Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective,randomized, single-blind,placebo-controlled clinical trial

BACKGROUND: Raloxifene hydrochloride is a synthetic non-steroidal drug used for the prevention and treatment of post-menopausal osteoporosis. Pre-clinical and clinical data have shown that raloxifene may have a beneficial effect on leiomyomas. The aim of this prospective single-blind, randomized, placebo-controlled clinical trial was to evaluate the effectiveness of the addition of raloxifene to GnRH analogues on uterine, leiomyoma, and non-leiomyoma sizes, and on the occurrence of leiomyoma-related symptoms. METHODS: After randomization using a computer-generated list, 100 pre-menopausal women with symptomatic uterine leiomyomas received either leuprolide acetate depot plus raloxifene 60 mg daily (group A) or leuprolide plus placebo tablet (group B) for six cycles of 28 days. At baseline and after treatment, uterine, leiomyoma and non-leiomyoma sizes, and leiomyoma-related symptoms were evaluated for each woman. Analysis was by intention-to-treat method. RESULTS: After six cycles of treatment, a significant decrease in uterine, leiomyoma, and non-leiomyoma sizes was detected in both groups in comparison with baseline. At the same time, no significant difference in uterine and non-leiomyoma sizes was observed between the groups. Leiomyoma sizes were significantly (P < 0.05) lower in group A than in group B. No difference was observed in leiomyoma-related symptoms between groups throughout the study period. CONCLUSIONS: In women treated with GnRH analogue, the raloxifene administration induces a higher reduction of leiomyoma sizes.     

Plasminogen activator system modulates invasivecapacity and proliferation in prostatic tumor cells

The malignant phenotype of prostatic tumor cells correlates with the expression of both uPA and itscell-membrane receptor (uPAR); however, there is little information concerning the role of cell-bound uPAin matrix degradation and invasion. Our results suggest that cell-associated uPA plays a key role in regulat-ingthe amount of plasmin present at the surface of prostatic carcinoma (PRCA) cells and show that differ-entialproduction of uPA corresponds with the capacity to bind and activate plasminogen. In addition, weprovide direct evidence that both uPA secretion and the presence of uPA-uPAR complexes characterize theinvasive phenotype of PRCA cells and suggest the existence of several pathways by which tumor cells acquireplasmin activity. LNCaP cells (which do not produce uPA but express uPAR) may activate plasmin throughexogenous uPA. In vivo, the source of uPA may be infiltrating macrophages and/or fibroblasts as observedin several other systems. PAI-1 accumulation in the conditioned medium (CM) limits plasmin action to thepericellular microenvironment. Our results indicate that MMP-9 and MMP-2 are also activated by plasmingenerated by cell-bound but not by soluble, extracellular uPA. Plasmin activation and triggering of the pro-teolyticcascade involved in Matrigel invasion is blocked by antibodies against uPA (especially by anti- A-chainof uPA which interacts with uPAR) and by PA inhibitors such as p-aminobenzamidine which mayregulate levels of cell-bound uPA. uPA may also regulate growth in PRCA cells. Indeed, antibodies againstuPA A-chain (and also p-aminobenzamidine treatment) interfere with the ATF domain and inhibit cell growthin uPA-producing PC3 and DU145 prostate cancer cell lines, whereas exogenous uPA (HMW-uPA with ATF)induces growth of LNCaP prostate tumor cell line. These data support the hypothesis that in prostatic can-cerpatients at risk of progression, uPA/plasmin blockade may be of therapeutic value by blocking both growthof the primary tumor and dissemination of metastatic cells. ©Kluwer Academic Publishers     

Enthalpy of polymerisation of ethylene oxide and of copolymerisation of ethylene oxide with 7-oxabicyclo[2.2.1]heptane

The enthalpies of combustion of poly(ethylene oxide), ΔH(c)=-1178,7 ± 1,3 kJ . mol^-1, and of a random copolymer of overall molar composition 0,41 (poly(ethylene oxide)) + 0,59 (poly(oxy-1,4-cyclohexylene)), ΔH(c)=-2566,4 ± 1,8 kJ . mol^-1, were measured at 298,15 K by high-precision bomb calorimetry. The enthalpy of polymerisation of ethylene oxide was derived as ΔH (l → c) = -102,4 ± 1,6 kJ . mol^-1. The enthalpy of copolymerisation of ethylene oxide and 7-oxabicyclo[2.2.1]heptane was ΔH (l → c) = -63,0 ± 2,1 kJ . mol^-1, compared with -68,1 ± 1,6 kJ . mol^-1 for producing the two homopolymers in the proportion in which the monomers were present in the copolymer. It is concluded that insertion of an ethylene oxide unit into a poly(oxy-1,4-cyclohexylene) chain does not affect the strain-energy by a significant amount.     

Impact of Consistent Atrial Pacing Algorithm on Premature Atrial Complexe Number and Paroxysmal Atrial Fibrillation Recurrences in Brady-Tachy Syndrome: A Randomized Prospective Cross Over Study

Aim of the study: The Consistent Atrial Pacing (CAP) algorithm has been designed to achieve a high percentage of atrial pacing to suppress paroxysmal atrial fibrillation. The aim of our study was to compare the impact of DDDR+CAP versus DDDR pacing on paroxysmal atrial fibrillation recurrences and triggers in patients with Brady-Tachy Syndrome. Methods: 61 patients, 23 M and 38 F, mean age 75±9 y, affected by Brady-Tachy Syndrome, implanted with a DDDR pacemaker, were randomized to DDDR or DDDR+CAP pacing with cross over of pacing modality after 1 month. Results: 78 % of patients in DDDR pacing and 73 % in DDDR+CAP pacing (p=n.s.) were free from symptomatic paroxysmal atrial fibrillation recurrences. During DDDR+CAP pacing, the atrial pacing percentage increased from 77±29 % to 96±7 % (p<0.0001). Automatic mode switch episodes/day were 0.73±1.09 in DDDR and 0.79±1.14 (p=n.s.) in DDDR+CAP. In patients with less than 50 % of atrial pacing during DDDR, automaticmode switch episodes/day decreased during DDDR+CAP from 1.13±1.59 to 0.23±0.32 (p<0.05) and in patients with less than 90 % from 1.23±1.27 to 0.75±1.10 (p<0.001). The number of premature atrial complexes per day decreased during DDDR+CAP from 2665±4468 to 556±704 (p<0.02). Conclusion: CAP algorithm allowed continuous overdrive atrial pacing without major side effects. Triggers of paroxysmal atrial fibrillation induction, such as premature atrial complexes, were critically decreased. Paroxysmal atrial fibrillation episodes were reduced in patients with atrial pacing percentage lower than 90 % during DDDR pacing.     

Central corneal thickness in children with growth hormone deficiency

Acta Ophthalmol. 2010: 88: 692–694

Abstract.

Purpose: To evaluate central corneal thickness (CCT), intraocular pressure (IOP) and eye refraction in patients with congenital growth hormone (GH) deficiency. Methods: Retrospective case series. Forty‐five patients with growth defect treated with recombinant GH and 45 healthy children underwent ophthalmological examination, including CCT measurements, applanation tonometry and cycloplaegic refraction. Results: The average CCT in the GH deficiency group was 570.6 μm [standard deviation (SD) 37.4]. In the control group, it was 546.0 (SD 24.9). The average IOP in the GH deficiency group was 18.2 mmHg (SD 3.4). In the control group, it was 14.6 (SD 2.0). The mean refractive error (spherical equivalent) in the GH deficiency group was 0.59 D (SD 1.9). In the control group, it was 0.11 (SD 2.1). Conclusion: GH and insulin‐like growth factor 1 are involved in ocular growth by influencing the synthesis of the extracellular matrix of the sclera. Children with congenital GH deficiency or insensitivity have a mean hyperopic defect related to a shorter axial length. A number of studies have demonstrated that CCT in newborns is significantly greater than in adults; a decrease in CCT is closely correlated with an increase in corneal diameter. This finding suggests that the growth of the eye, with possible remodelling and stretching of collagen fibres, may play an important role in the reduction of corneal thickness in the first years of life. Therefore, we conclude that a greater CCT can represent a sign of a delayed growth of the eye in patients with GH deficiency. Finally, our study confirms the influence of corneal thickness on IOP measures, and the prevalence of hyperopia among children with growth defect.     

Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative.

PURPOSE: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma. EXPERIMENTAL DESIGN: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array. RESULTS: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR. CONCLUSIONS: These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.     

Association of heart rate variability with arrhythmic events in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is associated with an increased risk of sudden cardiac death (SCD). Risk stratification of ARVC/D patients, however, remains an unresolved issue. In this study we investigated whether heart rate variability (HRV) can be helpful in identifying ARVC/D patients with increased risk of arrhythmic events. METHODS AND RESULts: We studied 30 consecutive patients (17 males; 45.4 ± 18 years) with ARVC/D, diagnosed according to guideline criteria; 15 patients (50%) had received an implantable cardioverter defibrillator (ICD) for primary SCD prevention. HRV was assessed on 24-h ECG Holter monitoring. The primary endpoint was the occurrence of major arrhythmic events (SCD, sustained ventricular tachycardia (VT), ICD therapy for sustained VT or ventricular fibrillation (VF)). During the follow-up period (19 ± 7 months), no deaths occurred, but 5 patients (17%) experienced arrhythmic events (4 VTs and 1 VF, all in the ICD group). All HRV parameters were significantly lower in patients with, compared with those without, arrhythmic events. Low-frequency amplitude was the most significant HRV variable associated with arrhythmic events in univariate Cox regression analysis (P=0.017), and was the only significant predictor of arrhythmic events in multivariable regression analysis (hazard ratio 0.88, P=0.047), together with unexplained syncope (hazard ratio 16.1, P=0.039). CONCLUSIONS: Our data show that among ARVC/D patients HRV analysis might be helpful in identifying those with increased risk of major arrhythmic events.     

Insulin resistance and executive dysfunction in older persons

OBJECTIVES: To evaluate the association between insulin resistance (IR) and executive dysfunction in a large, population-based study of older persons without diabetes mellitus (DM) or dementia. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in Greve in Chianti and Bagno a Ripoli, Italy. PARTICIPANTS: A total of 597 subjects aged 65 to 93 without DM or dementia. MEASUREMENTS: Anthropometric measurements; plasma fasting levels of glucose, insulin, cholesterol (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol), and insulin-like growth factor-1 (IGF-1); homeostasis model assessment (HOMA) to estimate degree of IR; Trail Making Test (TMT) A; TMT-B; TMT-B minus TMT-A (DIFF B-A); and Mini-Mental State Examination (MMSE). RESULTS: IR (HOMA) was associated with longer TMT-B (correlation coefficient (r)=0.11; P=.006) and DIFF B-A times (r=0.10; P=.022). Subjects in the upper tertile of IR were older and had longer TMT-B and DIFF B-A than participants in the lowest tertile. After adjusting for age, sex, and years of formal education, IR was significantly correlated with TMT-A, TMT-B, and DIFF B-A. After adjusting for age, sex, education, body mass index, waist:hip girth ratio, HDL-C, triglycerides, IGF-1, hypertension, drug intake, and physical activity, the results did not significantly change. After introducing MMSE score into the model, IR continued to be an independent determinant of TMT-A (beta=11.005; P=.021), TMT-B (beta=28.379; P<.001), and DIFF B-A (beta=17.374; P=.011). CONCLUSION: IR is independently associated with frontal cortex function evidenced by poor TMT times in older persons without DM or dementia.     

Surgical treatment of pleural recurrence from thymoma.

A complete surgical resection represents the cornerstone of the therapy of the thymic tumours. Pleural disease may already be present at the diagnosis representing an advanced stage thymoma (Masaoka IVA) or it may appear during the follow-up, representing a pleural recurrence. The treatment of Stage IVA thymoma is quite examined in the medical literature; however just a few reports analysed the surgical treatment of thymoma recurrences, whose exclusive pleural recurrences represent more than 90%. Our aim was to review the literature laying the stress on the incidence, diagnosis, treatment options and prognosis of this highly selected group of patients with pleural recurrence from thymoma.     

When should “chronic migraine” patients be considered “refractory” to pharmacological prophylaxis?

Patients with chronic headache forms evolving from a previous episodic migraine (‘chronic migraine’) are often difficult to treat. In this paper we focus attention on aspects we believe important for producing a definition of “refractory” in relation to this headache form. We propose a “chronic migraine” patient should be considered “refractory” to pharmacological prophylaxis when adequate trials of preventive therapies at adequate doses have failed to reduce headache frequency and improve headache-related disability and, in patients with medication overuse, reduce the consumption of symptomatic drugs. However before a definition of “refractory” chronic migraine can become established, generally accepted diagnostic criteria and treatment guidelines for this condition need to be developed.