Altered pattern of lipid metabolism in patients with lung cancer.

Cholesterol distribution in tumoral tissues and lipid composition in the plasma compartment were determined in patients affected by different histologic types of lung cancer. The results showed that tumoral lung tissues contained 2-fold more total cholesterol and 3.5-fold more esterified cholesterol than normal lung tissues. In the patients the alterations in intracellular cholesterol were also associated with peculiar changes in cholesterol distribution in the plasma compartment. Serum high-density lipoprotein (HDL) cholesterol levels were markedly lower in than in controls. No significant changes in other lipid parameters were observed in these patients. We suggest that the reduced levels of serum HDL cholesterol observed in patients with lung tumors may be a consequence of the disease, probably mediated by the greater utilization of cholesterol for new membrane biogenesis and by the accumulation of esterified cholesterol in tumoral tissues.     

Responses of human primary sensorimotor and supplementary motor areas to internally triggered unilateral and simultaneous bilateral one‐digit movements. A high‐resolution EEG study

We modelled the responses of human primary sensorimotor areas and supplementary motor area to simple, self-initiated unilateral and simultaneous bilateral middle finger movements using a novel high-resolution electroencephalography technology. The results support the view that these cortical motor areas are involved in parallel and present similar activity in the preparation, initiation, and execution of the contralateral and bilateral movements. Furthermore, the left primary sensorimotor area (dominant hemisphere) appears to be activated more than the right primary sensorimotor area during the preparation and performance of the ipsilateral movements.     

Mycobacterium tuberculosis subverts the differentiation of human monocytes into dendritic cells

Intracellular pathogens have developed strategies for evading elimination by the defenses of the host immune system. Here we describe an escape mechanism utilized by Mycobacterium tuberculosis that involves the interference with the generation of fully competent DC from monocytes. We show that monocytes infected with live M. tuberculosis differentiated into mature, CD83+ and CCR7+ DC (Mt-MoDC), but were characterized by a selective failure in the expression of the family of CD1 molecules. These cells also showed levels of MHC class II and CD80 (B7.1) that were reduced in comparison with LPS-matured DC. In addition, Mt-MoDC produced TNF-alpha and IL-10, but were unable to secrete IL-12. The generation of Mt-MoDC required the infection of monocytes with live M. tuberculosis, since infection with heat-killed bacteria partially abrogated the effects on monocyte differentiation. Interestingly, Mt-MoDC revealed an impaired antigen-presentation function as assessed by the reduced capability to induce proliferation of cord blood T lymphocytes. Further, naive T lymphocytes expanded by Mt-MoDC were unable to secrete cytokines, in particular IL-4 and IFN-gamma, suggesting that they could be ineffective in helping the macrophage-mediated killing of intracellular mycobacteria. Our results suggest that the interference with monocyte differentiation into fully competent DC is an evasion mechanism of M. tuberculosis that could contribute to its intracellular persistence by avoiding immune recognition.     

Observations on the arterial baroreflex in neurally mediated vasodepressor syncope

The arterial baroreflex was studied in subjects who had recently had an episode of vasodepressor syncope. This was determined using 2–3 mcg/kg intravenous boluses of phenylephrine and assessing the bradycardic response. The values were measured in ms/mmHg and expressed as the angular coefficient of the regression line between the increase in R—R interval on the electrocardiograph and the systolic arterial pressure. In subjects examined immediately after the vasodepressor syncope episode the bradycardic response was much more marked than in controls (p < 0.01) and in the subjects themselves 6 months after the episode, provided that they were symptom-free (p < 0.01). It is concluded that in vasodepressor syncope there is a phase in which the baroreflex is highly sensitive and that this is due not to a lowering of the stimulation threshold but to a gain in the efferent arc, which explains a vagotonic response.     

Migraine and cluster headache – the common link

Although clinically distinguishable, migraine and cluster headache share prominent features such as unilateral pain, common pharmacological triggers such glyceryl trinitrate, histamine, calcitonin gene-related peptide (CGRP) and response to triptans and neuromodulation. Recent data also suggest efficacy of anti CGRP monoclonal antibodies in both migraine and cluster headache. While exact mechanisms behind both disorders remain to be fully understood, the trigeminovascular system represents one possible common pathophysiological pathway and network of both disorders. Here, we review past and current literature shedding light on similarities and differences in phenotype, heritability, pathophysiology, imaging findings and treatment options of migraine and cluster headache. A continued focus on their shared pathophysiological pathways may be important in paving future treatment avenues that could benefit both migraine and cluster headache patients.     

Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy

OBJECTIVE: Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy. SUBJECTS AND METHODS: In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects. RESULTS: Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM. CONCLUSIONS: Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.     

Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism

OBJECTIVE: To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism (IHH). METHODS: In a retrospective study we analyzed the GnRHR and the GPR54 genes of 45 IHH patients and 50 controls. Genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon-intron boundaries of the GnRHR and GPR54 genes and analyzed by single-stranded conformation polymorphism gel electrophoresis and/or DNA sequencing. RESULTS: One heterozygous R262Q mutation of the GnRHR gene was identified in one patient with familial IHH. The silent single-nucleotide polymorphism (SNP) 453C > T occurred at the same frequency in patients and controls. One patient with sporadic IHH and consanguineous parents showed a novel homozygous sequence variation of the GPR54 gene (1001_1002insC) resulting in an open reading frame shift and elongation of 43 amino acids with an increased number of proline residues in the intracellular receptor domain. This patient had delayed puberty, low testosterone (3.4 nmol/l), and low-normal LH and FSH levels responsive to GnRH. Pulsatile GnRH administration normalized testosterone levels and induced spermatogenesis sufficiently to induce a pregnancy with assisted reproduction. Two common SNPs in exon 1 and exon 5 of the GPR54 gene showed similar frequency distribution and hormonal profiles in IHH and controls. CONCLUSIONS: Mutations of the GnRHR and of the GPR54 gene are rare in IHH and should be investigated especially in cases with autosomal recessive transmission. Common SNPs of the GnRHR and GPR54 genes do not play any role in IHH.     

Suppression and recovery of LH secretion by a potent and selective GnRH-receptor antagonist peptide in healthy early follicular-phase women are mediated via selective control of LH secretory burst mass

AIM: GnRH antagonists are competitive inhibitors of GnRH receptors. Their administration induces prompt suppression of the gonadal axis. In animals, GnRH antagonists upregulate the activity of GnRH-secreting neurones, which could cause gonadotrophin rebound following inhibition. The aim of this study was to evaluate the effects of a potent GnRH antagonist, Teverelix (TEV), on the gonadal axis in healthy young women. SUBJECTS AND MEASUREMENTS: In nine women [20-35 years old, body mass index (BMI) 19-25 kg/m2] in the early follicular phase, serum LH and FSH levels were evaluated every 10 min from 08.00 to 12.00 h before, and 24 h and 96 h after TEV injection (2.5 mg in 1 ml subcutaneously on day 0). Serum gonadotrophin and oestradiol levels were also evaluated at baseline and at 6, 8, 12, 48, 72 h after TEV. RESULTS: The antagonist reduced both serum LH and FSH concentrations; LH levels were significantly and promptly reduced at +6 h (nadir at +8 h) until +48 h and recovered at +72 h, while FSH levels were reduced (P<0.05) 24 h after the antagonist and normalized at +48 h. LH (but not FSH) concentrations at +96 h exceeded baseline (P<0.05). TEV suppressed oestradiol concentrations (P<0.05) with a nadir at +24 h, comparable reduction at +48 h and recovery to baseline at +72 h. Deconvolution analysis showed that the antagonist peptide suppressed (P<0.02) the pulsatile production rate, burst mass and amplitude of LH on day 1. Pulsatile FSH secretion also fell at this time (P<0.05). LH and FSH pulse frequency were not modified by TEV. At +96 h, LH pulsatility did not significantly differ from that at baseline. Suppression of mean LH or FSH concentrations did not affect the relative pattern regularity (approximate entropy) of LH and FSH secretion. CONCLUSIONS: This study demonstrates that the acute administration of a potent GnRH antagonist induces prompt inhibition of the gonadal axis lasting for 2 days in women due to mechanistically specific suppression of LH secretory burst mass and the mean FSH secretion rate. The trend toward rebound release of LH following the end of the pharmacological effect of the antagonist could reflect a rise in endogenous GnRH activity.     

Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness

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Relationship between international normalized ratio values,vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment

BACKGROUND AND OBJECTIVES: In vitro studies have shown that the rate of prothrombin activation is linearly related to the concentration of factor II (FII) in the assay system, suggesting a key role of prothrombin levels in the expression of the antithrombotic activity of oral anticoagulant treatment (OAT). We investigated the in vivo relationship between prothrombin activation and vitamin K-dependent clotting factor levels during the early and steady phases of OAT in patients and in healthy volunteers. DESIGN AND METHODS: The changes in international normalizezd ratio (INR) and in the plasma levels of FVII, FX, FII, protein C (PC) and prothrombin fragment 1.2 (F1+2) induced by OAT were monitored over 9 days in 10 patients not on heparin starting warfarin after heart valve replacement (HVR) and in 9 healthy volunteers submitted to an 8-day course of warfarin treatment. FII and F1+2 plasma levels were also measured in 100 patients on stable oral anticoagulant treatment with INRs ranging from 1.2 to 6.84. RESULTS: Because HVR patients had subnormal FVII, FX and FII levels after surgery, INR values > 2.0 were attained already 24 hours after the first warfarin dose. In healthy volunteers, INR values greater than 2.0 were first observed after 72 hours. Nadir levels of FVII, PC, FX and FII were reached between 40 and 88 hours in HVR patients and between 72 and 192 hours in healthy volunteers. The FII apparent half-disappearance time (t/2) was 99 hours in HVR patients and 115 hours in healthy volunteers (p = ns). In HVR patients there was no normalization of initially elevated F1+2 levels until day 7 with an apparent t/2 of 132 hours. In healthy volunteers, a decrease to subnormal F1+2 levels was observed by day 8 of treatment (apparent t/2 = 107 hours). In both HVR patients and healthy volunteers, FII and PC levels were independent predictors of the changes in F1+2 levels (p = 0.0001). In patients on stable OAT, only FII levels were independent predictors of the variation in F1+2 levels (p = 0.0001). INTERPRETATION AND CONCLUSIONS: During the early phase of oral anticoagulant treatment in vivo prothrombin activation is a function of the balance between FII and PC levels and is not significantly prevented until nadir levels of FII are obtained. This provides an explanation for the requirement of overlapping heparin and oral anticoagulant treatment for at least 48 hours after the achievement of therapeutic INR values in patients with thromboembolic diseases. In addition, in vivo prothrombin activation is a function of FII levels rather than INR values also in patients on stable oral anticoagulant treatment.