephalopathy. The cause of AFLP is unknown. It is of short duration and high risk of mortality. The aim of this paper is to describe a patient who was hospitalised in the 36th week of pregnancy due to jaundice and bleeding. Upon arrival the patient delivered a dead infant, and thereafter jaundice, severe bleeding and encephalopathy deteriorated. The patient's laboratory results revealed AFLP which was confirmed with increased echogenicity of the liver. Spontaneous delivery and maximal supportive therapy contributed to successful recovery of the patient in spite of severe haemorrhage, encephalopathy, acute ranal failure, polyserositis and adult respiratory distress syndrome.

[Wilson's disease and pregnancy]. / Vilsonova bolest i trudnoca.

Wilson's disease is rare autosomal-recessive disorder originated on the basis of metabolic copper over-storage. This is the case report of patient aged 28, who suffers Wilson's disease during last ten years. She has been treated by penicillamine unregularly from the beginning of her disease. She reported three spontaneous abortions in her previous history. She was treated by penicillamin and bedoxin in current pregnancy. Vaginal delivery was completed using oxytocin stimulation. Newborn was male, alive, with body weight of 2900 grams. Apgar score was 8. During puerperal period normal uterine involution was estimated, but lactation was ceased.

[Relation between Doppler echocardiography and the surface area of the mitral valve]. / Zavisnost nalaza Doppler ehokardiografije od povrsine mitralnog usca.

The Doppler signal of mitral flow velocity depends not only on the pressure drop across the mitral orifice, but on the volume flow also. Since the slope of the maximum velocity curve and the rate of decrease of pressure drop during diastole are influenced by the degree of obstruction, we compared the findings of the Doppler examination in our patients with different mitral valve areas determined by 2-D echocardiography.

[Doppler echocardiography in the evaluation of prosthetic valve function]. / Doppler ehokardiografija u proceni funkcije ugradhenih vestackih valvula.

The limitations of invasive and noninvasive procedures, including M-mode and 2-D echocardiography, in the follow-up of patients with prosthetic heart valve replacement, are numerous and well known. Doppler echocardiography helps the functional evaluation of prosthetic valves by reliable detection of valvular regurgitation through a malfunctioning prosthetic valve or due to paravalvular leaks. On the other hand, serial determinations of the values of pressure drops or effective valve orifice areas, calculated from the half-time pressure, enables the diagnosis of prosthetic valve obstruction or dehiscence. The results in the assessment of prosthetic valve function by Doppler echocardiography in a group of operated patients, are reported. Signs of prosthetic valve malfunction were not present in 6 patients with mitral valve prostheses and two patients with two-valve-prostheses (mitral and aortic) in the group ob 13 evaluated patients. In two patients with Björk mitral valves mitral regurgitation was found. It was due to valvular leakage in one patient and to paravalvular leakages in the other. In both patients with aortic prosthetic dysfunction a paravalvular leak was diagnosed. There was an invasive proof of prosthetic regurgitation in the same four patients. The only patient with biologic mitral valve prosthesis presented a significant flow obstruction.

[Hypocorticism, pregnancy, labor and the newborn infant]. / Hipokorticizam, trudnoca, porodaj i novorodence.

The authors followed up a pregnant woman with Addison's disease. Prior to, and throughout pregnancy, she received hydrocortisone in daily doses of 20 mg. The basic disease did not deteriorate during pregnancy. The pregnancy was terminated in the 41st week of gestation by induced labour. The infant's birth weight was below the 10th centile for the gestational age. Apgar score was 6. During the puerperium, the maternal basic disease got worse, requiring the increased substitution therapy. Both the mother and child discharged in good condition, on the 11th postpartal day.

[Etiological factors in sterility and infertility as risk factors in future pregnancies]. / O nekim etioloskim ciniocima steriliteta i infertiliteta kao faktorima rizika u buducim trudnocama.

An analysis was made of 1420 patients with threatened spontaneous or habitual abortions and pre-term deliveries, concerning the incidence of some etiological factors of infertility that might have been risk factors in the actual pregnancy. The number of pregnant women over 35 years of age in the treated series was significantly higher than in the control group. History data on sterility in the former group showed the incidence of 4.37% and in the control group 1.10%, the difference being highly significant (P less than 0.001). In the investigated series 154 patients (10.85%) had already had previous pre-term deliveries, while in the control group pre-term deliveries amounted to 3.20%, the difference being statistically highly significant (P less than 0.001). History data on spontaneous abortions in the first group showed the incidence of 69.57% (846 patients) and in the control group 16.20% (P less than 0.001). Uterine malformations were recorded in 69 gravidae (4.86%) in the treated group and in 1.20% in the control group, the difference being statistically highly significant (P less than 0.001). In addition to etiological factors, a high incidence of the following anomalies was also revealed: uterine hypoplasia and myoma, cervical laceration, cervico-isthmical insufficiency, and perinatal deaths in the history of the treated group. The importance of antenatal care of pregnant women with previous sterility and infertility is emphasized, as well as the need for considering the prophylactic use of beta-sympathomimetics.

[Analysis of causes of CNS damages in neonates delivered by cesarean section (author's transl)]. / Analiza uzroka ostecenja centralnog nervnog sistema novorodencadi rodene carskim rezom.

Of 27.978 newborns delivered at the University Hospital Department of Gynecology and Obstetrics in Beogradu, from 1978 to 1980, 2218 (7.92%) were born by cesarean sections. Clinical-biochemical and morphological elements of hypoxic and ischemic CNS lesions were found in 107 (4.82%) cases out of the infants born by cesarean section and in 1301 (5.05%) cases out of the infants born by vaginal delivery. The difference is not statistically significant. Investigations of the causes, i. e. risk factors of CNS lesions in infants born by cesarean section, in correlation with the control group consisting of 670 cesarean sections performed in 1980 without CNS lesions, have revealed: a) high risk factor (p less than 0.01) appeared to involve parity (para III and more), maternal diseases (hypertension, diabetes mellitus, EPH gestosis), placenta praevia, premature rupture of the membranes, prematurity birth weight below 2500 g, and low Apgar score (1-7); b) significant risk factors (p less than 0.05) are some social factors (unemployed mothers and mothers from rural areas), duration of labor (more than 10 hours), transverse presentation, hydramnion, previous spontaneous abortions and stillbirths. The analysis has shown that CNS lesions in infants born by cesarean section may result from different factors; medical, biological, and social.

[Use of simethicone in the prevention of postoperative abdominal discomfort and gastrointestinal distension after cesarean section]. / Prevencija postoperativnih abdominalnih tegoba i gastrointestinalne distenzije posle carskog reza simeticonom.

A double blind trial was performed in patients with Cesarean section in order to study the effect of Simeticon (Stuart Pharmaceutical Company, Pasadena, California) on the occurrence of subjective and objective signs of gas distress during the immediate postoperative period. The results obtained with Simeticon show a highly significant reduction of the analysed subjective complaints (nausea, vomiting, meteorism, discomfort in the stomach, abdominal pains) in relation to placebo. Peristaltic movements in patients treated with Simeticon appeared in the first two days in 100% of cases and only in 30% in the placebo group. Flatulence also appeared in all the patients receiving Simeticon, in contrast to only 20% in the placebo group. There was no difference in spontanous defecation between the groups. On the basis of the results obtained, and considering the non-toxicity of the drug, its chemical inertnees, good tolerance, and simple use, the authors consider simeticon very useful for the prevention and therapy of postoperative discomfort due to gas accumulation and gastro-intestinal distention after Cesarean section.

[Tocolysis in prevention of spontaneous abortion]. / Tokoliza u prevenciji spontanih pobacaja.

In the course of 1975 and 1976 the authors applied Partusisten (Th 1156 a) in 34 pregnant women at the risk of spontaneous abortion in the 16th to the 28th week of pregnancy. The therapy started with intravenous infusions by means of an automatic electromechanic infusion pump; peroral application of the drug followed, both in hospital and for a certain period in outpatient treatment under the gynecologist's supervision. Out of 34 women, 27 remained pregnant for more than 37 week of gestation and gave birth to a live at-term baby; in 5 cases the success was relative, and only in 2 cases was there no success at all. According to the tocolysis index, at index 2 or less, the success was achieved in 87% of cases and at index exceeding 2, the success was achieved in 63% of cases. The side-effect observed was invariably tachicardia in the mother, while all other untoward effects (tremor, sweating, slight restlessness, etc) were tolerated very well. An extremely good effect of Partusisten is obvious, because in doses of 4 micrograms/min, it promptly reduces the frequency and intensity of contractions.