The effect of opioid dependence on conventional and novel biochemical parameters of bone metabolism.

BACKGROUND: Opioids influence bone metabolism in several ways and osteoporosis associated with the long-term use of opioids is believed to be multifactorial. OBJECTIVES: To investigate the effect of opioid dependence on conventional and novel biochemical parameters of bone metabolism. To evaluate whether the concomitant HCV infection affects these parameters. METHODS: Fifty-nine opioid-dependent subjects and 23 healthy volunteers participated in the study. Parameters of bone metabolism were determined in serum. The determined parameters were procollagen type I N-terminal propeptide (PINP), serum Beta-Crosslaps Ι (ß-CTX), total calcium (Ca), inorganic phosphorus (P), parathormone (PTH) and alkaline phosphatase bone isoenzyme (ALP). RESULTS: The results of our study show that opioid-dependent subjects exhibit higher values in those biochemical markers that are indicative of increased osteoclast activity, such as ß-CTX and ALP, compared to healthy subjects. Furthermore, in opioid-dependent subjects the values of PTH were lower, while those of PINP were higher, in comparison to healthy individuals. No significant difference in the studied parameters was found when opioid-dependent subjects positive for anti-HCV antibodies were compared with opioid-dependent subjects negative for anti-HCV antibodies. CONCLUSION: Our findings show that there is increased bone turnover (bone metabolism) in opioid-dependent subjects, compared to healthy individuals. Future research on bone mineral density in these patients will help us evaluate whether the bone remodeling process is balanced or not.

Revisiting Temozolomide's role in solid tumors: Old is gold?

Temozolomide is an imidazotetrazine with a long history in oncology especially for the high grade malignant glioma and metastatic melanoma. However, last year's new indications for its use are added. Its optimum pharmacodynamic profile, its ability to penetrate the blood-brain barrier, the existence of methylation of MGMT in solid tumors which enhances its efficacy, the identification of new agents that can overcome temozolomide's resistance, the promising role of temozolomide in turning immune cold tumors to hot ones, are leading to expand its use in other solid tumors, giving oncologists an additional tool for the treatment of advanced and aggressive neoplasms.

Atrial natriuretic peptide decreases aorta stiffness in cholesterol-fed anesthetized rabbits.

Aortas from Watanabe heritable hyperlipidemic rabbits show in vitro impaired vasodilatory response to atrial natriuretic peptide (ANP) during atherosclerosis progression. To test a similar reaction in vivo, the effect of ANP administration on pulse wave velocity (PWV, index of aorta stiffness) was investigated in 10 normal and 10 cholesterol-fed (2% cholesterol-loaded feeding for 4 weeks) anesthetized male New Zealand White (NZW) rabbits. Invasively taken carotid and femoral blood pressures (BP) were recorded, simultaneously with ECG, and blood samples for ANP measurement (by RIA) were taken at 0 min and 20, 40, 60 min following an intravenous 20-min administration of either 0.2 microg kg(-1)min(-1) hANP in 5 ml normal saline or only 5 ml saline. Mild to moderate atherosclerosis was found in ascending aorta. BP decreased by ANP only at 20 min in both groups, whereas only in cholesterol-fed rabbits the borderline (p=0.09) increased at 0 min PWV was lowered (p=0.008) in all recording times. With any degree of increase of systolic BP (SBP) PWV increased less in ANP receivers. Atherosclerosis and SBP were the most important determinants of PWV and the effect of ANP was independent of confounding factors. It is concluded that short-term ANP administration in doses to achieve levels approximately threefold the pretreatment ones in normal and mildly to moderately atherosclerotic anesthetized NZW rabbits, causes an improvement of aorta stiffness only in atherosclerotic rabbits.

Physical training in patients on hemodialysis has a beneficial effect on the levels of eicosanoid hormone-like substances.

OBJECTIVE: The aim of this study was to evaluate the changes in the levels of vasoactive eicosanoid hormone-like substances PGE2, PGI2 and TXA2 in hemodialysis (HD)patients who were following a long-term physical training program during the hemodialysis session. DESIGN: A total of 50 patients with Chronic Kidney Disease (CKD) (stage 5)on hemodialysis and 35 healthy individuals who served as controls (C) were evaluated. The 50 CKD patients were divided into two groups: the HD group consisted of 31 patients who received usual care without any physical activity during the hemodialysis sessions, while group HD/Exer included 19 patients who followed a program of physical exercise for six months. Plasma levels of PGE2, 6-Keto-PGF1alpha (the stable derivative of PGI2) and TXB2 (the stable derivative of TXA2) were measured by reliable enzymo-immunoassay methods (EIA) in HD and HD/Exer patients before and after the hemodialysis sessions as well as in the group of C. RESULTS: The plasma levels of PGE2 and 6-keto-PGF1alpha in group HD Exer/before patients were higher than those in group HDbefore (20.39+/-5.82 and 1449.19+/-553.41 vs 17.68+/-5.36 and 1295.10+/-384.43 pg/ml, p=0.044 and p=0.067, respectively), while the plasma levels of TXB2 were lower in HD Exer/before patients compared to HDbefore(499.76+/-67.51 vs 608.01+/-80.23 pg/ml, p=0.041). The plasma levels of PGE2 and 6-keto-PGF1alpha in group HD Exer/after patients were significantly higher compared to those in HDafter patients (23.01+/-5.70 and 1618.19+/-435.07 vs 16.57+/-4.97 and 1005.44+/-317.16 pg/ml, p<0.001 and p<0.040, respectively). However, significantly lower values in the plasma levels of TXB2 in HD Exer/after compared to HDafter patients (363.10+/-51.91 vs 439.75+/-62.34 pg/ml, p=0.030) were detected. As expected, PGE2 and 6-keto-PGF1alpha values were lower in C than in the groups of patients with CKD. CONCLUSIONS: The data indicate that exercise training during HD exerts a beneficial effect on the levels of the vasoactive eicosanoid hormone-like substances in patients on HD.

Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease.

BACKGROUND/AIMS: Increased oxidative stress in chronic kidney disease (CKD) was suggested to be both a cause and an effect of renal injury. However, the evolution of oxidant stress from early stages of renal function decline is not fully clear. This study aimed to determine the oxidant-antioxidant balance across the whole range of renal function. METHODS: A total of 116 patients with CKD (85 predialysis patients divided into groups according to CKD stage, and 31 patients with end-stage renal disease (ESRD) on hemodialysis treatment), as well as 29 healthy subjects were evaluated. Plasma levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP), a valid marker of oxidant stress, as well as total antioxidant capacity (TAC) and serum levels of vitamin E were measured in all participants. RESULTS: Plasma 15-F(2t)-IsoP levels were higher in predialysis and ESRD patients compared to healthy subjects and were progressively increasing with advancing CKD stages (p < 0.001). In contrast, plasma TAC was similar between healthy subjects and predialysis patients, and presented a small reduction in ESRD patients (p < 0.001). Vitamin E levels were higher in healthy subjects compared to any other group (p < 0.001) and slightly higher in ESRD patients compared to predialysis patients (p < 0.01), but did not differ significantly between the groups of predialysis patients. Plasma 15-F(2t)-IsoP levels were inversely correlated with estimated glomerular filtration rate in predialysis patients (r = -0.65, p < 0.001). CONCLUSIONS: This study shows that 15-F(2t)-IsoP levels increase progressively with advancing CKD stages, whereas TAC and vitamin E levels remain rather stable with the loss of renal function and change only in patients with ESRD.

CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients.

PURPOSE: CD4(+)CD25(bright) regulatory T cells (Tregs) are increased in patients with several malignancies and correlate with disease stage and prognosis. Breast cancer patients represent a heterogeneous population with unpredictable disease progression even at advanced stages. Circulating Tregs in correlation with HER-2/neu (HER) status and treatment with chemotherapy, either alone or in combination with trastuzumab therapy, were monitored in advanced-stage breast cancer patients. EXPERIMENTAL DESIGN: Circulating Treg frequency and absolute counts of 46 HER(+) and 28 HER(-), stage III and IV, breast cancer patients before therapy and during trastuzumab therapy and/or chemotherapy have been compared with 24 healthy donors and correlated with plasma HER extracellular domain concentration and clinical outcome. RESULTS: Treg frequency in HER(+) patients was significantly increased compared with both HER(-) patients and healthy donors. Trastuzumab therapy, with or without combined chemotherapy, resulted in a progressive decrease of circulating Tregs. Percentage change in Tregs statistically correlated with percentage change in plasma HER extracellular domain. Furthermore, decrease in Tregs correlated with either objective clinical response or stable disease, whereas increased Treg frequency during trastuzumab therapy coincided with disease progression. No statistically significant change in Treg frequency following chemotherapy was observed in HER(-) patients. CONCLUSIONS: Treg cell frequency does not directly correlate with clinical stage in breast cancer, as stage III and IV HER(+) and HER(-) patients exhibit significantly different Treg profiles. Trastuzumab therapy, either alone or combined with chemotherapy, results in decreased Treg frequency in HER(+) advanced patients with an objective clinical response.

Enhanced oxidative stress with a gradient between plasma and muscle interstitial fluid in patients with end stage renal failure on hemodialysis.

OBJECTIVE: The concentration of 8-iso-prostaglandin-F2 alpha (8-iso-PGF2 alpha in biological fluids has been considered as the most reliable biochemical index of the lipid peroxidation and oxidative stress in patients with several pathological conditions including end stage renal failure. However, there is no reference regarding the influence of Hemodialysis (HD) on the values of 8-iso-PGF2 alpha in the muscle Interstitial Fluid (IF) of patients with end stage renal failure. The aim of our study was to determine 8-iso-PGF2 alpha concentration in the IF during hemodialysis and the gradient between plasma and IF in patients with end stage renal failure. DESIGN: In this study, two microdialysis probes were inserted into the vastus lateralis muscle of the right leg of six male patients with end stage renal failure who were on hemodialysis, and in six healthy males (controls). The samples of IF (12 dialysate fluids) were collected after an equilibration of 30 min: a) during the 1st hour preceding hemodialysis (group CRF0), b) during the 1st, 2nd, 3rd and 4th hour while on hemodialysis (groups CRF1, CRF2, CRF3 and CRF4) and c) during the 1st hour following hemodialysis (group CRF5). At the end of the above periods and simultaneously, blood samples were drawn from the arteriovenous fistula. In the controls, the IF samples (twelve dialysate fluids) were collected during a period of one hour and the blood samples at the end of this period. The levels of 8-iso-PGF2 alpha were measured with an enzyme-immunoassay method. Statistical evaluation was carried out with the statistical program NCSS 2000 and the ANOVA test. RESULTS: Plasma and IF levels of 8-iso-PGF2 alpha in the patients were significantly higher than in controls at base line. During hemodialysis, the 8-iso-PGF2 alpha rose progressively both in plasma and IF but remained higher in plasma than in IF. CONCLUSIONS: Lipid peroxidation is higher in patients on hemodialysis than in controls but it is lower in the IF compared to plasma. The mechanism for this gradient is speculative.

The effect of L-arginine and aprotinin on intestinal ischemia-reperfusion injury.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) results in local mucosal injury, systemic injuries, and organ dysfunction. These injuries are characterized by altered microvascular and epithelial permeability and villous damage. Activation of neutrophils, platelets, and endothelial factors are known to be involved in this process. Cytokines such as TNF-alpha, IL-1, IL-6, and oxygen-derived free radicals are believed to be important pathogenic mediators. Capillary no-reflow is also known to play a role in I/R. The aim of our study was to examine the role of L-arginine, a known nitric oxide (NO) donor, and aprotinin, a protease inhibitor with multiple effects, on intestinal I/R. METHODS: Pigs weighing 20-25 kg were used. Ischemia was established by clamping the superior mesenteric artery (SMA) at its origin and was sustained for 2 hours. Duration of reperfusion was 2 hours. The animals were divided into four groups: group A, the control group, which was submitted to I/R injury only; group B, in which L-arginine was administered at a rate of 5 mg/kg/min during ischemia and continuing throughout reperfusion; group C, in which aprotinin was administered with an initial bolus dose of 20,000 U/kg during ischemia followed by a continuous dose at 50 U/hour throughout reperfusion; and group D in which both substances were administered. In all groups TNF-alpha, IL-1, and IL-6 levels were measured using ELISA at baseline, 2 hours of ischemia, and 1 hour and 2 hours of reperfusion. SMA blood flow was measured with a Doppler probe at baseline, 10 min, 1 hour, and 2 hours of reperfusion. Histological changes of the intestinal mucosa were examined and graded on a five-point scale in all groups. RESULTS: In the control group, levels of TNF-alpha, IL-1, and IL-6 were significantly increased during reperfusion (p < 0.05) compared to baseline. Administration of L-arginine and aprotinin led to suppression of the release of TNF-alpha, IL-1, and IL-6 during reperfusion in a statistically significant manner (all p < 0.05). A synergistic or additive effect of L-arginine and aprotinin was not observed. SMA blood flow in the control group was decreased (p > 0.05) during reperfusion compared to baseline. In animals treated with L-arginine and aprotinin, SMA blood flow during reperfusion was significantly increased (p < 0.05) compared to the control group. Histologic examination of the intestinal mucosa was characterized by flattening of the villi and necrosis in the control group. In the treated animals, less severe histological changes were noted. CONCLUSIONS: Administration of L: -arginine and aprotinin may lead to amelioration of intestinal I/R injury. We did not note a synergistic or additive effect of these two substances. These findings warrant further studies in clinical settings for future treatment efforts.

Ghrelin serum levels during oral glucose tolerance test in prepubertal obese children with insulin resistance.

BACKGROUND: An involvement of ghrelin in glucose metabolism has been suggested; nevertheless, the relationship between ghrelin and insulin resistance (IR) remains unclear. AIMS: 1. To investigate the effect of glucose loading on ghrelin in prepubertal obese children with IR. 2. To assess possible correlations between IR and changes in circulating ghrelin. PATIENTS AND METHODS: Twenty prepubertal obese, insulin-resistant and 18 age- and sex-matched lean children were studied. Fasting glucose, insulin and ghrelin levels were measured. In the obese group, measurements were repeated during an OGTT. RESULTS: Ghrelin levels were decreased at 60 min, but thereafter increased to baseline values. The fall in circulating ghrelin was negatively correlated with IR and the respective rise in insulin levels. CONCLUSIONS: In prepubertal, insulin-resistant obese children, ghrelin is significantly suppressed shortly after glucose intake. It is possible that the above effect is attenuated by IR and the resultant increase in insulin levels.

Season of birth, clinical manifestations and Dexamethasone Suppression Test in unipolar major depression.

BACKGROUND: Reports in the literature suggest that the season of birth might constitute a risk factor for the development of a major psychiatric disorder, possibly because of the effect environmental factors have during the second trimester of gestation. The aim of the current paper was to study the possible relationship of the season of birth and current clinical symptoms in unipolar major depression. METHODS: The study sample included 45 DSM-IV major depressive patients and 90 matched controls. The SCAN v. 2.0, Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Scale (HAS) were used to assess symptomatology, and the 1 mg Dexamethasone Suppression Test (DST) was used to subcategorize patients. RESULTS: Depressed patients as a whole did not show differences in birth season from controls. However, those patients born during the spring manifested higher HDRS while those born during the summer manifested the lowest HAS scores. DST non-suppressors were almost exclusively (90%) likely to be born during autumn and winter. No effect from the season of birth was found concerning the current severity of suicidal ideation or attempts. DISCUSSION: The current study is the first in this area of research using modern and rigid diagnostic methodology and a biological marker (DST) to categorize patients. Its disadvantages are the lack of data concerning DST in controls and a relatively small size of patient sample. The results confirm the effect of seasonality of birth on patients suffering from specific types of depression.

Ghrelin and leptin levels in obese adolescents. Relationship with body fat and insulin resistance.

OBJECTIVE: Ghrelin and leptin levels are influenced by body fat (BF%), pubertal stage and possibly insulin resistance (IR). The aim of our study was: 1) To compare fasting ghrelin and leptin levels between obese and non-obese, adolescents, 2) to investigate possible correlations of these hormones with BF %, as well as IR. DESIGN: Twenty obese insulin resistant (IR) adolescents, twenty obese non IR (NIR) and fifteen healthy non-obese, age-matched adolescents were studied. In all participants, height, weight, body mass index (BMI) and BF % were measured. Fasting glucose, insulin, ghrelin and leptin levels were determined. IR was assessed using HOMA-IR index. RESULTS: BMI, BF %, insulin and HOMA-IR values were positively correlated with leptin and negatively with ghrelin levels. A negative correlation between circulating leptin and ghrelin levels was found. A suggestive positive correlation between leptin levels and BF %, independent of BMI, was also observed (P=0.075). Ghrelin levels were significantly correlated with insulin levels and HOMA-IR, independent of BMI (P=0.077). CONCLUSIONS: Obesity and IR may play an important role in the release of ghrelin as well as in the negative correlation between ghrelin and leptin.

Subclinical exocrine pancreatic dysfunction resulting from decreased cholecystokinin secretion in the presence of intestinal villous atrophy.

UNLABELLED: The aim of this study was to evaluate the concept that pancreatic dysfunction in patients having gluten sensitivity (celiac disease [CD]) or cow's milk protein enteropathy (CMPE) may result from the lack of pancreatic enzyme stimulation in the absence or decrease of cholecystokinin (CCK) secretion caused by villous atrophy. PATIENTS AND METHODS: The following parameters were measured: plasma CCK in response to a fatty meal and human pancreatic fecal elastase in 24 patients with CD while on gluten-free diet and after gluten provocation and in 12 patients with CMPE at diagnosis and after a 6-month period of cow's milk-free diet. Intestinal mucosa morphology was examined by small bowel biopsy. Sixty-three controls having no organic gastrointestinal problems were investigated once at the time of diagnostic evaluation. RESULTS: Fasting CCK, obtained at a time when patients with CD or CMPE had normal intestinal mucosa, was significantly different from postprandial and comparable to that of the control group. Fasting CCK obtained from patients with villous atrophy was also statistically different, but not significantly, from the postprandial. Fasting and postprandial plasma CCK and fecal pancreatic elastase values from patients having normal intestinal mucosa were significantly higher than those obtained from patients with villous atrophy. Significant correlation of intestinal mucosa morphology and CCK with fecal elastase concentration was documented. CONCLUSION: Exocrine pancreatic dysfunction in individuals having villous atrophy may be the consequence of decreased CCK secretion. Cholecystokinin and pancreatic secretion is restored to normal, with intestinal mucosa regeneration.

Insulin resistance and hyperinsulinemia in prepubertal obese children.

BACKGROUND: Tissue resistance to insulin has been demonstrated in obese individuals. Pancreatic beta-cells respond to the reduced tissue sensitivity with increased insulin secretion so that glucose homeostasis is maintained. OBJECTIVE: The purpose of this prospective study was to investigate the presence of hyperinsulinemia and insulin resistance in obese children and adolescents. SUBJECTS AND METHODS: Fasting glucose (FG) and insulin (FI) levels and fasting glucose to insulin ratio (FGIR) were measured in 26 obese prepubertal children and 20 obese adolescents, as compared to 20 non-obese prepupertal children and 20 adolescents with normal body weight. Furthermore, obese children and adolescents underwent an oral glucose tolerance test with measurements of glucose and insulin 2 hours post glucose load. RESULTS: In 14/26 (54%) obese prepubertal children and in 16/20 (80%) obese adolescents FI was >24 microU/ml. FGIR was <6 in 23/26 (88%) prepubertal obese children and in all obese adolescents. All non-obese prepubertal children and adolescents had normal FI. However, FGIR was <6 in 6/20 (30%) non-obese prepubertal children and in 15/20 (75%) non-obese adolescents. CONCLUSION: Hyperinsulinemia and insulin resistance are already present in prepubertal obese children. As hyperinsulinemia is a potentially reversible condition and the complications related to it may be prevented, early measurements should be undertaken so that obese children lose body weight before the onset of puberty which may enhance the problem of insulin insensitivity.

Response of biochemical markers of bone turnover to oral glucose load in diseases that affect bone metabolism.

OBJECTIVE: Postprandial suppression of bone resorption is considered one of the main contributors in the circadian rhythm of bone turnover markers. The aim of this study was to investigate this physiological response of bone tissue in diseases that affect bone metabolism. PATIENTS AND METHODS: In this study, 118 patients (45 hypothyroid, 40 hyperthyroid, and 33 ß-thalassemic patients) and 78 healthy individuals matched for age and body mass index were included. An oral glucose test (75 g glucose) was performed after overnight fasting. Serum levels of procollagen type-I N-terminal propeptide (P1NP), ß-C-terminal telopeptide of type I collagen (ß-CTX), and osteocalcin were assayed at 0, 60, and 120 min. RESULTS: Baseline values of bone turnover markers were significantly elevated in hyperthyroid and ß-thalassemic patients but not in hypothyroid patients compared with the control group. After oral glucose, the levels of ß-CTX but not P1NP or osteocalcin were significantly suppressed in all groups (mean change from baseline is 46.9% for ß-CTX, 7.9% for P1NP, and 8% for osteocalcin). The percentage change from baseline for ß-CTX was significantly augmented in hypothyroidism (52 vs 42%, P=0.009). CONCLUSION: The preservation or even augmentation of postprandial suppression of bone resorption in diseases that affect bone metabolism through distinct pathogenetic mechanisms suggests the importance of this physiological response to nutrients for the general homeostasis and functional integrity of the skeleton.

Early decreases in plasma lipid transfer proteins during weight reduction.

OBJECTIVE: To determine the effect of short-term weight loss in obese women on concentrations of plasma cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), two new risk factors for cardiovascular disease. RESEARCH METHODS AND PROCEDURES: Plasma CETP and PLTP mass concentrations were measured in 38 obese, non-diabetic women before and after a moderate, 4% weight loss that was obtained by a 1250 kcal/d diet for 4 weeks. Anthropometric and biological parameters were measured before and after weight loss. RESULTS: Plasma CETP concentration decreased substantially after weight loss (2.76 +/- 0.79 before and 2.31 +/- 0.69 mg/L after; p = 0.000), and the same was true for plasma PLTP concentration (9.01 +/- 2.44 mg/L before vs. 8.34 +/- 2.57 after; p = 0.043). The HDL profile shifted toward the small-sized range, with significant decreases in the relative abundance of HDL(2b) and HDL(2a) at the expense of HDL(3b) after weight loss. A significant, positive correlation between CETP and PLTP mass concentrations is reported for the first time in obese patients (r = 0.43, p = 0.004), and weight reduction was accompanied by early, concomitant, and parallel decreases in plasma CETP and PLTP levels (r = 0.47, p = 0.003). The significant relationship between CETP and PLTP levels was lost after the dietary intervention (r = 0.27; p = 0.11). DISCUSSION: CETP and PLTP correlate positively and significantly in obese patients. The hypocaloric dietary manipulation constitutes a relevant intervention to reduce rapidly and simultaneously plasma levels of CETP and PLTP. The impact of reduced PLTP activity on HDL size appeared to be more prominent than the impact of concomitant reduction in CETP activity.

Multifollicular ovaries in female adolescents with cystic fibrosis.

OBJECTIVE: To assess hormonal status and morphology of ovaries in cystic fibrosis (CF) adolescents. DESIGN: Prospective study. SETTING: University teaching hospital. PATIENT(S): Female adolescents: 18 with CF and 18 normal. INTERVENTION(S): Transabdominal pelvic ultrasonography and venipuncture. MAIN OUTCOME MEASURE(S): Hormone profile and ultrasound examination of ovaries and uterus. RESULT(S): Levels of LH, LH/FSH, androstenedione, and PRL were significantly higher in the CF adolescents. Levels of sex hormone-binding globulin (SHBG) were significantly lower and had negative correlation with percentage of body fat. Percentage of body fat and body mass index were significantly lower in CF and had significant correlation. Levels of E2, FSH, T, and DHEAS were comparable in the two groups. Ultrasound revealed cysts in eight (44%) of the CF subjects; six of these had LH/FSH >3, and three had been operated for ovarian torsion. Nine out of all of the CF subjects (50%) had DM. No obesity, hirsutism, or acne was observed. The Shwachman score was 87.44 +/- 4.83 and correlated significantly with the percentage of body fat. CONCLUSION(S): Multifollicular ovaries were frequent in CF adolescents. Hormone changes characteristic of polycystic ovary syndrome were detected. The low T levels, despite low SHBG, and the absence of hirsutism or acne may be a result of a lower percentage of body fat, disturbances at the pilosebaceous-adipocyte endocrine unit, or mechanical or other causes.

Multidisciplinary therapy of locally far-advanced or inflammatory breast cancer with fixed perioperative sequence of epirubicin, vinorelbine, and Fluorouracil chemotherapy, surgery, and radiotherapy: long-term results.

BACKGROUND: Based on phase II data in advanced breast cancer (BC), the fluorouracil, epirubicin, and vinorelbine (FEN) combination was assessed as perioperative chemotherapy, integrated in a multidisciplinary treatment for locally advanced BC. PATIENTS AND METHODS: Patients with newly diagnosed inoperable (stage IIIB or inflammatory) BC. Multimodality treatment protocol consisted of four preoperative courses of fluorouracil (600 mg/m(2) day 1), epirubicin (75 mg/m(2) day 1), and vinorelbine (25 mg/m(2) day1 and day 8), all i.v. every 21 days, followed by radical or conservative surgery according to clinical response and four postoperative identical chemotherapy courses aimed to eradicate micrometastatic disease. Locoregional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonotherapy according to hormone receptor status. The primary end points of the study were: (a) clinical and pathological response, (b) downstaging and conversion to operable disease, and (c) recurrence-free survival (RFS) and overall survival (OS). RESULTS: Forty-eight women, one stage IIIA, 27 (56.2%) stage IIIB, two stage IIIC (4.1%), and 12 (25%) with inflammatory BC, aged 34-75 years (median, 52), were accrued. Thirty-eight and 34 patients completed the planned pre- and postoperative chemotherapy, respectively. Totals of 175 and 135 cycles were administered pre- and postoperatively, respectively. Toxicity of both phases, mainly hematologic, was in general acceptable without treatment-related death. Venous reactions were a frequent problem. All but three tumors were converted to operable, 31.3% with breast conservation. The clinical response rate (RR) was 77.7% (22.2% complete) and pathological RR was 73.3% (complete, 20% in both primary and axilla). After a median follow-up of 72 months, 62.5% and 16.7% of patients remain relapse free at 3 and 5 years, respectively, while 83% and 58.3% were alive 3 and 5 years, respectively, after the start of chemotherapy. Median RFS and OS have not yet been reached, and are currently 37+ and 62+ months, respectively. CONCLUSION: This fixed number of FEN perioperative courses schedule followed by radiotherapy is safe and highly active in inducing both local and distant control of locally far-advanced BC. This strategy is at least not inferior to other established regimens or strategies for locally far-advanced BC, while the integration of taxanes or new targeted agents may help show its true value for this challenging clinical entity.

The influence of continuous seven-day elevated intra-abdominal pressure in the renal perfusion in cirrhotic rats.

Since hepatorenal syndrome is a functional renal failure due to renal ischemia in cirrhotics with refractory ascites, we investigated whether increased intra-abdominal pressure (IAP) impairs the renal function and perfusion in cirrhotic portal hypertensive rats. Eight groups of 32 rats each were studied, including 4 control and 4 CCl(4) cirrhotic groups. These were subdivided into two groups each, with and without an increased IAP, and further subdivided into groups of rats with and without NO inhibition. IAP was increased to 20 mm Hg for 7 consecutive days by means of an intraperitoneally placed balloon filled with water. The animals were studied in normal conditions and after inhibition of NO synthesis. Changes in mean arterial pressure and renal microcirculation by means of femoral artery catheterization and laser-Doppler technique, respectively, were recorded. Venous samples for determination of plasma renin-aldosterone activity, biochemical parameters of liver and renal function, and plasma nitrite/nitrate levels as an index of NO synthesis were drawn. Cirrhotic rats showed decreased renal microcirculation (P = 0.05), while elevated IAP produced a further decrease (P = 0.01). Renin-aldosterone levels found increased (P = 0.001) in cirrhotics, and elevated IAP produced a further increase (P = 0.01] in both groups. Inhibition of NO synthesis resulted in a nonsignificant decrease in both renal microcirculation and renin-aldosterone levels in all experimental groups. Liver and renal function was found to be impaired in cirrhotics, but increased IAP had a nonsignificant further functional impairment in both organs. In conclusion, chronically elevated IAP in cirrhotic rats is associated with an increase in renin-aldosterone levels and significant impairment of renal perfusion.

The effects of marathon swimming on serum leptin and plasma neuropeptide Y levels.

It seems likely that the neuropeptide Y (NPY)-leptin axis is involved in the regulation of energy expenditure in man. The purpose of this study was to observe the effect of a model of intense prolonged exercise-mediated energy expenditure (25 km swim race in 6.9-10.5 hours) on leptin and NPY concentrations in male long-distance swimmers. Sixteen long-distance swimmers (mean age 25, range 18-45 years) who took part in a 25 km sea swimming competition (Toroneos golf, Chalkidiki, Greece) participated in the study. Mean competition time was 8.5 hours (range 6.5-10.5). The participants were allowed food and beverage intake ad libitum before and throughout the 25 km race. Venous blood samples were taken prior and immediately after the race for the measurement of serum leptin and plasma NPY. Non-esterified free fatty acids (NEFFA) and glycerol levels were determined as indicators of adipose tissue lipids mobilization. Results showed that leptin levels after marathon swimming were significantly reduced (p<0.001) in all athletes. There was a statistically significant negative correlation (r=-0.812, p<0.01) between the values of leptin and glycerol just after the termination of swimming. Blood serum glycerol and free fatty acid levels were significantly increased (p<0.001) in all swimmers. Plasma NPY levels were also increased (p<0.01) in 81.2% of the swimmers. Linear regression analysis revealed a significant negative correlation between the values of leptin and NPY (r=-0.789, p<0.01). In conclusion, these data support our initial hypothesis that appropriate changes in leptin and NPY take place during marathon swimming to compensate for the negative energy balance produced due to this prolonged effort. This indicates the NPY-leptin axis involvement in the regulation of energy expenditure in man.