Is chest pain still the most important symptom of acute coronary syndrome?

BACKGROUND: Acute coronary syndrome (ACS) carries the risk of death due to electrical or haemodynamical disturbances. Thus, rapid in-hospital treatment is necessary. To achieve this, a patient, his family and his physician should correctly diagnose ACS, based mainly on clinical symptoms. AIM: To assess the symptomatology of ACS and to establish whether modern management of ischaemic heart disease did not change ACS clinical characteristics. METHODS: The study group consisted of 156 consecutive patients (96 males, mean age 65+/-15 years) admitted to hospital due to ACS. Physicians prospectively filled in a questionnaire addressing ACS symptomatology, including chest pain characteristics and clinical symptoms of painless ACS. RESULTS: Retrosternal chest pain was present in 119 (76%) patients, six (4%) patients had pain localised outside thorax (jaws or epigastric region) whereas 31 (20%) patients had painless ACS. In the latter group the most frequent symptoms were dyspnea and marked weakness. CONCLUSIONS: Chest pain remains the most frequent symptom of ACS and its prevalence is similar to that previously described in literature. Almost a quarter of patients have painless ACS; in those patients other intensive and sudden symptoms may suggest ACS.     

Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone

A multicenter, open-label, randomized efficacy and safety study was performed with combined human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) (Puregon(R)) treatment to induce spermatogenesis in hypogonadotropic hypogonadal male patients. Patients were pretreated for 16 weeks with hCG to normalize testosterone levels. A total of 30 of 49 (61%) subjects had normalized testosterone levels but were still azoospermic after the hCG-alone phase. These patients were randomized into 2 treatment schemes with recFSH (2 x 225 IU recFSH per week [group A] or 3 x 150 IU recFSH per week [group B]), in combination with hCG for a period of 48 weeks. Total testosterone increased during the hCG-alone period from 1.08 and 1.22 ng/mL to 6.26 and 4.52 ng/mL for groups A and B, respectively. Combined gonadotropin treatment was effective in inducing spermatogenesis (sperm count >/=1 x 10(6)/mL) in 14 of 30 subjects (47%) and this was achieved after a median duration of treatment of approximately 5.5 months. Treatment time necessary for first sperm cells to appear in the ejaculate was related to the initial testicular volume. Subjects with a history of maldescended testes (11 of 30 subjects, 37%) showed a lower mean response to treatment as indicated by the relatively lower number of subjects reaching levels of at least 1 x 10(6) sperm cells per milliliter. Combined testicular volume increased during combined gonadotropin treatment from 11.4 to 24.0 mL. Although subjects with a history of maldescended testes had a lower starting testicular volume, subjects with and without a history of maldescended testes showed approximately the same relative increase in testicular volume. Total testosterone levels showed only a minor further increase during the combined gonadotropin treatment period. In conclusion, a weekly dose of 450 IU (3 x 150 IU or 2 x 225 IU) recFSH, in addition to hCG, was able to induce spermatogenesis in many hypogonadotropic azoospermic men who failed to respond to treatment with hCG alone.     

Quality of Life Improvement after Videothoracoscopic Splanchnicectomy in Chronic Pancreatitis Patients: Case Control Study

The authors report on the effectiveness of videothoracoscopic splanchnicectomy (VSPL) as a method of pain treatment in patients with chronic pancreatitis (CP). A minimally invasive technique, VSPL is used in CP as an alternative method of pain treatment. The aim of the investigation was to evaluate by a prospective, semirandomized case-control study the influence of VSPL on the quality of life and the level of pain suffered by patients with CP. The study groups consisted of 32 patients who underwent VSPL between March 2000 and January 2001 and a control group of 32 CP patients who received conservative treatment. The effect of the therapy on subjective pain measures and multiparametric quality of life was measured before VSPL and throughout the first year thereafter. In the follow-up period there was a significant decrease in intensity of pain and an improvement in the quality of life of the patients—most significantly concerning emotional well-being and functioning in everyday life. We conclude that the VSPL is a safe, effective, and minimally invasive procedure and recommend that it be used in such cases.     

Lithium treatment alters brain concentrations of nerve growth factor,brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system. Since decreased size and impaired function of some neuronal populations may be relevant in depression it has been hypothesized that these molecules may have a functional role in the pathophysiology as well as treatment of depression. Using an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL), we investigated the effects of chronic lithium treatment on brain NGF, BDNF and GDNF. Lithium was administered as food supplementation during 6 wk. NGF, BDNF and GDNF measurements were performed by enzyme-linked immunosorbent assay (ELISA). Lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. Moreover, the changes were different in the two rat strains. Our data support the notion that neurotrophic factors play a role in depression and in the mechanism of the action of lithium.     

Recombinant human TSH-aided radioiodine treatment of advanced differentiated thyroid carcinoma: a single-centre study of 54 patients

We sought to evaluate the efficacy, biochemical effects, safety and outcome of recombinant human thyroid-stimulating hormone (rhTSH) as an adjunct to radioiodine treatment of advanced differentiated thyroid carcinoma (DTC). We also sought to determine whether rhTSH is useful as an adjunct to radioiodine treatment following isotretinoin re-differentiation therapy of DTC metastases that have lost function. Therefore, in 54 consecutive patients who had retained bulky metastatic and/or locoregional lesions of DTC despite the exhaustion of other therapeutic options, we gave one to four courses of two consecutive daily intramuscular injections of rhTSH, 0.9 mg, followed by a therapeutic activity of (131)I per os on day 3. Fifty patients had received prior radioiodine treatment aided by l-thyroxine (T(4)) withdrawal. We included in the study 23 patients who had received a trial of isotretinoin therapy for re-differentiation of confirmed de-differentiated metastases. In a blinded, within-patient comparison of post-therapy whole-body scans after the first rhTSH-aided and latest withdrawal-aided treatments in patients with functional metastases at baseline, 18 of 27 (67%) scan pairs were concordant, four (15%) were discordant in favour of the rhTSH-aided scan and five (19%) were discordant in favour of the withdrawal-aided scan. In total, 37 (74%) of 50 paired scans were concordant, eight (16%) favoured rhTSH and five (10%) favoured withdrawal. All differences appeared to be attributable to clinical causes, not to any difference between endogenous and exogenous TSH stimulation. Reflecting the biochemical activity of rhTSH and the release of thyroglobulin (Tg) due to tumour destruction, median serum Tg concentration rose approximately fourfold between baseline and day 6 of the rhTSH-aided treatment course. rhTSH was well tolerated, with mostly minor, transient toxicity, except for neck oedema in three patients with neck infiltrates and pathological spine fracture in one patient with a large vertebral metastasis. At 6 months, complete response occurred in one (2%), partial response in 12 (26%) and disease stabilisation in 19 (40%) of 47 evaluable patients. The rate of complete + partial response was 41% and that of disease stabilisation, 30%, in the 27 evaluable patients with functional metastases at baseline; the corresponding rates were 10% and 55% in the 20 evaluable patients with non-functional metastases at baseline. Although within-patient comparison of early outcome after both modalities is limited by a significantly greater median number of courses and a greater median cumulative activity of radioiodine given under withdrawal, response to rhTSH-aided and withdrawal-aided treatment was similar in 23 (52%) of 44 evaluable patients, superior with rhTSH in 12 (27%) and superior with withdrawal in seven (16%). In two patients, a superior response was obtained after isotretinoin pretreatment and rhTSH and attributed to re-differentiation therapy. In conclusion, our study provides preliminary evidence that rhTSH safely and effectively aids radioiodine treatment of advanced DTC, and does so to an at least equivalent degree as does T(4) withdrawal.     

ABL-kinase domain point mutation as a cause of imatinib (STI571) resistance in CML patient who progress to myeloid blast crisis

Imatinib mesylate (STI571) is a major therapeutic advance for the management of chronic myeloid leukaemia (CML), however, a proportion of patients are refractory to it, particularly those in more advanced phases of CML. Different mechanisms of resistance to imatinib are suggested, including point mutations within ABL-kinase domains. A point mutation leading to substitution at the ATP binding site of ABL-kinase and insensitivity to imatinib was detected in our patient treated with imatinib, who progressed to blast crisis. Additionally, clonal evolution could lead to BCR–ABL-independent proliferation. Early detection of ABL-kinase mutation could predict the progression of CML treated with imatinib.     

Synthesis and antitumor activity of conjugates of muramyldipeptide or normuramyldipeptide with hydroxyacridine/acridone derivatives

A series of MDP (muramyldipeptide) or nor-MDP (normuramyldipeptide) analogues modified at the C-terminus post of the molecule by a formation of an ester bond between the carboxylic group of isoglutamine and the hydroxyl function of the respective derivatives of 4-carboxamide-acridine/9-acridone or 1-nitro-9-hydroxyalkylaminoacridines were synthesized as potential anticancer agents. The compounds O-(1-O-benzyl-N-acetyl-muramyl-l-alanyl-d-gamma-isoglutaminyl)-9-(ethylamino)-1-nitroacridine ester 3j and O-(1-O-benzyl-N-acetyl-muramyl-l-alanyl-d-gamma-isoglutaminyl)-9-propylamino-1-nitroacridine ester 3k exhibited high in vitro cytotoxic activity against a panel of human cell lines, prostate cancer and AIDS-related lymphoma (ARL). Analogue 3j was also active in vivo in the hollow fiber assay. Antitumor activity of both compounds were tested in vivo against difference human tumor xenograft, but only analogue 3k showed in vivo activity against sc UACC-62 melanoma in mice.     

Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate

INTRODUCTION: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate. METHODS: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed. RESULTS: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%. CONCLUSIONS: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.     

Lipid Association Increases the Potency Against Primary Medulloblastoma Cells and Systemic Exposure of l-(2-Chloroethyl)-3-Cyclohexyl-1-Nitrosourea (CCNU) in Rats

Purpose. To reduce the systemic toxicity and prolong the systemic presence of l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized. Methods. The degree of CCNU association with lipid vesicles composed of 1,2-dimyristoyl-sn- glycero-3-phosphocholine (DMPC) and l,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and the drug decomposition rates of lipid-drug complexes were monitored. Effects of lipid association on drug potency against medulloblastoma cells and total systemic drug exposure in rats were determined. Results. At a CCNU:lipid molar ratio greater than 1:5, more than 90% of the drug was associated with the lipid vesicles. In aqueous suspensions, lipid association significantly reduced the first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited a 4-fold increase in drug sensitivity with medulloblastoma cells. IC₅₀ values for CCNU admixed and encapsulated with lipid vesicles were 18 ± 4.9 and 14.0 ± 2.2 M, respectively, compared to 83 ± 11.0 M for free CCNU. When administered to rats, lipid-associated CCNU increased the AUC (area under the concentration-time curve) of CCNU by approximately 2-fold (20.46 ± 2.15 compared to 39.59 ±1.87 gmin/ml), and the terminal half-life (t_1/2) by almost 9-fold (17 ± 9 compared to 147 ± 48 min) over free CCNU. Despite the increase in total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a significantly lower frequency of acute neurotoxicity. Conclusions. These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.     

Clinical Correlates of the NR3C1 Gene Methylation at Various Stages of Psychosis

BackgroundDysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P), and healthy controls with respect to clinical manifestation and a history of psychosocial stressors.MethodsWe recruited 40 first-episode psychosis patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals, and 56 healthy controls. The level of methylation at 9 CpG sites of the NR3C1 gene was determined using pyrosequencing.ResultsThe level of NR3C1 methylation was significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients compared with other subgroups of participants. Individuals with FHR-P and healthy controls had similar levels of NR3C1 methylation. A history of adverse childhood experiences was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis.ConclusionsPatients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that are significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of adverse childhood experiences and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations.