Pharmacological modulation of adaptive thermogenesis: new clues for obesity management?

BACKGROUND: Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment. PURPOSE: This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. ß3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.

New insights into the treatment of non-healing diabetic foot ulcers.

Diabetic foot ulcers (DFUs) are one of the most serious and devastating complication of diabetes mellitus, affecting about 15% of diabetic patients. This review describes the innovative treatment options currently available in the treatment of non-healing DFUs. The use of Platelet-Rich-Plasma (PRP) is a safe and valid approach in the treatment of DFUs. However, the methods used to obtain and prepare autologous PRP vary between the studies, thus further evidences are eagerly awaited. Adipose tissue-derived mesenchymal stem cells (ADSCs) are a promising tool in the treatment of DFUs, but additional largescale and long-term follow-up clinical trials are needed. Bone marrow mesenchymal stem cells (BM-MSCs) transplantation, on the other hand, revealed effective in reducing incidents and improving the quality of life of patients with amputations. Autologous Peripheral Blood Mononuclear Cells (A-PBMNCs) showed a good efficacy in the treatment of diabetic patients with CLI, but further RCTs are awaited to best investigate this new therapeutic approach. Photobiomodulation (PBM) therapy revealed effective in the treatment of DFUs in two RCTs, but a standardization of therapeutic protocols as well as level-I studies are needed.

Active site mapping of Loxosceles phospholipases D: Biochemical and biological features.

Brown spider phospholipases D from Loxosceles venoms are among the most widely studied toxins since they induce dermonecrosis, triggering inflammatory responses, increase vascular permeability, cause hemolysis, and renal failure. The catalytic (H12 and H47) and metal-ion binding (E32 and D34) residues in Loxosceles intermedia phospholipase D (LiRecDT1) were mutated to understand their roles in the observed activities. All mutants were identified using whole venom serum antibodies and a specific antibody to wild-type LiRecDT1, they were also analyzed by circular dichroism (CD) and differential scanning calorimetry (DSC). The phospholipase D activities of H12A, H47A, H12A-H47A, E32, D34 and E32A-D34A, such as vascular permeability, dermonecrosis, and hemolytic effects were inhibited. The mutant Y228A was equally detrimental to biochemical and biological effects of phospholipase D, suggesting an essential role of this residue in substrate recognition and binding. On the other hand, the mutant C53A-C201A reduced the enzyme's ability to hydrolyze phospholipids and promote dermonecrosis, hemolytic, and vascular effects. These results provide the basis understanding the importance of specific residues in the observed activities and contribute to the design of synthetic and specific inhibitors for Brown spider venom phospholipases D.

Thyroid and shoulder diseases: the bases of a linked channel.

The association between thyroid disorders and musculoskeletal diseases has long been suspected, but it is still debated whether they have a role in the pathogenesis of shoulder diseases. In vivo and in vitro studies describe the role of thyroid hormones in bone, cartilage and tendon biology. Retrospective studies and case reports suggest that thyroid diseases should be considered as risk factors and hold prognostic value in some of the most common causes of shoulder pain. Thus, it is advisable to search for underlying thyroid disorders in these patients. The pathophysiologic mechanisms by which thyroid hormone imbalance affects the onset, progression and response to treatment of these diseases are yet to be thoroughly defined and demand further studies.

Functional expression, monodispersity and conformational changes in the SBMV virus viral VPg on binding TFE.

Southern bean mosaic virus (SBMV) RNA purified from infected plants was used for cloning the viral genome-linked protein (VPg) and was subsequently expressed in Escherichia coli. Circular dichroism (CD), dynamic light scattering (DLS) and saturation transfer difference (STD) by nuclear magnetic resonance (NMR) measurements were employed to determine the degree of monodispersity and to investigate the conformational changes in the absence and presence of trifluoroethanol (TFE) which indicated increased helical content with increasing concentration of TFE. 8-Anilino-1-naphthalenesulfonic acid (ANS) was used as a probe to compare the unfolding regions of the protein before and after addition of TFE. The results indicated that although the TFE concentration influences VPg folding, it does not play a role in nucleotide binding and that the local solvent hydrophobicity causes significant conformational changes.

Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis.

The main objective of this study was to determine the effect of daily oral alendronate treatment on bone mass in postmenopausal women affected by osteoporosis. The efficacy of intranasal salmon calcitonin was also examined. Nine centers in Italy enrolled 286 postmenopausal women between the ages of 48 and 76 with spinal bone mineral density > or = 2 SD below adult mean peak in the two-year, double-blind, randomized, placebo-controlled trial. Patients were randomized to one of four treatment arms: double-blind placebo, alendronate 10 mg/day, alendronate 20 mg/day, or open-label intranasal salmon calcitonin 100 IU/day; all patients received 500 mg Ca++ supplements. Bone mass was measured by dual-energy x-ray absorptiometry every six months for two years. Patients who received alendronate 10 or 20 mg experienced significant increases in bone mass at all sites measured. At the end of the second year, the mean percent changes, for alendronate 10 and 20 mg relative to placebo, were 5.2% and 7.3% at the lumbar spine, 3.8% and 4.6% at the femoral neck, and 7.1% and 7.5% at the trochanter, respectively. In contrast, intranasal salmon calcitonin failed to increase bone mineral mass significantly at any site. Both alendronate doses significantly decreased serum alkaline phosphatase, serum osteocalcin, and urinary pyridinolines, markers of bone turnover, whereas placebo and intranasal calcitonin did not. Alendronate was generally well tolerated and no serious adverse events were attributed to its use.(ABSTRACT TRUNCATED AT 250 WORDS)

Italian double-blind multicenter study comparing S-adenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease.

In a double-blind study, the efficacy and tolerability of S-adenosylmethionine (SAMe) were evaluated in comparison with those of placebo and naproxen in the treatment of osteoarthritis of the hip, knee, spine, and hand. Thirty-three centers, 18 rheumatologic and 15 orthopedic, participated in this study. A total of 734 subjects, including 582 with coxarthrosis (hip osteoarthritis) or gonarthrosis (knee osteoarthritis), were enrolled. SAMe administered orally at a dose of 1,200 mg daily was shown to exert the same analgesic activity as naproxen at a dose of 750 mg daily. Both drugs were more effective than placebo (p less than 0.01). Tolerability of SAMe was significantly better than that of naproxen, both in terms of physicians' (p less than 0.025) and patients' (p less than 0.01) judgments and in terms of the number of patients with side effects (p less than 0.05). There was no difference between SAMe and placebo in the number of side effects. Ten patients in the SAMe group and 13 in the placebo group withdrew from the study because of intolerance to the drug.

Why are non-steroidal anti-inflammatory drugs important in peptic ulceration?

The pathogenetic role of non-steroidal anti-inflammatory drugs (NSAIDs) in peptic ulcer disease is reviewed, on the basis of available experimental and epidemiological knowledge. In addition, original clinical data are provided concerning the prophylactic and therapeutic role of the H2-receptor antagonists ranitidine and cimetidine, and colloidal bismuth subcitrate, in the treatment of NSAID-associated peptic lesions in rheumatic patients.

Peptic ulcer therapy with cimetidine versus tripotassium dicitrato bismuthate in rheumatoid arthritis patients undergoing chronic NSAID treatment.

AIM: To compare the efficacy of cimetidine and tripotassium dicitrato bismuthate (TDB) in arthritic patients who had developed gastric (GU) or duodenal (DU) ulceration while taking non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Eighty-six rheumatoid arthritis (RA) patients affected by endoscopically proven DU (n = 44) or GU (n = 42), and on chronic NSAID therapy which was not suspended during anti-ulcer therapy, were randomized to cimetidine (400 mg t.d.s.) or TDB (120 mg q.d.s.). A repeat endoscopy was planned after 4 weeks (and 8 weeks, in case of failed healing). The patients who were unhealed after 8 weeks of therapy were allocated to the alternative anti-ulcer drug for a further 8 weeks without interrupting the anti-inflammatory therapy. RESULTS: At week 4 of therapy. 14/24 (58%) DU and 9/20 (45%) GU patients treated with cimetidine were healed, compared with 12/20 (60%) and 10/22 (45%) TDB-treated patients (N.S.). At week 8 of therapy, the DU healing rates were 15/24 (63%) with cimetidine and 14/20 (70%) for TDB. The corresponding GU healing rates were 12/20 (60%) with cimetidine and 13/22 (60%) for TDB (N.S.). At week 16, complete healing with cimetidine was observed in 67% of DU and 57% of GU patients unhealed with TDB; the corresponding figures in the patients crossed to TDB were 83% for DU and 63% for GU patients (N.S. vs. cimetidine). CONCLUSIONS: No statistically significant difference was found between the healing activities of cimetidine and TDB in rheumatoid arthritis patients with peptic ulcer who did not interrupt their NSAID treatment for arthritis. This trial showed that the continued consumption of NSAIDs appears to slow the ulcer healing process, especially in GU patients.

Imidazole salicylate versus piroxicam in the treatment of arthrosis in elderly patients. A double-blind clinical and endoscopic trial.

The clinical efficacy and gastroduodenal tolerability of imidazole salicylate (imidazole 2-hydroxybenzoate, ITF 182), a new synthetic drug with an anti-inflammatory action, was evaluated endoscopically in comparison with those of piroxicam in elderly patients suffering from osteoarthrosis. Of the 41 patients entering the trial, only 38 completed the protocol (6 men and 32 women; mean age, 71; range, 65-80 years). After upper gastrointestinal endoscopy for the purpose of excluding gastric and duodenal mucosal lesions, the patients were allocated at random, according to a double-blind, double-dummy protocol, to treatment either with imidazole salicylate 750 mg three times daily or with piroxicam 20 mg once daily for a period of 4 weeks. Imidazole salicylate proved active in controlling a number of the pain symptoms caused by arthrosis, although its efficacy was inferior to that of piroxicam. Grade 2 gastric mucosal lesions were detected in 1 of 20 patients (5%) treated with imidazole salicylate; lesions corresponding to grades 2, 3, and 4 were found in 6 of 18 (33%) of those treated with piroxicam (P = .034). Painful dyspepsia was reported by 15% of the patients in the imidazole salicylate group and by 28% of those in the piroxicam group. On the basis of these results and under the experimental conditions adopted in this trial, the authors concluded that imidazole salicylate is characterized by good gastric tolerability and can thus be used in the treatment of rheumatic diseases in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)

A method for positioning electrodes during surface EMG recordings in lower limb muscles.

PURPOSE: The aim of this work is to provide information about the degree of inter-subject uniformity of location of innervation zone (IZ) in 13 superficial muscles of the lower limb. The availability of such information will allow researchers to standardize and optimize their electrode positioning procedure and to obtain accurate and repeatable estimates of surface electromyography (sEMG) signal amplitude, spectral variables and muscle fiber conduction velocity. METHODS: Surface EMG signals from gluteus maximus, gluteus medius, tensor faciae latae, biceps femoris, semitendinosus, vastus medialis obliquus, vastus lateralis, rectus femoris, tibialis anterior, peroneus longus, soleus, gastrocnemius medialis and lateralis muscles of ten healthy male subjects aged between 25 and 34 years (average = 29.2 years, S.D. = 2.5 years) were recorded to assess individual IZ location and signal quality. RESULTS: Tensor faciae latae, biceps femoris, semitendinosus, vastus lateralis, gastrocnemius medialis and lateralis showed a high level of both signal quality and IZ location uniformity. In contrast, rectus femoris, gluteus medius and peroneus longus were found to show poor results for both indexes. Gluteus maximus, vastus medialis obliquus and tibialis anterior were found to show high signal quality but low IZ location uniformity. Finally, soleus muscle was found to show low signal quality but high IZ location uniformity. CONCLUSIONS: This study identifies optimal electrode sites for muscles in the lower extremity by providing a standard landmarking technique for the localization of the IZ of each muscle so that surface EMG electrodes can be properly positioned between the IZ and a tendon.

The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide.

OBJECTIVE: To define the optimal dose of nimesulide (NIM) for treating psoriatic arthritis. METHODS: Eighty patients entered a 4-week, double-dummy, randomised, controlled study. Each patient was allocated to one of the following treatment groups: NIM 100 mg/day, NIM 200 mg/day, NIM 400 mg/day, or placebo. Primary end points for arthritis assessment were the scores for tender and swollen joints, and the physician's and patient's global assessment of efficacy. RESULTS: 76/80 patients completed the study. NIM decreased the score for tender and swollen joints from baseline to the end swollen joints from baseline to the end of therapy (p < 0.05). Pain severity on a visual analogue scale (VAS) was reduced by NIM 200 mg (p = 0.03) or NIM 400 mg (p = 0.019) compared to placebo, as was morning stiffness (p = 0.038 and p = 0.008, respectively), but the trends with 100 mg were not statistically significant. The investigators and patients assessed the global efficacy of the NIM 200 and 400 mg/day groups as better than placebo or NIM 100 mg. Side effects were observed in 12 patients (15%) during treatment. They were mostly mild, only one patient withdrew from the study as a result, and the trend for a higher incidence with NIM was not statistically significant. The Psoriasis Area Severity Index (PASI) and the ESR did not show any significant changes. Patients in the placebo group took more paracetamol per day compared with those in the NIM groups (p = 0.007). CONCLUSIONS: Nimesulide 200 and 400 mg/day are effective and safe in psoriatic arthritis.

Oral type II collagen in the treatment of rheumatoid arthritis. A six-month double blind placebo-controlled study.

OBJECTIVE: To evaluate the efficacy of oral chicken type II collagen (CII) in the treatment of rheumatoid arthritis (RA). METHODS: Sixty patients with clinically active RA of long duration (mean 7.2 +/- 5.5 years) were treated for 6 months with oral chicken CII at 0.25 mg/day (n = 31) or with placebo (n = 29) in a double-blind randomized study. RESULTS: The response rate to treatment of the collagen-treated group, based on the ACR 20% criteria, was higher than that of the control group but this difference was not statistically significant at any time. Intention-to-treat (ITT) analysis did not show statistically significant improvement in any of the several secondary outcome measures over the 6 months of the study in the collagen-treated patients in comparison with the placebo-treated group. However, in 2 collagen-treated patients we observed a clinical remission according to the criteria of the American Rheumatism Association. CONCLUSION: Our study seems to show that the oral treatment of RA patients with chicken CII is ineffective and results in only small and inconsistent benefits. Furthermore, our results raise the possibility that in a sub-group of patients oral collagen administration, usually considered devoid of harmful effects, may actually induce disease flares.

An electromyographic investigation of subluxation of the patella.

An electromyographic investigation of patients with subluxation of the patella has been carried out on the parts of the extensor apparatus which actively contribute to the alignment of the patella, both before and after the operation to correct this disorder. The electromyographic pictures have revealed a sharp fall in the activity of the vastus medialis, with full recovery to normal values after a corrective operation. Even if the aligning function of the patella is altered by a variety of factors, the present study confirms the importance of the vastus medialis in the pathogenesis of malalignment of the extensor mechanism.

Surface EMG alterations induced by underwater recording.

BACKGROUND AND PURPOSE: This study aims to verify if amplitude and spectral characteristics of surface EMG signal are modified due to recording in a wet environment. METHODS: Isometric contractions of the biceps brachii muscle of ten subjects were performed in several different set-up combinations, both in dry (D) and in water from hydrotherapy pools (PW), with (PWM) or without moving the pool water and with (T) or without water-resistant adhesive taping. RESULTS: In PW condition the amplitude of the recorded signal is reduced to 5-10% of the corresponding signal recorded in D condition. In PWM the power spectrum is drastically reduced and altered by the water movement that introduces an increase of spectral power in the frequency range 0-20 Hz. The use of T modality allows to record signals with both amplitude and spectral frequencies comparable with those obtained in the D conditions. DISCUSSION AND CONCLUSION: This work demonstrates the need for water resistant taping when EMG signals are recorded in water. Signals recorded without such a protective film are strongly affected in their amplitude and frequency characteristics by the conductivity and the movement of water.

Timegadine: long-term open study in rheumatoid arthritis.

The efficacy and tolerability of Timegadine, a new antirheumatic agent, administered at a dose of 250 mg twice daily was evaluated in an open trial of 24 weeks' duration in 31 patients with active rheumatoid arthritis. The subjective and objective clinical parameters improved significantly from the 2nd to 6th week of treatment. For some of the parameters further improvement was observed during the continuation of the treatment. At 6 weeks the ESR was significantly decreased, and a further reduction of the ESR was seen with the continuation of the treatment. At the end of the treatment period other humoral parameters of the disease were significantly modified. Moreover, in 65% of the patients with seropositive rheumatoid arthritis a reduction of the rheumatoid factor titre by at least two dilutions was observed. Five of the 31 patients were withdrawn from treatment due to the appearance of side effects. Although the study was open and the number of patients relatively small, the observed changes in the laboratory parameters of disease activity encourage further investigations to assess the potential of Timegadine as a remissive drug.

Geometrical factors in surface EMG of the vastus medialis and lateralis muscles.

Surface EMG signals detected in dynamic conditions are affected by a number of artefacts. Among them geometrical factors play an important role. During movement the muscle slides with respect to the skin because of the variation of its length. Such a shift can considerably modify sEMG amplitude. The purpose of this work is to assess geometrical artefacts on sEMG during isometric contractions at different muscle lengths. The average rectified value (ARV) of 15 single differential signals was obtained by means of a linear array of 16 bar electrodes from the vastus medialis and lateralis muscles. The knee angle was changed from 75 degrees to 165 degrees in steps of 30 degrees and voluntary isometric contractions at a low, medium and high force level were performed for each angle. The ARV pattern was normalized with respect to the mean activity to compare signals from different joint angles. From the data collected it was possible to separate the geometrical changes from the changes due to different intensities of activation. In three out of five subjects, we found (within the resolution of our measures) a 1 cm shift for the vastus medialis muscle while no shift was observed for the other two subjects. For the vastus lateralis muscle a 1 cm shift was found in two out of four subjects. Such a shift produces the main contribution to geometrical artefacts. To avoid such artefacts the innervation zones should be located and the EMG electrodes should not be placed near them.

Twenty years of experience with intra-articular rifamycin for chronic arthritides.

Rheumatoid arthritis is a chronic progressive disease causing substantial morbidity and mortality for which current treatments are largely unsatisfactory. Over the past 20 years we have developed a novel therapeutic approach based on the intra-articular administration of rifamycin. The published studies on rifamycin therapy of rheumatoid arthritis and other chronic arthritic disorders, mainly from our group, are reviewed. Our results indicate that intra-articular rifamycin is effective against active synovitis and can profitably be combined with any basic therapy with slow-acting antirheumatic drugs. There is good evidence that the development of new erosions can be prevented or delayed by this treatment and that the balance between side-effects (mainly local pain) and antiarthritic activity is very favourable in the long term. Our observations have led us to hypothesize a possible systemic effect of rifamycin injected multilocally in peripheral joints; we believe that the available data deserve further investigation by independent researchers.

Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: a 90-day open study.

The efficacy and tolerability of 5-hydroxy-L-tryptophan (5-HTP) were studied in an open 90-day study in 50 patients affected by primary fibromyalgia syndrome. When all the clinical variables studied throughout the trial (number of tender points, anxiety, pain intensity, quality of sleep, fatigue) were compared with baseline results, they all showed a significant improvement (P less than 0.001). The overall evaluation of the patient condition assessed by the patient and the investigator indicated a 'good' or 'fair' clinical improvement in nearly 50% of the patients during the treatment period. A total of 15 (30%) patients reported side-effects but only one patient was withdrawn from the treatment for this reason. No abnormality in the laboratory evaluation was observed. It is concluded that 5-HTP is effective in improving the symptoms of primary fibromyalgia syndrome and that it maintains its efficacy throughout the 90-day period of treatment.

Clinical improvement in ankylosing spondylitis with rifamycin SV infiltrations of peripheral joints.

In an open study, a new treatment modality was evaluated in 22 patients with active ankylosing spondylitis and compared with oral treatment. Patients were given a 10-week course of rifamycin SV infiltrations to all large peripheral joints, whether or not affected, and were followed for up to 12 months after the end of treatment. Clinical improvements observed at the end of the 10-week treatment cycle persisted for 12 months: morning stiffness (P less than 0.02); subjective pain (P less than 0.0001); Schober's test (P less than 0.006); hand-ground distance (P less than 0.001); erythrocyte sedimentation rate (P less than 0.001); and C-reactive protein (P less than 0.04). The number of painful joints became significantly lower at 6 (P less than 0.01) and 12 months (P less than 0.02) of the follow-up period. Oral administration of rifampin at three times the intra-articular dosage was devoid of any therapeutic activity. It is not known how treatment of peripheral joints influenced the inflammatory process at the level of the axial skeleton. These results must be considered preliminary due to the small number of patients and the short follow-up period, and because it was an open study.