Determination of the nateglinide polymorphic purity through DSC

It is well known that the control of the crystallization of drugs to ensure that only the approved and desired polymorph is present in the formulation is a crucial point of a preformulation study. In this regard, the aim of the present work is to devise a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B. In order to achieve this goal, binary systems of known composition have been prepared and the melting peaks of both polymorphs have been recorded by differential scanning calorimetry. Experiments have determined that the method of preparation of the mixtures has to be carefully evaluated. Indeed it has been shown that grinding the samples induces transition from B to H form. Furthermore, it could be observed that the enrichment of the binary mixture with H form is caused by heating. Therefore, after having prepared the mixture without grinding stage, we propose a method to evaluate the content of H polymorph in mixture with the B one from the melting peak of B.     

Contextual determinants of the social-transfer-of-learning effect

A recent study (Milanese et al. in Cogn 116(1):15-22, 2010) showed that performing a spatial compatibility task with incompatible S-R links (i.e., the practice task) alongside a co-actor eliminates the Simon effect in a subsequent joint Simon task (i.e., the transfer task). In the present study, we conducted three experiments to individuate which elements of the practice task need to remain constant for this social-transfer-of-learning to occur. In Experiment 1, participants performed the practice task alongside a co-actor and the Simon task with a different co-actor; in Experiment 2, they performed the practice task alongside a co-actor and the Simon task with the same co-actor after exchanging their seats. Results showed a modulation of the joint Simon effect in Experiment 1 only. In Experiment 2, we found a regular joint Simon effect. These results indicate that, while co-actor identity is not crucial, other elements of the context, such as keeping the same position across tasks, are necessary for the social-transfer-of-learning to occur. On the whole, our data suggest that the social-transfer-of-learning effect is not tuned to a specific co-actor and depends on spatial parameters of the practice and transfer tasks.     

PIN-1 promoter polymorphisms in mild cognitive impairment and susceptibility to Alzheimer's disease: a preliminary report

BACKGROUND AND AIMS: Peptydil prolyl cis-trans isomerase (PIN-1), which specifically regulates the conformational changes following phosphorylation of several proteins, targets the inactive hyper-phosphorylated tau on the Thr231-Pro motif and directly restores its biological function. Interestingly, PIN-1 is oxidatively inhibited not only in Alzheimer's disease brain but also in the hippocampi of mild cognitive impairment (MCI) subjects. The PIN-1 gene is characterized by two single nucleotide polymorphisms (SNPs) in the promoter region which are associated with the risk of Alzheimer's disease. The aim of this study was to analyse the genotype and allele distributions of these PIN-1 SNPs in MCI subjects diagnosed respectively as amnestic MCI (a-MCI) and multiple impaired cognitive domains (mcd-MCI) on the basis of cognitive features. METHODS: -667 T/C and -842 C/G SNPs were genotyped by polymerase chain reaction (PCR) amplification and direct sequencing in 43 MCI subjects, with the intention of comparing -667 and -842 SNP frequencies with those previously described in 111 Alzheimer's disease patients (AD) and 73 healthy controls (HC). RESULTS: The allele frequencies of the -842 C/G SNP in a-MCI subjects are similar to those of AD subjects, while those of mcd-MCI are comparable to HC (G allele 83% in both a-MCI and AD; 95% and 94% in mcd-MCI and HC, respectively). A similar trend is also observed in -842 C/G genotypes. CONCLUSIONS: Since a-MCI is thought to be the preclinical form of AD, the similar genotype distribution of -842 SNP in AD and a-MCI, but not in mcd-MCI, suggests that it is potentially involved in the conversion of a-MCI to AD. In conclusion, these findings support the theory that polymorphisms of the PIN-1 gene can affect neurodegeneration and its clinical progression.     

The synergistic apoptotic effects of thiophenfurin, an inosine monophosphate dehydrogenase inhibitor, in combination with retinoids in HL60 cells

New effective cytotoxic agents and combinations are urgently needed in cancer treatment. The enzyme inosine monophosphate dehydrogenase is a potentially useful target for drug development, since its activity has been shown to be amplified in malignant cells. Thiophenfurin, an inhibitor of the enzyme synthesized by us, is endowed with a significant apoptotic activity in promyelocytic leukaemia HL60 cells. Since retinoids were successfully employed in the treatment of patients with leukaemia, demonstrating significant differentiation-inducing and apoptotic effects, we carried out this study to evaluate the effects of the combination of thiophenfurin and several retinoid molecules, acting in different phases of the cell cycle in vitro. The results show that thiophenfurin is capable of eliciting significant S phase-specific antiproliferative effects in different sensitive and resistant cell lines with the IC50s ranging from 6.7 to 26 microM. When HL60 cells were treated with thiophenfurin in combination with retinoids, the effects on cell growth were additive or synergistic, depending on the kind of retinoid used and the sequence of treatment. In particular, we observed additive effects when the cells were exposed to thiophenfurin and all-transretinoic acid either simultaneously or sequentially. Instead, when the new heterocyclic retinoid isoxazole benzoic acid was used, synergism was obtained in the cells treated sequentially. The combination of thiophenfurin and isoxazole benzoic acid determined synergistic apoptotic effects through a mitochondrion-dependent mechanism, suggesting the possible usefulness of this combination in the treatment of leukaemia.     

Potential therapeutic targets in cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy is a recently identified pathological condition defined as "a chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease". Overall there seems to be a link between the progression of liver function impairment, the development of portal hypertension and the degree of hyperdynamic circulation, the hallmark of the deranged cardiovascular function in advanced liver diseases. Although mechanical factors contribute to much of the increased resistance within the liver in portal hypertension, there is clearly a vasculogenic component to the development, perpetuation and progression of this syndrome as well. The vascular component of portal hypertension includes an increase in splanchnic blood flow, as well as an increase in intrahepatic vascular resistance. Dysregulation of the nitric oxide system appears to play a key role in both these processes with a paradoxical reduction of intrahepatic availability despite increased disposal in the splanchnic and other vascular districts with adverse effects on cardiac function and structure. Nevertheless, other putative mediators of cardiac damage in cirrhosis have been proposed and their role in the pathogenesis of cirrhotic cardiomyopathy investigated. This review involves a discussion of data achieved on pathogenesis and clinical features of cirrhotic cardiomyopathy but mainly focuses on considerations on potential therapeutic targets, in the light of the evidence that this mainly subclinical condition merges to clinical relevance when challenged with those therapeutic interventions and procedures currently employed to treat the major complications of cirrhosis that might produce a negative impact on the cardiovascular system.     

Analysis of Epstein–Barr virus (EBV) type and variant in spontaneous lymphoblastoid cells and Hu-SCID mouse tumours

Epstein–Barr virus (EBV) type and strain variations were examined using both lymphoblastoid cell lines (LCLs), spontaneously derivedin vitrofrom peripheral blood mononuclear cells (PBMC) of 15 HIV-1-seropositive individuals, and SCID mouse tumours induced by inoculation of PBMC from 11 healthy human donors (Hu-SCID tumours). Polymerase chain reaction (PCR) analysis disclosed that all but one of the 26 EBV+ samples harboured EBV nuclear antigen (EBNA) 2 and 3C type A virus. On the other hand, single strand conformation polymorphism (SSCP) analysis using Epstein–Barr encoded RNA (EBER) specific primers detected an AG876-like (type B) band pattern in 21 of the 26 EBV+ samples. Three Hu-SCID tumours scored as B95.8-like (type A), and two showed neither a type A nor a type B SSCP migration pattern. Sequence analysis of the amplified EBER fragments confirmed the PCR-SSCP findings; moreover, additional mutations were present not only in the two EBV+ samples with anomalous SSCP pattern, but also in two other samples with a standard SSCP profile. Thus, EBER analysis did not correlate with EBNA typing, and appeared to be unsuitable for EBV type assessment. Latent membrane protein (LMP) analysis disclosed, on the whole, seven size variants: as expected, the differences were due to the variable numbers of a 33-bp repeat in the amplified fragment, as assessed by direct sequencing. The broader variability detected by LMP analysis should prove more useful than typing for assessing the presence of single and/or mixed variants resulting from EBV reactivation and/or reinfection.     

Value of symptoms to predict tilt testing outcome in patients with clinical suspicion of vasovagal syncope

Studies to assess the value of clinical symptoms to predict the head-up tilt test (HUT) outcome in patients with suspicion of vasovagal syncope have shown controversial results. We undertook this study to compare the frequency of symptoms between subjects with and without history of syncope, its association with syncopal spells in those with a history of syncope and positive or negative HUT, and to identify clinical predictors of HUT outcome. Sixty seven subjects with a history of unexplained syncope and 26 subjects without a history of syncope were interviewed using a structured questionnaire before undergoing HUT, which was performed first in a passive phase and, if negative, was repeated with pharmacological challenge using 5 mg of sublingual isosorbide. Questionnaire included the 16 symptoms most frequently reported in previous studies. Only five symptoms were reported more frequently by subjects with history of syncope in comparison with subjects without it: visual blurring, dysesthesia, sighing dyspnea, tremor in fingers, and diaphoresis. Comparison of symptom frequency between patients with history of syncope and positive or negative HUT revealed that only two were significantly different: nausea and hot flashes. However, a detailed analysis of the data indicates that only hot flashes occurring just before the syncope were more common in those with a positive HUT. Although some symptoms were found more frequently in patients with a history of syncope than in those without it, the use of a structured questionnaire in the group of patients failed to predict the outcome of the HUT.     

Selective decontamination of the digestive tract reduces bacterial bloodstream infection and mortality in critically ill patients. Systematic review of randomized, controlled trials

A systematic review and meta-analysis of randomized controlled trials (RCTs) of selective decontamination of the digestive tract (SDD) was undertaken to evaluate the impact of this procedure on bacterial bloodstream infection and mortality. Data sources were Medline, Embase, Cochrane Register of Controlled Trials, previous meta-analyses, and conference proceedings, without restriction of language or publication status. RCTs were retrieved that compared oropharyngeal and/or intestinal administration of antibiotics as part of the SDD protocol, with or without a parenteral component, with no treatment or placebo in the controls. The three outcome measures were patients with bloodstream infection, causative micro-organisms, and total mortality. Fifty-one RCTs conducted between 1987 and 2005, comprising 8065 critically ill patients were included in the review; 4079 patients received SDD and 3986 were controls. SDD significantly reduced overall bloodstream infections [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.59-0.90; P=0.0036], gram-negative bloodstream infections (OR, 0.39; 95% CI, 0.24-0.63; P<0.001) and overall mortality (OR, 0.80; 95% CI, 0.69-0.94; P=0.0064), without affecting gram-positive bloodstream infections (OR, 1.06; 95% CI, 0.77-1.47). The subgroup analysis showed an even larger impact of SDD using parenteral and enteral antimicrobials on overall bloodstream infections, bloodstream infections due to gram-negative bacteria and overall mortality with ORs of 0.63 (95% CI, 0.46-0.87; P=0.005), 0.30 (95% CI, 0.16-0.56; P<0.001), and 0.74 (95% CI, 0.61-0.91; P=0.0034), respectively. Twenty patients need to be treated with SDD to prevent one gram-negative bloodstream infection and 22 patients to prevent one death.     

Problems of the management of insulinomas. Review of 132 cases treated with medical measures

Summary A collective review of 132 cases of insulin-secreting tumors of the pancreas treated by medical measures is reported. The most widely used drugs were diazoxide, corticoids and streptozotocin which have been effective in controlling hypoglycemia respectively in 48 out of 88 cases, in 15 out of 43 cases and in 10 out of 18 cases. Other drugs were of benefit only in a few cases, or were not sufficiently investigated. Results of treatment, evaluation of toxicity and incidence of side-effects suggest that the drug of choice in the treatment of insulinomas is diazoxide. Streptozotocin must be employed only in patients with malignant disease. The role and indications of medical management in patients with insulinomas are discussed.