CGRP blockade by galcanezumab was not associated with reductions in signs and symptoms of knee osteoarthritis in a randomized clinical trial.

OBJECTIVE: This study tested whether galcanezumab, a humanized monoclonal antibody with efficacy against migraine, was superior to placebo for the treatment of mild or moderate osteoarthritis (OA) knee pain. METHOD: In a multicenter, double-blind, placebo- and celecoxib-controlled trial, patients with moderate to severe OA pain were randomized to placebo; celecoxib 200 mg daily for 16 weeks; or galcanezumab 5, 50, 120, and 300 mg subcutaneously every 4 weeks, twice. The primary outcome was change from baseline at Week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore measured by 100 mm visual analog scale (VAS). The trial was considered positive if ≥1 dose of galcanezumab demonstrated ≥95% Bayesian posterior probability of superiority to placebo and ≥50% posterior probability of superiority to placebo by ≥9 mm. A planned interim analysis allowed termination of the study if posterior probability of superiority to placebo by ≥9 mm was ≤5%. Secondary endpoints included WOMAC function subscore and Patient Global Assessment (PGA) of OA. Safety and tolerability were also assessed. RESULTS: The study was terminated after interim analysis suggested inadequate efficacy. Celecoxib significantly reduced WOMAC pain subscore compared with placebo [-12.0 mm; 95% confidence interval (CI) -23 to -2 mm]. None of the galcanezumab arms demonstrated clinically meaningful improvement (range: 1.5 to -5.0 mm) or met the prespecified success criteria. No improvement in any secondary objective was observed. Galcanezumab was well tolerated by OA patients. CONCLUSIONS: This study failed to demonstrate sufficient statistical evidence that galcanezumab was efficacious for treating OA knee pain. STUDY IDENTIFICATION: NCT02192190.

Diazoxide postconditioning induces mitochondrial protein S-nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE.

Postconditioning (PostC) can be obtained either with brief cycles of ischemia/reperfusion (I-PostC) or with a direct targeting of mitochondria with Diazoxide (pharmacological PostC, P-PostC). I-PostC may induce the activation of RISK and SAFE pathways and may favor nitric oxide production with S-Nitrosylation of proteins and redox signaling. It is not clear whether Diazoxide can lead to similar effects. We compared the effects of I-PostC and P-PostC on (a) kinases of RISK- and SAFE pathway, (b) S-Nitrosylation of mitochondrial proteins and (c) reduction of death signals (PKCδ, cleaved caspase-3 and Beclin-1) in cytosolic and mitochondrial fractions. Isolated rat hearts underwent (1) perfusion without ischemia (Sham), (2) ischemia/reperfusion (30-min ischemia plus 2-h reperfusion), (3) I-PostC (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia), (4) P-PostC (Diazoxide 30 µM in the first of 3-min of reperfusion) or (5) I-PostC + MPG or P-PostC + MPG (MPG, 2-mercaptopropionylglycine 300 µM). Using Western blot and biotin switch assay, we found that P-PostC induced a redox sensible phosphorylation/translocation of Akt, ERK1/2 and GSK3ß into the mitochondria, but not of phospho-STAT3, which was translocated into the mitochondria by I-PostC only. Either I-PostC or P-PostC increased mitochondrial S-Nitrosylated proteins (e.g., VDAC) and reduced the levels of phospho-PKCδ, cleaved caspase-3 and Beclin-1. Therefore, direct targeting of mitochondria with Diazoxide (a) activates the RISK pathway via a redox signaling, (b) favors discrete mitochondrial protein S-Nitrosylation, including VDAC and (c) decreases signals of death. Intriguingly, phospho-STAT3 translocation is induced by I-PostC, but not by P-PostC, thus suggesting a redox-independent mechanism in the SAFE pathway.

Collateral presence and extent do not predict myocardial viability and ischemia in chronic total occlusions: A stress-CMR study.

BACKGROUND: Well-developed collaterals are assumed as a marker of viability and ischemia in chronic total occlusions (CTO). We aim to correlate viability and ischemia with collateral presence and extent in CTO patients by cardiac magnetic resonance (CMR). METHODS: Multicentre study of 150 CTO patients undergoing stress-CMR, including adenosine if normal systolic function, high-dose-dobutamine for patients with akinetic/>2 hypokinetic segments and EF ≥35%, otherwise low-dose-dobutamine (LDD); all patients underwent late gadolinium enhancement (LGE) imaging. Viability was defined as mean LGE transmurality ≤50% for adenosine, as functional improvement for dobutamine-stress-test, ischemia as ≥1.5 segments with perfusion defects outside the scar zone. RESULTS: Rentrop 3/CC 2 defined well-developed (WD, n = 74) vs poorly-developed collaterals (PD, n = 76). Viability was equally prevalent in WD vs PD: normo-functional myocardium with ≤50% LGE in 52% vs 58% segments, p = 0.76, functional improvement by LDD in 48% vs 52%, p = 0.12. Segments with none, 1-25%,26-50%,51-75% LGE showed viability by LDD in 90%,84%,81%,61% of cases, whilst in 12% if 76-100% LGE (p < 0.01). There was no difference in WD vs PD for ischemia presence (74% vs 75%, p = 0.99) and extent (2.7 vs 2.8 segments, p = 0.77). CONCLUSIONS: In a large cohort of CTO patients, presence and extent of collaterals did not predict viability and ischemia by stress-CMR. Scar extent up to 75% LGE was still associated with viability, whereas ischemia was undetectable in 25% of patients, suggesting that the assessment of CTO patients with CMR would lead to a more comprehensive evaluation of viability and ischemia to guide revascularization.

Prognostic factors and outcomes in 28 cases of uterine leiomyosarcoma.

OBJECTIVES: It was the aim of this study to evaluate clinicopathological characteristics and prognostic factors of uterine leiomyosarcomas (LMS). METHODS: Twenty-eight patients with uterine LMS were evaluated in this retrospective study. Their features and survival were analyzed by Kaplan-Meier and log-rank tests. RESULTS: The median age of the patients was 52 years (range 25-74). Nine patients had a disease with a mitotic count <10/10 high-power fields. Twenty-one patients presented with stage I disease, 1 with stage II and 6 with stage IV. Twelve patients underwent total hysterectomy and bilateral salpingo-oophorectomy, 2 simple hysterectomy, 5 myomectomy and 9 more comprehensive surgical treatments. Adjuvant chemotherapy was administered to 16 patients, whereas chemoradiation was given only to 2 patients. Fifty percent presented with recurrence of the disease. The median overall survival was 46 months. Age, mitotic count, type of surgery, adjuvant therapy, recurrence and clinical response to chemotherapy were not found to affect survival, while the menopausal status and FIGO (International Federation of Gynecology and Obstetrics) stage were found to be prognostic factors. CONCLUSION: In our series, the menopausal state and FIGO stage were found to be prognostic factors related to survival.

Long-term topotecan therapy in recurrent or persistent ovarian cancer.

BACKGROUND: The objective of this study was to evaluate feasibility, safety and clinical outcome of long-term therapy with topotecan (Hycamtin) in recurrent or persistent ovarian cancer. PATIENTS AND METHODS: A retrospective chart review was conducted on all patients treated with topotecan (TPT) at the Department of Obstetrics and Gynecology, University of Bari, Italy between 1999 and 2007. Pertinent clinicopathologic information, response and toxicity following treatment with TPT were collected. TPT was given at a dosage ranging between 1.5 and 1.0 mg/m2 every three to four weeks. All patients were evaluated for toxicity acording to the CTC and response according to the RECIST response criteria. Time to progression (TTP) was calculated from initiation of TPT treatment and start of the next chemotherapy regimen. RESULTS: A total of 30 patients received TPT for at least eight cycles for recurrent ovarian (22), fallopian tube (3) or primary peritoneal carcinoma (5). A total of 432 cycles of chemotherapy were given, with an average of 14.4 cycles per patient (range 8-22). Dose reduction was necessary in 20 patients (66%). About half of the patients required blood transfusions and growth factors. Non hematologic toxicity was mild and manageable. Responses were observed in 16/30 patients (53%), the remaining having SD. Median time to treatment progression was 28 months (range 9-88). CONCLUSION: Long-term treatment with topotecan in recurrent/persistent ovarian cancer is feasible with limited evidence of cumulative toxicity. The results of this retrospective analysis suggest a potential role for late response and survival benefit for those patients without disease progression who continue topotecan therapy beyond six cycles of treatment.

Neonatal intestinal colonization with extended-spectrum ß-lactamase-producing Enterobacteriaceae-a 5-year follow-up study.

OBJECTIVES: To analyse Klebsiella pneumoniae (KP) isolates from an outbreak of extended-spectrum ß-lactamase (ESBL)-producing KP and Escherichia coli (EC) among infants admitted to neonatal intensive care units and to determine the duration of the intestinal colonization. METHODS: We performed a prospective cohort study of intestinal ESBL-KP/ESBL-EC colonized neonates after a 5-month outbreak in two neonatal intensive care units. Whole genome sequencing, multilocus sequence typing, core genome multilocus sequence typing, pulsed-field electrophoresis and PCR for blaCTX-M were performed on the first isolates. Stool cultures were performed every second month after discharge until 2 years after discharge and at 5 years of age. The last positive samples were analysed with pulsed-field gel electrophoresis and PCR for blaCTX-M. The intestinal relative dominance of ESBL-producing Enterobacteriaceae was determined. RESULTS: Thirteen of 17 patients colonized with ESBL-KP/ESBL-EC survived. Isolates from 16 of 17 patients were available for analysis and featured the same strain type of ESBL-KP: sequence type 101. The strain had capsule type K29 and harboured blaCTX-M-15. The virulence genes irp1, irp2, iutA, kfu and mrk were detected in all isolates. The median length of colonization was 12.5 months (range, 5-68 months). After 2 years, two of 13 patients were carriers of ESBL-KP and one of 13 of ESBL-EC. At 5 years of age, one neonate was colonized with ESBL-EC. No infant experienced an ESBL-KP/EC-infection during follow-up. CONCLUSIONS: Two years after discharge, almost one fourth of the study participants were ESBL/KP-EC carriers. ESBL-KP sequence type 101 persisted in two of 13 children for 23 to 26 months. One patient was colonized with ESBL-EC at age 5 years.

Cardiac magnetic resonance for ischaemia and viability detection. Guiding patient selection to revascularization in coronary chronic total occlusions: The CARISMA_CTO study design.

BACKGROUND: It is debated whether percutaneous revascularization (PCI) of total coronary chronic occlusion (CTO) is superior to optimal medical therapy (OMT) in improving symptoms, left ventricular (LV) function and major adverse cardiac/cerebrovascular events (MACCE). Furthermore, CTO-PCI is a challenging technique, with lower success rate than in other settings. A systematic analysis of baseline LV function, infarction extent and ischaemic burden to predict response to revascularization has never been performed. PURPOSES: To establish a CMR protocol to identify patients (pts) who can benefit most from CTO-PCI. Myocardial viability/ischaemia retains high biological plausibility as predictors of response to revascularization. Therefore, baseline viability (necrotic tissue extent, response to inotropic stimulation) and ischaemia (perfusion defect, wall motion abnormality during stress) will be studied as potential predictors of mechanical LV segmental improvement and ischaemic burden reduction in CTO territory (primary endpoint), LV remodelling and global function, Seattle Angina Questionnaire, and MACCE improvement (secondary endpoints) in the follow-up. METHODS: Pts with CTO suitable for PCI undergo stress-CMR for viability/ischaemia assessment. Pts with normal LV function undergo adenosine, those with moderately-reduced ejection fraction (EF) and wall motion abnormalities high-dose dobutamine, pts with EF <35% low-dose dobutamine. All pts undergo late gadolinium enhancement and repeat the same scan at 12 ±â€¯3 months, regardless of PCI success or decision for OMT. CONCLUSIONS: A multi-parameter CMR protocol tailored on pts characteristics to study viability/ischaemia could help in identifying responders in terms of LV function, ischaemic burden and clinical outcome among pts suitable for CTO-PCI, improving selection of best candidates to percutaneous revascularization.

ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage.

ZAP-70 tyrosine kinase is involved in signalling pathways following T-cell receptor stimulation and was originally described only in T cells and natural killer cells. ZAP-70 expression has been reported in normal mouse B lineage cells and in human malignant B lymphocytes, mainly in chronic lymphocytic leukemia (CLL) where it correlates with clinical outcome. We analyzed several B-cell lines and ex vivo malignant B cells, ranging from acute lymphoblastic leukemia to multiple myeloma and reflecting different stages of B-cell differentiation, and they showed ZAP-70 expression regardless their maturation stage. We then analyzed by Western blot and flow cytometry different human normal B-lymphocyte subpopulations: naïve, germinal center and memory B cells from tonsils, CD19+ CD5+ cells from cord blood and CD19+ lymphocytes from peripheral blood. All expressed ZAP-70 protein, though at different levels depending on their differentiation, activation and tissue localization. In addition, ZAP-70 expression levels could be modulated following stimulation via the B-cell receptor. These findings implicate a potential role of ZAP-70 in the signalling pathway of B lymphocytes at different maturational stages, indicate that ZAP-70 expression is not a CLL-specific feature among B-cell malignancies and suggest that the absence of ZAP-70 rather than its presence should be considered abnormal for malignant B lymphocytes.

Differential effects on CLL cell survival exerted by different microenvironmental elements.

Selected microenvironmental stimuli confer to leukemic cells a growth advantage and an extended survival. We aimed at dissecting the differential support provided by the different cellular components of the microenvironment where CLL cells accumulate. To this end we cultured purified CLL cells in vitro in the presence or absence of different accessory cells (stromal cells, autologous T lymphocytes) and/or soluble molecules (IL-4, sCD40L) and assessed the leukemic cell response in terms of cell viability and chemoattracting capacity. The results indicate that both T lymphocytes and stromal cells are involved in sustaining the survival of leukemic B cells, but indicate that their support is different in terms of time of onset and duration. T cells have a short-term support activity while stromal cells provide long-term support.

Procollagen type I carboxy-terminal propeptide as a marker of osteoblastic bone metastases.

Collagen type I is the sole collagen type found in bones and tendons. Carboxyterminal propeptide, deriving and cleaved from procollagen type I (PICP) during collagen synthesis, is delivered into the blood, where it can be measured. According to current knowledge, PICP correlates with bone collagen synthesis and bone formation rate. Elevated serum levels of PICP in patients with Paget's disease, compared with normal subjects and correlated with serum alkaline phosphatase (Alk.Ph.), have been previously described. Thus, PICP may be a valuable marker of bone formation. PICP, serum Alk.Ph., serum bone Gla protein and 24-h urinary hydroxyproline:creatinine ratio have been measured in 47 cancer patients: 27 with predominantly osteolytic lesions (5 myeloma, 15 breast, 3 lung, 2 kidney, 1 bladder, 1 thyroid) and 20 with predominantly osteoblastic lesions (18 prostate and 2 breast). The higher levels of PICP were noted in patients with osteoblastic or mixed metastases. In the entire group of patients, a statistically significant correlation between PICP and bone Gla protein (r = 0.57; P < 0.001), PICP and Alk.Ph. (r = 0.80; P < 0.001), and bone Gla protein and Alk.Ph. (r = 0.44; P < 0.01) was noted. In those patients with osteoblastic metastases we observed a significant correlation only between PICP and Alk.Ph. (r = 0.62; P < 0.003). During chemotherapy, 13 of 20 patients with osteoblastic metastases who achieved objective response or stable disease showed a more rapid and significant decrease in PICP with respect to the other bone markers. Serum PICP level could be considered a good marker of osteoblastic activity.

Trends in the incidence of hip fracture in Siena, Italy, from 1980 to 1991.

There is general agreement that the crude incidence of proximal femur (hip) fractures is rising in conjunction with the ageing of the underlying population. To explore possible changes in hip fracture incidence over time we analysed all femoral fractures occurring in the county of Siena from 1980 to 1991. Data were collected from hospital record charts of the Department of Orthopaedics, recording all hip fractures occurring during the 12-year period. In this period, the mean resident population in Siena was 238,369 inhabitants (aged 0 to 90+ years) and the crude number of all femoral fractures was 2,238. However, in calculating incidence rates, only hip fractures occurring in the population aged over 50 years were considered. In this population, the number of hip fractures was 1,825 with a male/female ratio of 1:2.8. A time-series data analysis (temporal trend) of the incidence of hip fracture during the 12-year period revealed a linear and significant (p < 0.001) trend to increase, but only in males, with an annual increasing rate of 3.62 per 100,000 person-years. In the female population, the temporal analysis did not show any significant trend during the observation period.

Hip fracture in Italy: epidemiology and preventive efficacy of bone-active drugs.

In this paper we report the results on the epidemiology of hip fracture and the preventive efficacy of bone-active drugs in Italy, observed in men and women aged 50 years or over, recruited in the three Italian centres participating in the Mediterranean Osteoporosis Study (MEDOS), namely Parma, Rome, and Siena. The number of fractures observed was 1,437 in a catchment area population of 847,508 individuals, with a total incidence of 169.6/100,000--a female-to-male ratio of 3.5 and a doubling-time of about 5.5 years. The female excess becomes evident in the age groups over 60 years. The mean age of fractures was 77 years in females and 73 in males. From the data collected, the estimated number of fractures per year in the Italian population aged over 50 years is 32,000. The pattern of use and the preventive efficacy of bone-active drugs was examined in women. Calcitonin and calcium were the drugs mainly used; less than 3% had taken vitamin D or oestrogen and only a minor percentage had taken anabolic steroids. Fluorides were not used at all. As seen in the European sample, the protective effect of calcium and calcitonin is statistically significant even in Italy, while vitamin D is not. The use of anabolic steroids was associated with a decrease in risk. Oestrogen administration does not seem to reduce the relative risk of hip fracture in Italian women, probably due to the small sample size.

Management of osteoporosis and Paget's disease. An appraisal of the risks and benefits of drug treatment.

Osteoporosis is a major public health problem occurring primarily among the postmenopausal population. Osteoporosis is a preventable disease, but despite several advances in its prevention, treatment of the established disease to date remains a major challenge to be managed by primary care physicians. Stabilisation of bone mass and prevention of falls are of paramount importance in any therapeutic programme for osteoporotic patients with established vertebral fractures. Drug therapy for osteoporosis can be divided operationally into 2 main categories: those that inhibit bone resorption, and thus reduce bone turnover, and those that stimulate bone formation, exerting an anabolic effect. Therapeutic agents that inhibit bone remodeling would appear to be best suited to those patients with high turnover osteoporosis (about 30%). Included in this category are calcium, vitamin D and its metabolites, gonadal steroids, calcitonin, ipriflavone and bisphosphonates. Although estrogen replacement therapy has been proven to be effective in older females, calcitonin appears to be the treatment of choice for this population since it stabilises or increases bone mass and also has reported analgesic properties. Drugs that stimulate bone remodeling or bone formation would be best suited to patients with low turnover osteoporosis (about 70%). The agent in this class that is widely used is sodium fluoride. New therapies include intermittent injections of synthetic parathyroid hormone, and cyclic bisphosphonates to activate then depress resorption and formation. Any attempts to stabilise the skeleton with any drug regimen must be accompanied by an adequate calcium supply, i.e. 1200 to 1500 mg/day). The theoretical basis of tailoring treatment for osteoporosis to the underlying histology has not yet been fully proven, but there is increasing experimental support to this approach. Drugs that inhibit bone turnover, such as calcitonin, appear to be effective in increasing bone mass for 1.5 to 2 years, about the time it would take to replenish the remodeling space in a patient with high turnover osteoporosis. In contrast, although bone mass appears to increase for as long as 5 years in patients treated with sodium fluoride, there has been no consistent reduction in occurrence of vertebral or hip fractures. Paget' disease of bone is a focal disorder of the skeleton characterised by excessive resorption and subsequently disorganised formation of bone. The aetiology of the disease is unknown. Paget's disease may be mono-ostotic or polyostotic; pain and bone deformities due to enlargement of skeletal segments represent the main clinical aspects. However, in many patients the disease may be asymptomatic.(ABSTRACT TRUNCATED AT 400 WORDS)

Importance of premeal injection time in insulin therapy: Humalog Mix25 is convenient for improved post-prandial glycemic control in type 2 diabetic patients with Italian dietary habits.

We investigated the use, in a short period, of Humalog Mix25 (Mix25) in a twice-daily administration regimen compared to a twice-daily injection therapy with Humulin 30/70 (30/70) in diabetic patients with Italian dietary habits. We studied 33 type 2 diabetic patients aged 59.1 +/- 8.1 years, BMI 29.8 +/- 2.7 kg/m2, duration of diabetes and insulin therapy of 14.4 +/- 9.8 and 4.2 +/- 4.6 years, respectively. After a 4-day lead-in period of twice-daily human insulin 30/70 treatment, patients were randomized to one of two treatment sequences: (1) a twice-daily regimen with Mix25 just 5 minutes before the morning and evening meals for 12 days, followed by a twice-daily therapy with human insulin 30/70 given 30 minutes before the morning and evening meals for an additional 12 days; or (2) the alternate sequence. Each patient underwent a mixed meal test: Humulin 30/70 was administered 30 minutes before the meal, while Mix25 was given 5 minutes before. The 2-hour post-prandial glucose concentration after breakfast was significantly lower during treatment with Mix25 than with Humulin 30/70 (157 +/- 43.2 vs. 180 +/- 43.2 mg/dl, p<0.05). The glycemic excursion after dinner on Mix25 treatment was significantly lower than with Humulin 30/70 (12.2 +/- 48.01 vs. 35.5 +/- 36.92 mg/dl, p<0.05). AUCglucose after Mix25 was lower than after Humulin 30/70. Glycemia after test meal was significantly lower with Mix25 than with Humulin 30/70. Insulin and free insulin concentrations after the test meal were significantly higher with Mix25 in comparison to Humulin 30/70. AUC serum insulin and free insulin curves after Mix25 were significantly higher than after Humulin 30/70 (p=0.028 and p=0.005, respectively). Twice-daily injections of Humalog Mix25, compared to human insulin 30/70 in type 2 diabetic patients with Italian dietary habits, provide improved and lasting post-prandial glycemic control, with the great convenience of the injection just before the meal.

[Ultrasound transmission velocity in the patella of normal subjects and in patients with postmenopausal osteoporosis]. / La velocità di trasmissione degli ultrasuoni nella patella in soggetti normali ed in pazienti con osteoporosi postmenopausale.

Recently, ultrasound transmission velocity (UTV) has been used to assess skeletal status. The basic principle of UTV measurement of bone is that the speed at which ultrasounds propagate in bone is determined by the mass density and by the index of elasticity, which is intimately correlated with bone strength. Theoretically UTV should provide more information about bone fragility than the absorptiometric techniques of measurement of bone mass. To test this hypothesis, UTV was measured using the SIGNET(TM) (Osteo Technology, Framingham, MA, USA) in the patella of 79 postmenopausal nonobese women. The subjects were divided into 2 groups: 29 postmenopausal normal women (NPM) and 50 patients with at least one vertebral crush fracture due to postmenopausal osteoporosis (PMO). Besides UTV measurements in all subjects lumbar spine bone mineral density (BMD) was measured by dual energy Rx (Hologic QDR 1000). UTV in NPM (mean age 57.9 +/- 8 SD years) averaged 1867 +/- 62 m/sec, and in PMO (mean age 63.5 +/- 7.8 SD years) averaged 1771 +/- 74 m/sec. It follows that the difference between the two groups was about 96 m/sec. UTV correlated significantly with BMD measured in the lumbar spine (r = 0.51; p less than 0.001), giving a discrimination power virtually identical to that obtained by using spine BMD values. This preliminary data are promising for the use of this new technique which offers a simple, noninvasive measure of bone quality without the limitation of radiation exposure.

[Ultrasonography techniques in the evaluation of the osteoporotic patient]. / Tecniche di ultrasonografia nella valutazione del paziente osteoporotico.

Previous studies have shown a significant but weak correlation between speed of sound (SOS) and broadband ultrasound attenuation (BUA) in bone, and densitometric bone measurements. These findings indicate that these techniques reflect different properties of bone. We measured SOS and BUA in the os calcis (Achilles, Lunar Corp.) and bone mineral density of the lumbar spine (BMS-LS; by DEXA) and of the ultradistal radius (BMD-UDR; by DPA) in 60 postmenopausal women (age range 50-65): 30 were osteoporotic women (OP) and 30 were age-matched normal postmenopausal women (N). Mean values of SOS and BUA resulted significantly lower in OP group (p < 0.001). SOS and BUA measurements significantly correlated with DEXA of the lumbar spine (r = 0.52 p < 0.001, r = 0.56 p < 0.001, respectively) and DPA of ultradistal radius (r = 0.60 p < 0.001 and r = 0.62 p < 0.001, respectively). In conclusion, these techniques show good correlations with absorptiometric techniques. The best correlation has been found between BUA and DPA of ultradistal radius. Furthermore, US techniques are able to separate a normal from an osteoporotic population. Therefore, US techniques seem to be a useful tool for screening of osteoporotic disease.

[Clinical efficacy of treatment with salmon calcitonin, administered intranasally for 1 year, in stabilized postmenopausal osteoporosis]. / Efficacia clinica di un trattamento con calcitonina di salmone, somministrata per via endonasale per un anno, nell'osteoporosi postmenopausale stabilizzata.

Several controlled clinical studies have confirmed the rationale of calcitonin therapy in postmenopausal osteoporosis. However, administration by injection and side-effects reduced patient compliance and flexibility of dosage. Recently, evidence has been given that an intranasal spray may provide an effective alternative administration route for calcitonin. Forty women with established postmenopausal osteoporosis (at least on vertebral crush fracture) divided into three groups, entered and completed a one-year controlled study on the effects of treatment with synthetic salmon calcitonin nasal spray on bone mass and mineral metabolism. The first group (n = 20) received a daily treatment with 100 I.U. of salmon calcitonin (sCT) nasal spray; the second group (n = 10) received 100 I.U. of sCT by subcutaneous injection every second day; the control group (n = 10) received an oral calcium supplement, 1 g per day. Bone mineral content (BMC), evaluated by dual photon absorptiometry, was measured at the distal radius before and after 6 and 12 months of treatment. Every three months, throughout the year, an evaluation of some parameters of bone remodeling was made. BMC increased (p less than 0.01) in the treatment groups, whereas at the end of treatment, a decrease (p less than 0.05) was observed in the control group. Biochemical estimates of bone resorption, such as urinary hydroxyproline excretion showed a significant decrease in the calcitonin groups. No changes in markers of bone formation, serum alkaline phosphatase and osteocalcin were observed in all patients. This study demonstrates that one-year treatment with sCT nasal spray is able to increase bone mass in osteoporotic patients without important local side-effects.

[The evaluation of the antiarrhythmic activity of L-carnitine and propafenone in ischemic cardiopathy]. / Valutazione dell'attività antiaritmica della L-carnitina e del propafenone nella cardiopatia ischemica.

In order to evaluate a possible antiarrhythmic action of L-carnitine (C) in ischemic heart disease, 30 patients (20 males, 10 females, average age 64 years +/- 11) with ischemic heart disease who at examination with 24-hour dynamic ECG showed extrasystolic ventricular multifocal arrhythmia with a mean hourly rate of > 300 were randomized into three groups, the first of which was given a daily oral dose of 6 g C in three divided doses; groups 2 and 3 were given propafenone (P), 900 mg daily in three divided doses. After one week, all patients were again submitted to 24-hour dynamic ECG after which treatment was continued for another week as follows: group 1 continued on C (6 g daily), group 2 continued on P (900 mg daily), group 3 continued on P (900 mg daily) plus C (6 g daily). At the end of the second week, a further 24-hour ECG was performed the results of which showed that L-carnitine can significantly reduce the antiarrhythmic activity of the ischemic myocardium. In addition, at the end of the second week, a further significant reduction of the number of premature beats compared to the first week was found in patients for whom L-carnitine had been added to propafenone treatment.

STAT3 can serve as a hit in the process of malignant transformation of primary cells.

The transcription factor signal transducer and activator of transcription 3 (STAT3) acts downstream of many pro-oncogenic signals, including cytokines, growth factors and oncogenes, and is accordingly constitutively active in a wide variety of tumors that often become addicted to it. Moreover, STAT3 is a key player in mediating inflammation-driven tumorigenesis, where its aberrant continuous activation is typically triggered by local or systemic production of the pro-inflammatory cytokine IL-6. We recently showed that mouse embryonic fibroblasts (MEFs) derived from STAT3C k/in mice, which express physiological levels of the constitutively active mutant STAT3C, display features of transformed cells such as increased proliferation, resistance to apoptosis and senescence, and aerobic glycolysis. Here, we show that pre-existing constitutively active STAT3 is sufficient to prime primary MEFs for malignant transformation upon spontaneous immortalization. Transformation is strictly STAT3-dependent and correlates with high resistance to apoptosis and enhanced expression of anti-apoptotic/pro-survival genes. Additionally, hypoxia inducible factor (HIF)-1α level is elevated by twofold and contributes to STAT3 oncogenic activity by supporting high rates of aerobic glycolysis. Thus, constitutively active STAT3, an accepted essential factor for tumor growth/progression, can also act as a first hit in multistep carcinogenesis; this ability to predispose cells to malignant transformation may be particularly relevant in the pro-oncogenic niche represented by chronically inflamed tissues.