Pulmonary arterial hypertension: guidelines and unmet clinical needs.

The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.

The safety of iloprost in systemic sclerosis in a real-life experience.

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient's tolerance, 1 day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10 ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20 ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10 ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10 ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient's drug tolerance.

Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature.

Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease's features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61 ± 15.1 years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8 ± 4.1 ng/ml vs. 26 ± 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r = -0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30 ng/ml (8/15 vs. 6/34; p = 0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25-OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations.

Unusual association between Budd-Chiari syndrome secondary to antiphospholipid syndrome and relapsing polychondritis: a case report and review of the literature.

Relapsing polychondritis is a rare immune-mediated condition, characterized by episodic inflammation of the cartilaginous tissue, in particular the ears, nose, and eyes, and involvement of joints and respiratory tract. Nearly one third of patients showed other associated diseases, such as systemic vasculitides, connective tissue diseases, or myelodysplastic syndromes. Antiphospholipid antibodies can be found in relapsing polychondritis in patients with no clinical thrombotic disease. However, when antiphospholipid syndrome is present, its clinical manifestations can be severe and life threatening. We describe the case of a patient with relapsing polychondritis associated to Budd-Chiari syndrome due to antiphospholipid syndrome. The present clinical observations together with the updated review of the literature suggest a search for antiphospholipid antibodies in all patients with relapsing polychondritis.

Total synthesis of bioactive peptides and depsipeptides from marine opisthobranch molluscs.

This chapter covers the synthetic aspects of both linear or cyclic peptides and depsipeptides isolated from opisthobranch molluscs. In many cases, synthetic effort not only determined the absolute stereostructure of these compounds but also made it possible to supply sufficient amounts for the evaluation of pharmacological activities. A summary of the synthetic work associated with each compound is reported after a short description of its natural source and biological properties. Discussion in the text concentrates on key reactions and synthetic efficiency.

The metabolism of nicotinamide in human liver cirrhosis: a study on N-methylnicotinamide and 2-pyridone-5-carboxamide production.

OBJECTIVES: Nicotinamide methylation followed by urinary excretion of N-methylnicotinamide increases in cirrhotic patients, despite the derangement of the overall methylation processes in liver disease. The rise in N-methylnicotinamide could depend, at least in part, on a reduced transformation of this molecule into 2-pyridone-5-carboxamide. The aim of this study was to investigate this hypothesis. METHODS: Serum and urinary levels (mean +/- SEM) of N-methylnicotinamide and urinary excretion of 2-pyridone-5-carboxamide were measured in 10 healthy controls and 10 patients with liver cirrhosis in basal conditions and after a nicotinamide oral load (1.5 mg/kg body weight). RESULTS: N-methylnicotinamide serum levels increased significantly (p < 0.01) in cirrhotic patients compared to controls, both as basal values (0.43 +/- 0.07 nmol/ml; 0.15 +/- 0.01) and as area under the curve 5 h after a nicotinamide load (cirrhotics: 562.4 +/- 50.5 nmol/ml x min; controls: 314.4 +/- 23.8). Twenty-four-hour urinary excretion of N-methylnicotinamide and 2-pyridone-5-carboxamide was also significantly (p < 0.05) increased in cirrhotic patients versus controls, both in basal conditions (N-methylnicotinamide: 82.0 +/- 8.4 micromol, 48.8 +/- 4.8; 2-pyridone-5-carboxamide: 129.3 +/- 23.0, 64.6 +/- 9.8) and after a nicotinamide oral load (N-methylnicotinamide: 290.1 +/- 23.1, 180.8 +/- 7.4; 2-pyridone-5-carboxamide: 694.7 +/- 32.5, 391.0 +/- 21.9). Moreover, 24 h N-methylnicotinamide/2-pyridone-5-carboxamide ratio was similar in patients and controls (basal: 0.78 +/- 0.39, 0.90 +/- 0.51; load: 0.42 +/- 0.11, 0.48 +/- 0.16). CONCLUSIONS: In cirrhotic patients nicotinamide methylation is increased, as shown by the rise in urinary N-methylnicotinamide and 2-pyridone-5-carboxamide that is concurrent and proportional (constant 24-h metabolite ratio). The hyperfunction of this methylating pathway might play a protective role against the toxic effect of intracellular accumulation of nicotinamide deriving from the catabolic state of cirrhosis.

Regional Italian allele frequencies at nine short tandem repeat loci.

An Italian population study was performed on the loci D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317, D7S820 and a portion of the X-Y homologous gene Amelogenin for gender determination using the AmpFlSTR Profiler kit (PE Biosystems, Foster city, CA). This study was done on a population of 618 unrelated Italian individuals from 18 regions in Italy (except for Valle d'Aosta and Sardinia) to determine allele frequencies for each STR locus, and to evaluate STR technology for developing an Italian Offender DNA database.

Italian population allele and genotype frequencies for the AmpliType PM and the HLA-DQ-alpha loci.

The distribution of six genetic loci analyzed by PCR using the commercial AmpliType PM (PolyMarker) kit (Perkin Elmer, Norwalk, CT) was evaluated in 200 unrelated Italian individuals. The examined loci included: Group-specific component (Gc) (1), D7S8 (2), hemoglobin G gammaglobin (HBGG) (3), glycophorin A (GYPA) (4), low density lipoprotein receptor (LDLR) (5), and HLA DQ-alpha (6). The AmpliType PM Kit analysis is based on the reverse dot blot format and the results are interpreted by reading the pattern of blue dots which determine the alleles present at each locus. The population data collected allow the implementation of AmpliType PM into routine casework.

4-acetylaplykurodin B and aplykurodinone B, two ichthyotoxic degraded sterols from the Mediterranean mollusk Aplysia fasciata.

Two ichthyotoxic lactones, 4-acetylaplykurodin B [1] and aplykurodinone B [2], were isolated from the external parts of the body of the mollusk Aplysia fasciata. Their structures, determined by spectroscopic and chemical means, are closely related to aplykurodin B [3] previously isolated from Aplysia kurodai. The interconversion of delta- and gamma-lactones in the aplykurodin derivatives has been also investigated.

A novel multifunctional metabolic pathway in a marine mollusc leads to unprecedented prostaglandin derivatives (prostaglandin 1,15-lactones).

The discovery of high levels of prostaglandin (PG) 1,15-lactones of both the E and F series and their co-existence with PGs has been recently described in the opisthobranch mollusc Tethys fimbria. The present study was undertaken in order to investigate the biosynthesis of these novel natural PG derivatives in vivo using radiolabelled precursors, and to gain a preliminary understanding of their biological role. PGE2 1,15-lactone was shown to be produced from both PGE2 and PGF2 alpha in the mollusc mantle and appeared to be quickly transferred to the mollusc dorsal appendices (cerata). The detachment of the latter during the typical defence behaviour of T. fimbria was accompanied by the conversion of PGE2 and PGE3 1,15-lactones back to the corresponding PGs. Both PGE2 and PGE2 1,15-lactone were also shown to be biosynthesized from arachidonic acid. Lactones of the F series were present as 11-acetyl derivatives in T. fimbria mantle and as 9- and 11-fatty acyl esters in the mollusc egg-mass and reproductive gland, and their biosynthesis from PGF2 alpha was demonstrated in all of these tissues. A multiple biological role of PG 1,15-lactones in T. fimbria defensive behaviour, smooth muscle contraction and egg production/fertilization control is hypothesized. The high amounts of PG derivatives found in T. fimbria and the biosynthetic studies described herein indicate that this marine mollusc may be a useful model for future studies on PG biosynthesis.

A marine mollusc provides the first example of in vivo storage of prostaglandins: prostaglandin-1,15-lactones.

Prostaglandin-(PG) 1,15-lactones and, in smaller amounts, free acids, were isolated from both the mantle and the dorso-lateral appendices of the opisthobranch mollusc Tethys fimbria. In vivo conversion of PGs into the corresponding lactones and accumulation of PGE2- and PGE3-1,15-lactones in the appendages were shown. The detachment of these appendages from the molested mollusc caused the in vivo conversion of PGE2- and PGE3-lactones back to PGE2 and PGE3 respectively, thus providing the first example of a mechanism by which prostaglandins can be stored and, when needed, released.

Non-equilibrium pH gradient electrophoresis (NEPHGE) on ultrathin polyacrylamide gels containing separators: improved erythrocyte phosphoglucomutase (PGM) and esterase D (EsD) diagnosis in red cell lysates and bloodstains.

Two rapid and reliable electrophoretic techniques for PGM1 and EsD typing on ultrathin polyacrylamide gels are described. They have been based on non-equilibrium pH gradient electrophoresis and on the addition of chemical spacers (EPPS for PGM1 and HEPES for EsD) to the gel mixture.

Team physician #4. Avulsion fracture of the distal tibial epiphysis in skeletally immature athletes (juvenile Tillaux fracture).

Adolescent athletic injuries are special in that they differ from those of the skeletally mature athlete in several respects. The physis is weaker than the ligaments, so that the typical mechanism of injury, which might be expected to result in a syndesmosis sprain of the ankle in adults with subsequent tearing of the ligaments, frequently causes an epiphyseal avulsion in children. The potential for leg length discrepancy and growth aberrations exists only if a significant amount of growth remains in the unfused epiphysis. The juvenile Tillaux fracture of the anterolateral distal tibial epiphysis is rare because it requires a specific mechanism of injury of dorsiflexion and external rotation at a time when the tibial epiphysis is fused medially but open laterally. We have also noted in these injuries a tear of the interosseous ligament, which has not previously been stressed in the literature. Intraoperative findings have helped to clarify the pathoanatomy and mechanism of injury. Anatomic reduction is necessary to prevent posttraumatic sequelae.

Team physician #2. Peroneus brevis transfer for Achilles tendon rupture in athletes.

We feel peroneus brevis transfer is especially advantageous for patients interested in sports. We have used this technique in 55 athletes, and to date there have been no re-ruptures (Table 1). Two patients had mild superficial wound problems which did not affect the end result. This method has advantages in comparison with nonoperative treatment and other operative techniques. The danger of re-rupture is avoided and loss of strength minimized because the tendon transfer adds power to the injured triceps. In addition, the proximal retracted triceps is restored to length and securely repaired under physiological tension. Postoperative immobilization in a short leg cast at a right angle plus early weightbearing facilitate rehabilitation. A prolonged period of rehabilitation requiring many months of treatment has not been necessary. The extended rehabilitation and prolonged incapacity necessary to recover from immobilization in the plantarflexed position have been avoided. Early weightbearing helps prevent calf weakness and atrophy. Transferring the peroneal tendon has not resulted in any biomechanical functional imbalance to the foot.

Insect antifeedant activity and hot taste for humans of selected natural and synthetic 1,4-dialdehydes.

The antifeedant activity towards larvae of Leptinotarsa decemlineata and Spodoptera littoralis and the hot taste for the human tongue have been determined for natural and synthetic 1,4-dialdehydes. Among the bicyclic dialdehydes the biological activity has been found to be dependent on the distance between the two aldehyde groups; tricyclic and pentacyclic dialdehydes are inactive in both tests. A short synthetic route to (-)- and (+)-polygodial is reported.

Achilles tendon ruptures--peroneus brevis transfer.

Peroneus brevis tendon transfer has been utilized in 40 individuals during the last 13 years. All cases consisted of complete Achilles tendon ruptures. In 34 cases the rupture was in the distal one-third of the tendon substance, in four cases bony avulsion of the calcaneal tuberosity occurred, and in two cases there was a diffuse tear in the proximal two-thirds of the tendon near the musculotendinous junction. The middle-aged athlete sustained the majority of these injuries during sports. Eleven patients were less than 30 years old, 23 patients were 30 to 40 years old, and six were over 40 years old. Five patients had reruptures that involved prior nonoperative treatment of cast immobilization, and one had undergone simple direct suture. This repair has been used in acute, chronic, and recurrent ruptures of the tendoachillis. Thirty-three patients presented within 1 week of injury, and seven after more than 1 week. A. Perez Teuffer personally described the preferred technique in 1971 and subsequently published in 1978. The transfer of the peroneus brevis is combined with a direct end-to-end suture of the triceps surae tendon that allows a secure reconstruction with the foot at a right angle. The peroneus brevis tendon is detached from the base of the fifth metatarsal and then tunnelled through the distal Achilles tendon stump. The distal portion of the tendon transfer is then drawn proximally along the medial calcaneal tendon border. The proximal triceps surae tendon is pulled distally and secured to the peroneal tendon.(ABSTRACT TRUNCATED AT 250 WORDS)