Post-mortem toxicology in the diagnosis of sudden death in young and middle-aged victims.

OBJECTIVE: We aimed to investigate the impact of the toxicological results found in cases of sudden death (SD) and to correlate the clinical, autopsy and genetic findings with the toxicology results. MATERIALS AND METHODS: Consecutive SD in people aged between 16 and 50 years with medico-legal autopsies and toxicology studies were included over a 3-year period. The comparison between the toxicological data and demographic characteristics, clinical circumstances, autopsy, and genetic results were taken into account. RESULTS: 101 cases were finally included. They were predominately males (84%) and the mean age was 39.8 years. 52 (51.5%) cases had positive toxicological findings and in 25 cases (24.8%), toxic compounds were considered the first cause of death. Ethanol was the most frequently identified agent (69%), following by licit drugs (56%) and drugs of abuse (39%). Cases with positive toxicology were younger than those with negative results (37.9±9.1 vs. 41.9±7.8; p=0.02). Patients with more than 3 comorbidities showed an association with positive toxicological results (n=14 vs. n=3; p=0.017). The genetic study was performed in 70 (69.3%) SD cases. We identified pathogenic or likely pathogenic variants in 17.1% cases and uncertain significance variants in 42.8% cases. 58% of these variants were probably related to the cause of death. CONCLUSIONS: A large fraction of SD victims had positive toxicological findings and a quarter of deaths were directly caused by toxic substances. The identification of the factors that trigger SD provides a good approach to contribute in avoiding future episodes.

Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking.

Tobacco smoking induces an inflammatory response in the lungs of all smokers but, for reasons that are still poorly understood, only a proportion of them develop chronic obstructive pulmonary disease (COPD). Recent evidence indicates that this inflammatory response persists after smoking cessation, suggesting some type of auto-perpetuation mechanism similar to that described in autoimmune disorders. T-lymphocytes (CD4+ and CD8+) have been implicated in the pathogenesis of both COPD and several autoimmune processes. A subtype of regulatory CD4+ T-cells expressing CD25 (Tregs) plays a critical role in the maintenance of peripheral tolerance and the prevention of autoimmunity, but their potential role in COPD has not been explored. The present study sought to evaluate maturation (CD45RA/CD45R0) and activation markers (CD28) of T-lymphocytes and to explore potential Treg abnormalities in COPD. Flow cytometry was used to characterise T-lymphocytes obtained from blood and bronchoalveolar lavage fluid (BALF) in 23 patients with moderate COPD, 29 smokers with normal lung function and seven never-smokers. The main findings were that in BALF: patients with COPD showed higher CD8+CD45RA+ and lower CD8+CD45R0+ than smokers with normal lung function; and compared with never-smokers, smokers with preserved lung function showed a prominent upregulation of Tregs that was absent in patients with COPD. These observations indicate a final maturation-activation state of CD8+ T-lymphocytes in chronic obstructive pulmonary disease and, for the first time, identify a blunted regulatory T-cell response to tobacco smoking in these patients, further supporting a potential involvement of the acquired immune response in the pathogenesis of the disease.

[Comparison of the effectiveness of pentobarbital and thiopental in patients with refractory intracranial hypertension. Preliminary report of 20 patients]. / Comparación de la eficacia del pentobarbital y el tiopental en el control de la hipertensión intracraneal refractaria. Resultados preliminares en una serie de 20 pacientes.

OBJECTIVE: To assess the effectiveness of pentobarbital and thiopental to control raised intracranial pressure (ICP), refractory to first level measures, in patients with severe traumatic brain injury. MATERIAL AND METHODS: Prospective, randomized study to compare the effectiveness between two treatments: pentobarbital and thiopental. The patients will be selected from those admitted to the Intensive Care Unit with a severe traumatic brain injury (postresuscitation Glasgow Coma Scale equal or less than 8 points) and raised ICP (ICP>20 mmHg) refractory to first level measures according to the Brain Trauma Foundation guidelines. The adverse effects of both treatments were also collected. RESULTS: We present the results of the first 20 patients included. Ten received pentobarbital and the other ten thiopental. There were no statistically significance differences in patients'characteristics (age, sex, severity of the trauma at admission and comorbilities). There were no differences between both groups neither in the Glasgow Coma Scale at admission (thiopental six points; pentobarbital seven points; P=0.26) nor in the admission Cranial Tomography, according to the Traumatic Coma Data Bank Classification. Thiopental treatment controlled raised ICP in five cases and pentobarbital in two cases (P=0.16). Five patients in the thiopental group died and eight in the pentobarbital group (P=0.16). There were no statistically differences between both groups regarding to the presence of hypotension (P=1) or infectious complications. CONCLUSIONS: These preliminary results indicate that thiopental could be more effective than pentobarbital in patients with refractory intracranial hypertension. These results support previous experimental findings that show that both treatments are not equal and justify to continue this study.

Relationships between Serum Levels of Atazanavir and Renal Toxicity or Lithiasis.

The main aim of this study is to describe the relationship between serum levels of atazanavir, renal toxicity, and lithiasis. This is a prospective observational study of patients being treated with atazanavir (ATV) at Son Espases Teaching Hospital, Palma de Mallorca, between 2011 and 2013. The study includes 98 patients. Sixteen were found to have a history of urolithiasis. During a median monitoring period of 23 months, nine patients suffered renal colic, in three of whom ATV crystals were evidenced in urine. Cumulative incidence of renal colic was 9.2 per 100 patients. The variables related to having renal colic were the presence of alkaline urine pH and lower basal creatinine clearance. The mean serum level of ATV was slightly higher in patients with renal colic-1,303 µg/L versus 1,161 µg/L-but did not reach statistical significance. Neither were any significant differences detected by analysing the levels according to the timetable for ATV dosage. Cumulative incidence of renal colic was high in patients being treated with ATV, in 33% of whom the presence of ATV crystals was evidenced in urine. We were unable to demonstrate a relationship between ATV serum levels and renal colic or progression towards renal failure.

GH secretion in two siblings with Laron's dwarfism: the effects of glucose, arginine, somatostatin, and bromocryptine.

The secretion of GH in two siblings with clinical dwarfism and high GH plasma levels (the mean of several basal values; 233.83 ng/ml in patient A and 178.16 in patient B has been studied with several dynamic tests. An arginine infusion increased GH levels in both cases (+193.55% for A, +140.27% for B). No significant modifications were obtained with oral glucose tolerance test +18.70% for A, +24.32% for B). A bolus of somatostatin almost completely prevented the rise in GH levels in response to arginine. Pretreatment with bromocryptine clearly increased basal GH plasma levels (A, +58.66%; B, +56.03%) and the response to arginine. As in the case of a normal hypothalamus, the hypothalamus of Laron's syndrome responds to arginine and bromocryptine, with GH elevations. Somatostatin suppresses GH levels. A lack of response to glucose can be considered as a nonspecific effect of the very low biological activity of the stimulus in a hyperstimulated hypothalamus. We suggest that GH secretion by the hypothalmo pituitary system in Laron's syndrome is normal, and that GH hyperproduction may be due to a generalized defect in GH receptors or to the low levels of somatomedin.

Serum growth hormone-binding protein is unchanged in adult panhypopituitarism.

The role of GH in regulating GH-binding protein (GHBP) and GH receptor concentrations in humans is not clear. Studies performed mostly in children and on a minor scale in adults are somewhat controversial. The key question as to whether GHBP levels are altered in hypopituitarism before GH treatment is instituted remains unanswered. In this study, we have selected a severely GH-deficient group of adult patients with panhypopituitarism, acquired as a result of surgery and irradiation of hypothalamic-pituitary tumors, to evaluate the GHBP/receptor status by measuring GHBP activity in plasma. Twenty panhypopituitary patients (8 males and 12 females; age range, 20-74 yr) and 20 age (22-68 yr)- and sex-matched normal subjects were studied. GH deficiency was confirmed by insulin-induced hypoglycemia and arginine infusion tests; the peak GH response was less than 2 micrograms/L. Plasma insulin-like growth factor-I levels were below or in the low normal range (mean +/- SD, 88.3 +/- 53.6 micrograms/L) and were significantly different from insulin-like growth factor-I (IGF-I) levels in the normal group (mean +/- SD, 189 +/- 49.8 micrograms/L; P < 0.01). Plasma GHBP activity, measured using a GH-binding/gel chromatography assay, showed similar values in the GH-deficient group (mean +/- SD, 14.1 +/- 3.83%) and the control group (mean +/- SD, 13.7 +/- 3.79%), with no statistically significant difference. Neither the intra- nor intergroup comparison of GHBP levels according to age and sex showed statistically significant differences or age trends. In the light of these data and considering that GHBP activity in plasma probably reflects the GH receptor status in tissues, we may assume that the GH receptor was unaffected by chronic GH deficiency. These findings also support the previously reported concept that the GHBP/receptor level is a relatively fixed determinant of growth, established individually and independently of GH secretory status in early life, perhaps on a genetic basis.

The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing's disease.

Transsphenoidal microsurgery is the standard treatment for patients with Cushing's disease. However, there is general lack of agreement regarding the definition of cure. We studied 58 patients with corrected hypercortisolism after transsphenoidal surgery for Cushing's disease. Plasma and urinary cortisol levels were measured after surgery. After the postsurgical hypocortisolism stage (or periodically in patients without hypocortisolism), urinary free cortisol, plasma cortisol at 0800 h and 2300 h, morning cortisol after 1 mg dexamethasone, and cortisol response to insulin-induced hypoglycemia were performed. Patients were classified in 3 groups: group I, patients with transient hypocortisolism and normal hypothalamus-pituitary-adrenal axis afterwards; group II, patients with transient hypocortisolism and abnormalities in the circadian rhythm or the stress response afterwards; and group III, patients without postoperative hypocortisolism. Thirty-three patients were included in group I, 8 in group II, and 17 in group III. Groups I and II were similar in postsurgical plasma cortisol (46.9 +/- 30.3 vs. 60.7 +/- 38.6 nM) and mean follow-up (69.8 vs. 68.8 months) but were significantly different in their recurrence rate (3.4% vs. 50%, P < 0.001). Patients in group III had normal postsurgical plasma and urinary cortisol but persistent abnormalities in circadian rhythm and stress response. After a mean follow-up of 39.1 months, their recurrence rate was similar to that of group II (64.7% vs. 50%). The complete normalization of the adrenocortical function, which is always preceded by postsurgical hypocortisolism, is associated with a very low recurrence risk and should be considered, in our opinion, the main criterion of surgical cure in Cushing's disease.

Treatment of invasive growth hormone pituitary adenomas with long-acting somatostatin analog SMS 201-995 before transsphenoidal surgery.

The purpose of this study was to determine whether the long-acting somatostatin analog SMS 201-995 (octreotide) shrinks growth hormone (GH)-secreting adenomas and improves the results of subsequent transsphenoidal surgery. Ten previously untreated active acromegalic patients (nine women and one man) with invasive tumors were treated with SMS 201-995 (100 micrograms subcutaneously every 8 hours) for 6 weeks prior to transsphenoidal surgery. The clinical activity, mean GH secretion, insulin-like growth factor (IGF)-I concentration, and tumor volume were measured under basal conditions and on Days 14, 28, and 42 of treatment. The SMS 201-995 improved the symptoms of acromegaly in all patients. Mean levels of both GH and IGF-I (+/- standard deviation) were significantly decreased by Day 14 (from 92.9 +/- 30.5 to 44.9 +/- 20.3 micrograms/liter and from 10.6 +/- 7.4 to 5.9 +/- 2.6 U/ml, respectively), after which there were only slight further decreases. Six (60%) of the 10 patients experienced tumor shrinkage ranging from 9% to 78% (mean 30%). When it occurred, tumor shrinkage was significant by Day 14 (7.9 +/- 6.3 to 6.5 +/- 5.1 cu cm) and no further shrinkage was achieved by longer administration. Transsphenoidal surgery reduced postoperative GH levels to less than 2 micrograms/liter and IGF-I to less than 1.5 U/ml in six patients (60%). This percentage of cure is higher than expected from the literature and the authors' previous experience. However, an investigation of the influence of this drug on several parameters, such as reduction of tumor size or GH and IGF-I concentrations, has failed to prove any relationship. Only pretreatment size of the tumor was of predictive value with respect to the surgical outcome.

Effects of dipyridamole, soluflazine and related molecules on adenosine uptake and metabolism by isolated human red blood cells.

The suggestion that adenosine may have beneficial effects on post reperfusion survival following cardiac ischaemia has led to the search for agents which increase the concentration of this substance in the ischemic region as a possible therapeutic approach to the treatment of angina and myocardial infarction. In the present study, dipyridamole, soluflazine and lidoflazine, known inhibitors of the nucleotide exchange system, have been shown using an HPLC method to prevent the decrease in the concentration od added adenosine outside human red blood cells in vitro. However, the results suggest that this effect was due to inhibition of adenosine deaminase rather than inhibition of nucleotide exchange as had previously been suggested. The selective inhibitor of adenosine deaminase erythro-9-(2-hydroxy-3-nonyl adenosine) exhibited the same profile of activity in the human red blood cell assay. pIC50 values for the four compounds named above were found to be 6.80 +/- 0.09, 6.95 +/- .03, 6.10 +/- 0.14 and 7.39 +/- 0.05 vs adenosine disapearance observed in the extracellular incubation medium respectively. Thus, as the disappearance of adenosine outside the cells was not due to its uptake but to its catabolism, this in vitro method does not appear to be predictive for the ability of compounds to act on adenosine uptake into cardiac myocytes. Any antiischemic action of these agents is more readily explained by an inhibition of the catabolism of adenosine and not by the inhibition of its transport across the membrane of cardiac myocytes.

Growth hormone secretory response to intravenous galanin infusion in acromegalic patients.

Galanin is a 29-amino acid neuropeptide which stimulates the secretion of growth hormone (GH) in normal men. Although the diagnosis of acromegaly involves demonstrating hypersecretion of GH and/or abnormalities in GH secretory dynamics, sometimes it is difficult to establish the activity of the disease. The aim of our study was to assess the response to galanin infusion in acromegalic patients (active and cured). We studied 19 subjects: 5 healthy volunteers (group I), 9 patients with active acromegaly (group II), and 5 with acromegaly cured after transsphenoidal surgery (group III). We performed a test of infusion with porcine galanin (8 microg/Kg/h) to study the secretory response of the GH. Galanin produced a marked increase in GH in the controls, group I (F9,36 = 5.34; p < 0.01) and in the cured patients, group III (F9,36 = 7.35; p < 0.01). On the other hand, galanin did not significantly modify the secretion of GH in the patients with active disease, group II. The areas under the curve (AUC) were higher in groups I and III compared to group II (p < 0.01). Nevertheless, there were no statistically significant differences in the AUC of groups I and III. Our results indicate that the differences in the GH response to galanin in patients with active and cured acromegaly could be of value in the study of the disease.

Increased insulin receptor binding in erythrocytes from growth hormone-deficient children.

Erythrocytes from growth hormone-deficient children (GHd-children) (n = 10) showed a statistically significant increase in insulin binding at low unlabeled insulin concentrations, together with a threefold decrease in apparent receptor affinity, as compared to control children (C) (n = 11). Scatchard analysis of the binding data using the two-site model revealed that both the receptor concentration R1 [GHd-children 0.10 +/- 0.01 ng/ml and C 0.03 +/- 0.002 ng/ml] and the dissociation constant KD1 [GHd-children (0.48 +/- 0.05) x 10(-9) M and C (0.19 +/- 0.01) x 10(-9) M] for high affinity-low capacity sites were significantly increased in erythrocytes from GHd-children, while neither receptor concentrations (R2) nor the dissociation constant (KD2) for low affinity-high capacity sites proved to be altered. These events were accompanied by a normal sensitivity to insulin as well as glucose tolerance in the GHd-group. The meaning of the increased insulin binding with normal insulin sensitivity in GH-deficiency is discussed.

[Treatment of solitary toxic thyroid nodule with 131I: results in 43 patients]. / Tratamiento del nódulo tiroideo solitario tóxico con 131I: resultados en 43 pacientes.

BACKGROUND: Evaluation of the therapy with high-dose 131I in solitary toxic thyroid adenoma, with particular attention to the effects on thyroid function and on the nodular size. METHODS: A retrospective study of 43 patients with solitary thyroid nodule treated with radioactive iodine (mean dose 26.6 mCi, range 10-35) and followed up for 49.7 +/- 36.6 months (range 6-186) with periodical clinical, laboratory and echographic evaluations. RESULTS: Thirty-two patients (74.4%) had a normal thyroid function during follow-up. Five (11.6%) remained with hyperthyroidism and in 6 (13.9%) hypothyroidism developed 6-30 months after the administration of radioactive iodine. Three of these 6 had subclinical hypothyroidism, with mild increases in serum thyrotropin (TSH). Neither the development of hypothyroidism nor its persistence were significantly correlated with the initial thyroxin (T4) or triiodothyronine (T3) levels, the nodular size, the 131I dose, the incomplete inhibition of the extranodular thyroid parenchyma or the previous therapy with antithyroid drugs. The nodule diminished in size in 15 cases (38.4%), it disappeared in 9 (23%), it remained unchanged in 12 (30.7%) and it increased in 3 (7.7%). CONCLUSIONS: The treatment of the solitary toxic thyroid nodule with relatively high 131I doses is a safe and effective procedure, with a prevalence of residual hypothyroidism which is lower than previously reported. The disappearance of the nodule was only achieved in a minority of cases.

Prognostic value of serum CA125 levels in diffuse large B-cell lymphoma: potential role of a new sex- and age-adjusted reference value.

CA125, a tumor marker normally used to follow the clinical course of ovarian cancer, also may have a role in lymphoma. All available series were analyzed using the standard reference value 35 U/ml, but age and sex may influence serum CA125 (sCA125) levels. We aim to study the prognostic value of serum CA125 (sCA125) levels in diffuse large B-cell lymphoma (DLBCL), considering the influence of age and sex on sCA125 levels. We investigated the relationship between sCA125 and clinical outcome after treatment in 42 patients with DLBCL, comparing both the standard (35 U/ml) and a new age and sex adjusted (sex/age-adjusted) reference value proposed by our group. We found that patients with elevated sCA125 levels had significantly more adverse prognostic factors at diagnosis, lower CR rates, higher relapse rates and worse survival. In the low-risk IPI categories, the presence of elevated sCA125 defined a particularly high-risk subgroup with poorer 3-year PFS when compared with patients with normal sCA125 levels. The use of a sex/age-adjusted reference value for sCA125 may increase the sensitivity to identify those patients with elevated sCA125 levels truly related to DLBCL activity.

Proposed reference value of the CA 125 tumour marker in men. Potential applications in clinical practice.

INTRODUCTION: CA 125 is a tumour marker usually used to monitor the clinical course of the patients with ovary cancer. The frequently used reference value of this marker is 35 U/mL. However, some arguments to allow us to question us the validity of the classical reference value: i) a second generation of immunoassays, ii) diverse studies related to the factors that influence in the CA 125 serum concentrations and iii) the new applications of CA 125 in pathologies different to the ovary cancer. OBJECTIVES: 1) To propose a reference value of CA 125 in men; 2) To evaluate the CA 125 serum concentration according to different variables, some of which can be altered in pathologies where CA 125 level can be monitored and/ or altered. MATERIAL AND METHODS: 65 healthy men were included (age: 40.21+/-10.60 years). A survey containing different parameters and an analytic that contained a hemogram, hepatic, renal, pancreatic profile, ionogram, thyroid function, tumour markers and NT-Pro-BNP was carried out to exclude the presence of a pathological situation. The percentile 95 (P(95)) was calculated to obtain the reference value. Correlations among the CA 125 and the different variables were analyzed by the Spearman test. RESULTS: The median [ranges] and the P(95) were: 7.50 [3.00-25.00] and 20.17 U/mL, respectively. 78% of the values of CA 125 were < or =10 U/mL, 94% were < or =15 U/mL and 95% were < or =20 U/mL. Furthermore, the studied variables don't seem to influence in the concentrations of this marker. CONCLUSIONS: The proposed reference value obtained in healthy male subjects is significantly lower than the one used in the clinical practice. This value should be kept in mind when extending the use of this marker to other pathologies which was not used up to now.

Intracellular cytokine profile of T lymphocytes in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by an excessive inflammatory response to inhaled particles, mainly tobacco smoking. T lymphocytes are important regulatory cells that secrete several cytokines and participate actively in this inflammatory response. According to the pattern of cytokines secreted, the immune response is classified as cytotoxic or type 1 [interferon (IFN)-gamma-, interleukin (IL)-2-dependent] and humoral or type 2 (IL-4-, IL-5-, IL-10- and IL-13-dependent). This paper sought to compare the intracellular profile of cytokine expression determined by flow cytometry in T lymphocytes harvested from bronchoalveolar lavage (BAL) and peripheral blood in patients with COPD, smokers with normal lung function and never smokers. We found that BAL T lymphocytes from COPD patients had a higher percentage of positive stained cells for most of the cytokines analysed when compared to never smokers or smokers with normal lung function. Differences reached statistical significance for IL-4, IL-10 and IL-13, particularly in CD8(+) T cells. Furthermore, the expression of most of these cytokines was related inversely to the degree of airflow obstruction present suggesting local activation and/or selective homing of T lymphocytes to the lungs in COPD patients. These observations were not reproduced in circulating T lymphocytes. These results suggest that BAL T lymphocytes in patients with COPD produce more cytokines than in controls and tend to show a type 2 pattern of intracellular cytokine expression, particularly a Tc-2 profile. This is related inversely to the degree of airflow obstruction present.