[Association between hematopoietic stem cell transplantation and Parsonage Turner syndrome: coincidence or cause-effect relationship?] / Asociación de trasplante de progenitores hematopoyéticos y síndrome de Parsonage-Turner: ¿coincidencia o relación causa-efecto?

Parsonage-Turner syndrome or idiopathic brachial neuritis is a total or partial inflammation of the brachial plexus, with a typical presentation as a sudden and very intense pain in the shoulder, followed by weakness and early amyotrophy. The etiology is still unknown, although an immune mediated mechanism is thought to be involved. Hematopoietic stem cell transplantation is a well-established treatment for hematological malignancies, but with a growing implication in the treatment of autoimmune diseases. The neurological side effects are probably underdiagnosed. The association of the Parsonage-Turner syndrome and the hematopoietic stem cell transplantation is scarce. We describe two clinical cases of idiopathic brachial plexopathy after hematopoietic stem cell transplantation. The reconstruction of the immune system after a transplant may be the trigger of a brachial plexopathy, but more studies are necessary for the etiology of this disease to be understood and to establish a cause-effect relation with the transplant.

Patient-related features associated with a delay in seeking care after stroke.

BACKGROUND: Different factors may weight on time from stroke onset to hospital arrival, and patients' alert certainly contributes to it. We sought to identify clinical and sociodemographic factors associated with a delayed alert and to delineate the profile of the potential latecomer in Catalonia (Spain). METHODS: We used data from the Stroke Code (SC) registry that prospectively recruited consecutive patients with acute stroke, in whom SC was activated (SCA) or not (SCNA), admitted to all Catalan hospitals. Additionally, SCNA patients underwent a structured interview to explore additional beliefs and attitudes related to a delayed alert. We applied a 6-h cut-off to define alert delay according to the time limit for SC activation in Catalonia. We determined independent predictors of delay amongst clinical and sociodemographic data by multivariate logistic regression and applied sample weighting because of different study periods in the SCA and SCNA arms. RESULTS: Of the patients, 37.2% delayed alert beyond 6 h. Compared to non-delayers, latecomers were more likely diabetics, illiterates, belonged to an unfavored social class, and were living alone. Fewer had concomitant atrial fibrillation and alerted through emergency medical service (EMS)/112 whilst suffering a mild or moderate stroke. Amongst patients interviewed, being unaware of stroke's vascular nature and erroneously self-perceiving stroke as a reversible or irrelevant condition independently predicted a longer delay. CONCLUSIONS: Delaying alert after stroke shows a multifactorial background with implication of pre-stroke health status, socioeconomic factors, stroke-related features and patients' beliefs and attitudes toward the disease. In planning future educational campaigns, all these features should be considered.

Stroke unit care in clinical practice: an observational study in the Florence center of the European Registers of Stroke (EROS) Project.

BACKGROUND: Randomized trials and meta-analyses indicate positive effects of stroke unit (SU) care on survival and dependency of patients with stroke. However, data on the advantages of SU in 'real-world' settings are limited. We prospectively assessed, in a large University Hospital, the effect of SU versus other conventional wards (OCW) care on all-cause mortality, death or dependency, death or institutionalization. METHODS: In a prospective observational study in the European Registers of Stroke Project, patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, 3-month and 1-year survival, and functional outcome. RESULTS: Overall, 355 patients (54.1% men, mean age 73.4 ± 14.5 years) were registered, 140 (39.4%) admitted to the SU, and 215 (60.6%) to OCW. OCW patients were older, whilst SU patients had more severe strokes according to NIHSS (P for trend = 0.025). SU patients were significantly more often treated by specialists in stroke medicine, stroke nurses, physiotherapists and speech therapists (all P < 0.001), psychologists (P = 0.025), dietitians (P < 0.001), and social workers (P = 0.003). MRI, carotid, and transcranial Doppler were significantly more often performed in SU patients (all P < 0.001). Intravenous fluids (P = 0.003) and intravenous anticoagulation (P < 0.001) were more often prescribed in SU. Controlling for case-mix, SU significantly reduced 1-year mortality (P = 0.020), death or dependency at 3 months (P = 0.006) and 1 year (P = 0.043), and death or institutionalization at 3 months (P = 0.001) and 1 year (P = 0.009). CONCLUSIONS: We confirmed the benefits of SU care in a clinical setting. Further analyses should define the contribution of individual components of care to stroke outcome.

Assessment of neurocognitive decline in cancer patients, except brain cancer, under long-term treatment with bevacizumab.

PURPOSE: We performed a cross-sectional study of neurocognitive function in non-brain cancer patients treated with long-term bevacizumab. METHODS/PATIENTS: From 2015 to 2017, we included patients with different types of cancer treated with bevacizumab with or without chemotherapy (BEV; N = 20) or only chemotherapy (ChT; N = 19) for at least 34 weeks, patients who received non-brain radiotherapy (RxT; N = 19), and healthy controls (HC; N = 19) were assessed once at week 34 of treatment (BEV and ChT) or at completion of radiotherapy. Neurocognition was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R) total and delayed recall, the Trail Making Test A and B, and the Controlled Oral Word Association Test in the four groups. Non-parametric tests were used to assess differences between groups. RESULTS: The BEV, ChT, and RxT groups scored significantly lower than the HC group on all tests and especially on the HVLT-R total recall. In no case were the mean scores of the BEV group significantly lower than those of the ChT or RxT groups. CONCLUSIONS: Neurocognitive impairment was seen even in patients treated with local non-brain radiotherapy. Treatment with bevacizumab for a long period of time does not seem to worsen neurocognitive function to a greater extent than chemotherapy.

Chemotactic tripeptides incorporating at position 2 alpha-aminoacid residues with unsaturated side chains.

New N-For-Met-Leu-Phe-OMe (fMLF-OMe) analogues incorporating three different gamma-delta-didehydro-alpha-aminoacid residues (namely: Alg = (S)-Allylglycine; Dag = Diallylglycine; Cpg = 1-Aminocyclopent-3-ene-1-carboxylic acid) replacing the native (S)-Leucine have been synthesized and their activity towards human neutrophils has been evaluated in comparison with that shown by the reference tripeptide fMLF-OMe. Chemotaxis, lysozyme release and superoxide anion production have been measured. (1)H NMR titration experiments and NOESY spectrum of the Cpg containing model 10 have been discussed in order to ascertain the preferred solution conformations. A fully extended (C(5)) conformation at position 2 and a folded conformation with two consecutive gamma-turns (C(7) structure) have been proposed for the Dag and Cpg containing tripeptides, respectively.

Synthesis, conformation and biological activity of centrally modified pseudopeptidic analogues of For-Met-Leu-Phe-OMe.

For-Met-betaAlapsi[CSNH]-Phe-OMe (3), For-Met-betaAlapsi[CH2NH]-Phe-OMe (5), For-Met-NH-pC6H4-SO(2-Phe-OMe 8a), For-Met-NH-mCH4-SO2-Phe-OMe (8b) and the corresponding N-Boc precursors (2, 4, 7a, b) have been synthesized and their activity towards human neutrophils has been evaluated in comparison with that shown by the reference tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe). Chemotaxis, lysozyme release and superoxide anion production have been measured. (1)H NMR titration experiments and IR spectra have been discussed in order to ascertain the preferred solution conformation adopted by the tripeptide 3 with particular reference to the presence of a folded conformation centred at the centrally positioned thionated beta-residue.

Male fertility: core chemical structure in pharmacological research.

Research in male fertility is of interest in connection with both contraception and treatment of sterility. Several compounds have been shown to inhibit fertility by various mechanisms. The most significant of them are reviewed, including some recently described indazole carboxylic acids. Concerning sterility treatment, no effective treatment is so far available, with the exception of hormonal dysfunctions. The hypothesized role of an excess of free radicals in male sterility suggests a potential therapeutic value of free radicals scavengers. In this connection, indazole derivatives appear of special interest, as some of them display an anti-denaturant activity resulting in a peculiar scavenger-like activity. Some synthetic approaches are proposed, leading to new compounds of potential interest either as male contraceptives or in the treatment of male sterility.

Design and synthesis of glutathione analogues.

This review reports recent structural modifications (since 1989) performed on the glutathione molecular both in the oxidized and reduced form. Relevant chemical aspects, biochemical consequences and therapeutical implications are illustrated. Natural thiols related to glutathione are also considered.

Modified chemotactic peptides: synthesis and biological activity of HCO-Met-delta ZLeu-delta ZPhe-OMe.

For-Met-delta ZLeu-delta ZPhe-OMe (3) has been synthesized as a new analogue of the prototypical chemotactic agent For-Met-Leu-Phe-OMe (fMLP-OMe). Compound 3 is characterized by presence of two consecutive alpha,beta-didehydro amino acid residues [delta ZLeu = (Z)-alpha,beta-didehydroleucine; delta ZPhe = (Z)-alpha,beta- didehydrophenylalanine] located at the central and C-terminal position, respectively. When tested on human neutrophils the N-formyltripeptide 3, although less active than the parent, is able to induce chemotaxis, superoxide anion production and lysozyme release. The activity of 3 has been compared to that of related fMLP-OMe analogues containing a single delta ZPhe residue located at the C-terminal position.

Synthesis and activity on human neutrophil functions of fMLF-OMe analogs containing alkyl spacers at the central position.

We report here the synthesis and activity of new analogs of the N-formyl and N-tert-butyloxycarbonyl (Boc) derivatives of the tripeptide Met-Leu-Phe-OMe containing an achiral omega-amino acid residue replacing the hydrophobic central leucine. The tripeptides HCO-Met-NH-(CH2)n-CO-Phe-OMe and Boc-Met-NH-(CH2)n-CO-Phe-OMe (n = 3-5) containing the central homomorphic residue of 5-aminopentanoic acid (delta-aminovaleric acid; delta-Ava; n = 4) and the two non-homomorphic residues of 4-aminobutanoic acid (gamma-aminobutyric acid; gamma-Abu; n = 3) and 6-aminohexanoic acid (epsilon-aminocaproic acid; epsilon-Aca; n = 5) have been examined. The activity as agonists and antagonists in chemotaxis, lysozyme release, and superoxide anion production of the new analogs has been determined. The N-Boc derivatives 2a and 2b, incorporating the gamma-Abu and the delta-Ava residues, show good and selective antagonist activity on superoxide anion production.

Biscarbamate analogues of the chemotactic tripeptide fMLF-OMe.

Based on the sequence of the prototypical chemotactic tripeptide HCO-Met-Leu-Phe-OH (fMLF) and by taking into account the versatility shown by its N-terminal carbamate analogues, the new biscarbamates MeOCO-Met-Leu-gPhe-COOMe (2) and Boc-Met-Leu-gPhe-COOMe (4) were synthesized. These two new ligands are characterized by the presence of a gem-diamino residue (gPhe) replacing the C-terminal Phe and a carbamate functionality positioned at both the ends of the molecule. The activity of the two new compounds has been determined on human neutrophils and compared to that shown by the corresponding N-terminal monocarbamates MeOCO-Met-Leu-Phe-OMe (1) and Boc-Met-Leu-Phe-OMe (3).

Hybrid alpha/beta-peptides: for-Met-Leu-Phe-OMe analogues containing geminally disubstituted beta2,2- and beta 3,3-amino acids at the central position.

The two fMLF-OMe analogues For-Met-beta(3)hAc(6)c-Phe-OMe (6) and For-Met-beta(2)hAc(6)c-Phe-OMe (12) and their corresponding N-Boc derivatives 5 and 11 have been synthesized and their biological activity towards human neutrophils evaluated. The N-formyl peptides 6 and 12 exhibit good activity as chemoattractans and 12 is highly active in superoxide anion production. The preferred solution conformation of the two N-formyl derivatives has been discussed.

Biochemical properties of new synthetic carnosine analogues containing the residue of 2,3-diaminopropionic acid: the effect of N-acetylation.

Three novel carnosine analogues 7-9 containing the residue of L(+)2,3-diaminopropionic acid with different degree of N-acetylation instead of beta-alanine have been synthesized and characterized. Comparative analysis of hydrolysis by carnosinase revealed that the mono- and bis-acetylated compounds 8 and 9 are resistant to enzymatic hydrolysis and act as competitive inhibitors of this enzyme. The hydroxyl radical scavenging potential of the three analogues was evaluated by their ability to inhibit iron/H(2)O(2)-induced degradation of deoxyribose. The second-order rate constants of the reaction of compounds 7-9 with hydroxyl radical were almost identical to that of carnosine. These compounds were also found to act as protective agents against peroxynitrite-dependent damage as assessed by their ability to prevent nitration of free tyrosine induced by this species.

Potential energy calculations on phenylalanine rotamers in different boat forms of proline-containing cyclic dipeptides.

Previous potential energy calculations have always indicated that the folded conformation is the most stable one for cyclic dipeptides containing benzylic side chains. We have carried out intramolecular van der Waals potential energy calculations on cyclo-(D-Phe-L-Pro), N-(N-phenylacetyl-L-alanyl)-cyclo-(L-Phe-D-Pro) and N-(pyruvoyl)-cyclo-(L-Phe-D-Pro) adopting the geometries found in their crystal structures. The calculations made on these compounds, having the peptide skeleton made of the same aminoacid residues but differing in the degree of buckling of the boat, show that there is a dependence between diketopiperazine ring and phenylalanine side-chain conformations. The folded conformer is preferred as long as it is allowed by the degree of buckling of the boat. When the boat becomes highly buckled, as in the case of the pyruvoyl derivative, the folded rotamer is no longer favoured. This is the first energy calculation to demonstrate that the folded rotamer is not always the most stable one.

Prevention of peroxynitrite-dependent damage by carnosine and related sulphonamido pseudodipeptides.

The naturally occurring dipeptides carnosine and anserine have been proposed to act as antioxidants in vivo. We investigated whether these compounds can act as protective agents able to counteract peroxynitrite-dependent reactions. The results showed that the dipeptides efficiently protect tyrosine against nitration, alpha1-antiproteinase against inactivation and human low-density lipoprotein against modification by peroxynitrite. Carnosine exerts its protective effect at concentrations similar to those found in human tissues. In addition, some synthetic pseudodipeptides, stucturally related to carnosine but stable to hydrolytic enzymes, possess protective properties against peroxynitrite-dependent damage similar to the natural dipeptides. These pseudodipeptides may represent stable mimics of the biologically active carnosine suitable for pharmacological applications.

Cyclization under mild conditions of anthraniloyl- and N-methyl-anthraniloyl dipeptides.

Anthraniloyl- and N-methyl-anthraniloyl dipeptides containing C-terminal L and D proline residues have been synthesized and subjected to cyclization reaction under mild conditions. The influence of substituents and of the chirality of the residues on the output of the reaction is discussed.

Structure and conformation of peptides containing the sulphonamide junction. III. Synthesis, crystal and molecular structure of a taurine containing peptidic oxa-cyclol.

The insertion of the (S)-lactyl residue into the cyclodipeptide cyclo (-Tau-Pro-) 3 leads in good yields to the first example of a stable tetrahedral adduct (oxa-cyclol) 5 containing the sulphonamide junction. Compound 5 does not show a significant tendency towards tautomeric equilibria and possesses an unexpected syn-orientation involving the hydroxyl group and the Pro-H alpha. The crystal structure and molecular conformation of 5 has been determined. Crystals are orthorhombic, s.g. P2(1)2(1)2(1), with a = 6.607, b = 12.297, c = 16.622 A. The cisoidal conformation around the S-N bond is very similar to that found in the previously studied linear and cyclic peptides containing a sulphonamide junction. The taurine nitrogen is practically planar whereas the proline nitrogen, bound to the SO2 group, is highly pyramidal. In the tricyclic system of 5 the seven-membered ring adopts a twist-chair conformation while the pyrrolidine and oxazolidinone rings show an envelope conformation. The crystal packing is characterized by three hydrogen bonds all formed by means of a water molecule.