Orofacial antinociceptive effect of Mimosa tenuiflora (Willd.) Poiret.

Mimosa tenuiflora (Willd.) Poiret, popularly known in Brazil as "jurema-preta" is widely used against bronchitis, fever, headache and inflammation. Its antioxidant, anti-inflammatory and antinociceptive potential has already been reported. To assess the orofacial antinociceptive effect of M. tenuiflora, ethanolic extracts of M. tenuiflora (leaves, twigs, barks and roots) were submitted to in vitro tests of antioxidant activity. The extract with the highest antioxidant potential was partitioned and subjected to preliminary chemical prospecting, GC-MS, measurement of phenolic content and cytotoxicity tests of the fraction with the highest antioxidant activity. The nontoxic fraction with the highest antioxidant activity (FATEM) was subjected to tests of acute and chronic orofacial nociception and locomotor activity. The possible mechanisms of neuromodulation were also assessed. The EtOAc fraction, obtained from the ethanolic extract of M. tenuiflora barks, was the one with the highest antioxidant potential and nontoxic (FATEM), and Benzyloxyamine was the major constituent (34.27%). FATEM did not alter the locomotor system of mice and reduced significantly the orofacial nociceptive behavior induced by formalin, glutamate, capsaicin, cinnamaldehyde or acidic saline compared to the control group. FATEM also inhibited formalin- or mustard oil-induced temporomandibular nociception. In addition, it also reduced mustard oil-induced orofacial muscle nociception. However, FATEM did not alter hypertonic saline-induced corneal nociception. Neuropathic nociception was reversed by treatment with FATEM. The antinociceptive effect of FATEM was inhibited by naloxone, L-NAME and glibenclamide. FATEM has pharmacological potential for the treatment of acute and neuropathic orofacial pain and this effect is modulated by the opioid system, nitric oxide and ATP-sensitive potassium channels. These results lead us to studies of isolation and characterization of bioactive principles.

Pregnancy and neonatal outcomes among a cohort of HIV-infected women in a large Italian teaching hospital: a 30-year retrospective study.

The primary study objective was to investigate three decades from 1985 to 2014 of changes in pregnancies among HIV-infected women. The secondary objective was to assess risk factors associated with preterm delivery and severe small-for-gestational-age (SGA) infants in HIV-infected women. A retrospective review of deliveries among pregnant HIV-infected women at the University of Genoa and IRCCS San Martino-IST in Genoa between 1985 and 2014 was performed. Univariate and multivariable analyses were used to study the variables associated with neonatal outcomes. Overall, 262 deliveries were included in the study. An increase in median age (26 years in 1985-1994 vs. 34 years in 2005-2014), in the proportion of foreigners (none in 1985-1994 vs. 27/70 (38·6%) in 2005-2014), and a decrease in intravenous drug use (75·2% (91/121) in 1985-1994 vs. 12·9% (9/70) in 2005-2014) among pregnant HIV-infected women was observed. Progressively, HIV infections were diagnosed sooner (prior to pregnancy in 80% (56/70) of women in the last decade). An increase in combined antiretroviral therapy (cART) prescription during pregnancy (50% (27/54) in 1995-2004 vs. 92·2% (59/64) in 2005-2014) and in HIV-RNA <50 copies/ml at delivery (19·2% (5/26) in 1995-2004 vs. 82·3% (53/64) in 2005-2014) was observed. The rate of elective caesarean section from 1985 to 1994 was 9·1%, which increased to 92·3% from 2004 to 2015. Twelve (10·1%) mother-to-child transmissions (MTCT) occurred in the first decade, and six (8·3%) cases occurred in the second decade, the last of which was in 2000. Preterm delivery (<37 weeks gestation) was 5% (6/121) from 1985 to 1994 and increased to 17·1% (12/70) from 2005 to 2014. In univariate and multivariable logistic regression analyses, advancing maternal age and previous pregnancies were associated with preterm delivery (odds ratio (OR) 2·7; 95% confidence intervals (CI) 1-7·8 and OR 2·6; 95% CI 1·1-6·7, respectively). In the logistic regression analysis, use of heroin or methadone was found to be the only risk factor for severe SGA (OR 3·1; 95% CI 1·4-6·8). In conclusion, significant changes in demographic, clinical and therapeutic characteristics of HIV-infected pregnant women have occurred over the last 30 years. Since 2000, MTCT has decreased to zero. An increased risk of preterm delivery was found to be associated with advancing maternal age and previous pregnancies but not with cART. The use of heroin or methadone has been confirmed as a risk factor associated with severe SGA.

Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor.

Conserved T cell and natural killer cell function in treatment-experienced adults receiving tenofovir plus didanosine as nucleoside reverse transcription inhibitor backbone.

Anti-retroviral treatment (ART) usually results in efficient control of virus replication and in immune reconstitution. Among potential adverse effects, impairment of immune responses in terms of CD4(+) T cell counts has been attributed to some ART regimens, as with didanosine-tenofovir. We studied the functional integrity of adaptive and innate immunity during didanosine-tenofovir-containing ART. Two groups of extensively pretreated patients completing at least 48 weeks of ART containing either lamivudine-didanosine (n = 21) or tenofovir-didanosine (n = 25) were identified. In addition to standard clinical immune and virological parameters, we performed a flow cytometric analysis of natural killer (NK) cells, of memory and naive CD4(+) T cells and of T cell receptor alphabeta(+) T cells co-expressing inhibitory NK receptors. Functional analysis consisted in specific and total interferon-gamma production by NK cells and of recall antigen proliferation of peripheral blood mononuclear cells. Comparable clinical immunological reconstitution and virological control were confirmed in the two groups of patients in the absence of clinically relevant adverse effects. The proportion of CD4(+)CD45RA(+) T cells and of functionally inhibited killer immunoglobulin-like receptor T cell receptor alphabeta(+) cells, the proliferation to recall antigens as well as NK cell phenotype and function as determined by interferon-gamma production in patients treated with tenofovir-didanosine were comparable to those treated with a different regimen. Thus, no differences in functional innate or adaptive immune reconstitution are detected in drug-experienced human immunodeficiency virus-infected patients on tenofovir-didanosine nucleoside reverse transcription inhibitor regimens.

Melkersson-Rosenthal syndrome associated with parvovirus B19 viraemia and haemophagocytic lymphohistiocytosis.

We describe a 23-year-old patient who presented acutely with haemophagocytic lymphohistiocytosis (HL) and Melkersson-Rosenthal syndrome (MRS). MRS and HL are two unusual and complex clinical patterns that may present acutely and to our knowledge, an association between them has never been reported. The clinical investigations in this patient led to identification of parvovirus B19 (PB19) viraemia by PCR. Parvovirus infection has been reported as a cause of virus-associated HL, but the presence of PB19 has never been sought or reported as a possible trigger for MRS. This observation suggests a possible association between PB19 and HL, and opens the possibility of its association also with acute-onset MRS. Further investigations for the presence of PB19 in cases of MRS are warranted.

Persistence of Candida albicans candidemia in non-neutropenic surgical patients: management of a representative patient in the absence of second-line treatment guidelines.

Primary treatment failure and mortality in non-neutropenic patients with candidemia is high according to clinical trial experience. Current guidelines are mainly useful only for first line treatment strategies.We describe treatment failure and persistent protracted Candida albicans candidemia without clinically evident ocular involvement nor catheter recolonization in a malnourished non-neutropenic surgical patient with peritonitis. Primary antifungal treatment failure with fluconazole and secondary treatment failure with caspofungin occurred in the absence of evident Candida seeding the eye, valvular endocardium, or the intravascular catheter. Switch to liposomal amphotericin B was followed by clinical and microbiological cure. In patients with multiple risk factors for the acquisition of candidemia and life-threatening clinical conditions, the possibility of primary/secondary failure of new potent antifungal regimens may be initially neglected. Additional multicenter controlled clinical data are needed to guide the timing and choice of secondary antifungal treatment regimens in non-neutropenic candidemia patients.

Recursos imaginológicos no diagnóstico de neoplasias óssea malígnas do complexobucal e maxilofacial / Imaginologic resources in the diagnosis of malignants bony neoplasias of the oral and maxillofacial complex

As neoplasias ósseas malignas se apresentam sob diversas formas e, na maioria dos casos, por serem assintomáticas e de crescimento rápido, são detectadas já em estágios avançados, o que aumenta o porte da cirurgia e piora o prognóstico do paciente. Este trabalho tem por objetivo apresentar os diversos recursos imaginológicos que podem ser utilizados para o diagnóstico precoce e estadiamento das neoplasias malignas do complexo bucal e maxilofacial, bem como as limitações e indicações de cada exame, sempre procurando estabelecer um protocolo eficaz e acessível para o paciente, além de tornar a cirurgia mais conservadora e adequada a cada caso

Synthesis, structure, and second-order nonlinear optical properties of copper(II) and palladium(II) acentric complexes with N-salicylidene-N'-aroylhydrazine tridentate ligands.

Two new N-salicylidene-N'-aroylhydrazines ligands have been prepared: N-4-diethylaminosalicylidene-N'-4-nitrobenzoyl-hydrazine (L(1)) and N-4-diethylaminosalicylidene-N'-4-(4-nitrophenylethylidene)-benzoyl-hydrazine (L(2)). The ligands are properly functionalized with strong electron donor-acceptor groups and are of potential interest in second-order nonlinear optics (NLO). Dimeric copper(II) and palladium(II) complexes with L(1) and L(2) have been prepared, and, starting from these, mononuclear acentric adducts with pyridine as a further ligand have been prepared and characterized. The X-ray structures of three adducts are also reported. The NLO activity of the adducts has been determined by EFISH measurements giving mubeta values up to 1500 x 10(-48) esu for an incident wavelength of 1.907 microm.

Identification, molecular cloning and functional characterization of NKp46 and NKp30 natural cytotoxicity receptors in Macaca fascicularis NK cells.

Natural killer (NK) cell recognition and function in humans is regulated by multiple cell surface receptors. The "on" signal leading to NK cell triggering is primarily mediated by natural cytotoxicity receptors (NCR). Analysis of NK cells in primate animal models is of particular relevance because NK cells may play an essential role in host defenses against infections. We analyzed Macaca fascicularis PBMC and in vitro-derived NK cell populations and clones by cytofluorometry, using a wide panel of mAb, and by cytolytic activity assays. In addition, RT-PCR strategy and transient transfections were used to isolate M. fascicularis NCR. NCR-specific mAb reactivity (anti-NKp46 and anti-NKp30) was present on M. fascicularis PBMC and on NK cell cultures. Macaque NCR were functional in both redirected killing and in mAb-mediated masking assays. Cloning of macNKp46 and macNKp30 NCR homologous genes showed a high sequence similarity (86 % and 88 %, respectively) with their human counterparts. Attempts at identifying NKp44 surface reactivity and at cloning the macaque homologue were unsuccessful. NKp46 and NKp30 NCRs, but not NKp44, are highly conserved in M. fascicularis NK cells. This suggests the possibility of a staged appearance of the NCR during phylogenesis and provides a useful tool for the study of natural immunity correlates of protection in primate SIV/SHIV infection models.

The MHC class II transactivator: prey and hunter in infectious diseases.

The MHC class II transcriptional activator (CIITA) is the major regulator of expression of MHC class II genes. Thus, CIITA plays a fundamental role in the regulation of the immune response. Here, we discuss our findings on the dual role of CIITA during infections, as the target (prey) for certain pathogens but the host effector (hunter) against other pathogens, including HIV-1. This dual role is placed in an evolutionary context as a rather peculiar example of a strategy used by pathogens to evade host defenses and a counteraction of the host to minimize the survival and spread of the pathogen.

Differential disappearance of inhibitory natural killer cell receptors during HAART and possible impairment of HIV-1-specific CD8 cytotoxic T lymphocytes.

BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with a decrease in viral replication to undetectable levels and with an increase in CD4 T lymphocytes. Residual HIV-1 replication occurs together with incomplete recovery of cytotoxic CD8 T lymphocyte (CTL) numbers and function. We sought to determine whether expression of HLA class I-specific inhibitory natural killer receptors (iNKR) on the CTL of patients who had been treated successfully with HAART for 24 months could be involved, at least in part, in residual CTL functional inhibition. METHODS: Two-colour cytofluorometry was used to analyse the expression of six different iNKR including p58.1, p58.2, p70, p140, CD94/NKG2A and LIR1/ILT2 on the CD3, CD8 lymphocytes of eight patients with successful long-term suppression of viral replication before and after 3, 6 and 24 months of HAART. Healthy subjects were analysed as controls. HIV-1-specific cytotoxic activity was determined after 24 months of HAART in the presence and absence of iNKR-masking. RESULTS: No significant reduction of iNKR expression on CD8 T cells was observed by 6 months. Expression of p70 and p140 was inversely correlated with the increasing CD4 numbers. After 24 months CD8 T-lymphocytes expressing p58.1, p58.2, p70, p140 and CD94/NKG2A returned to levels indistinguishable from those of the healthy controls. A significantly increased proportion of CD8 CTL still expressed LIR1/ILT2, a receptor with broad HLA-class I specificity. Functional analysis of freshly separated cells revealed that the disruption of the interaction between LIR1/ILT2 and HLA-class I could partly restore HIV-1-specific lysis. CONCLUSIONS: A decrease in CD3CD8iNKR cells is observed beyond 6 months of HAART. In some patients functional impairment due to LIR1/ILT2 expression may persist even after 24 months of successful HAART.

Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction.

BACKGROUND: Although echocardiography is an important tool for making the diagnosis of left ventricular (LV) dysfunction, the cost of this procedure limits its use as a routine screening tool for this purpose. Brain natriuretic peptide (BNP) accurately reflects ventricular pressure, and preliminary studies have found it to be highly sensitive and highly specific in diagnosing congestive heart failure in the emergency department. We hypothesized that BNP might therefore be useful as a screening tool before echocardiography in patients with suspected LV dysfunction. METHODS: Subjects included patients referred for echocardiography to evaluate the presence or absence of LV dysfunction. Patients with known LV dysfunction were excluded from analysis. BNP was measured by a point-of-care immunoassay (Biosite Diagnostics, San Diego, Calif). The results of BNP levels were blinded from cardiologists making the assessment of LV function. Patients were divided into those with normal ventricular function, abnormal systolic ventricular function, abnormal diastolic function, and evidence of both systolic and diastolic dysfunction. RESULTS: Two hundred patients in whom LV function was unknown were studied. In the 105 patients (53%) whose ventricular function was subsequently determined to be normal by echocardiography, BNP levels averaged 37 +/- 6 pg/mL. This was significantly less than in those patients with either ultimate diastolic dysfunction (BNP 391 +/- 89 pg/mL (P <.001) or systolic dysfunction (BNP 572 +/- 115 pg/mL (P <.001). A receiver-operator characteristic curve showing the sensitivity and specificity of BNP against the echocardiography diagnosis revealed the area under the curve (accuracy) was 0.95. At a BNP level of 75 pg/mL was 98% specific for detecting the presence or absence of LV dysfunction by echocardiography. CONCLUSIONS: A simple, rapid test for BNP, which can be performed at the bedside or in the clinic, can reliably predict the presence or absence of LV dysfunction on echocardiogram. The data indicate that BNP may be an excellent screening tool for LV dysfunction and may, in fact, preclude the need for echocardiography in many patients.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

OBJECTIVE: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. METHODS: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. RESULTS: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. CONCLUSIONS: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Multiple HLA-class I-specific inhibitory NK receptor expression and IL-4/IL-5 production by CD8+ T-cell clones in HIV-1 infection.

Several mechanisms may contribute to the decline in HIV-1 specific CD8+ cytotoxic T-lymphocyte (CTL) activity that is observed in infected patients, including loss of CD4+ cell help, antigenic shift, impaired clonogenicity and functional impairment due to expression of inhibitory NK receptors (iNKRs). In addition to a decrease in HIV-1-specific cytolytic activity, an increased proportion of CD8+ T-cells producing IL-4 and IL-5 has been recently observed in advanced HIV-1 infection. Remarkably, an impaired HIV-1-specific CTL activity was primarily detected among the TC0/Tc2 CD8+ CTLs. A series of CD3+CD8+ T-cell clones expressing inhibitory NK receptors (iNKRs) isolated from HIV-1 infected patients was analyzed in order to determine their cytokine production pattern and to assess the extent of iNKR expression at the single cell level. Our data indicate that iNKR+CD3+CD8+ clones isolated from infected patients frequently express multiple iNKR and may produce IL-4 and IL-5 to a relevant extent.

HLA-class I-specific inhibitory receptors in HIV-1 infection.

One of the most characteristic and, at the same time, puzzling features of the cellular immune response towards HIV-1 is represented by an early vigorous HIV-specific CD8+ CTL response that does not prevent disease progression in the vast majority of patients. In this context, there is a striking mismatch over the course of disease progression between increasing numbers of activated CD8+ T cells and apparent decrease of virus-specific CD8+ CTLs. Inhibitory NK receptors (iNKRs) specific for HLA class I molecules can be expressed on CD8+ T-cells of healthy individuals and deliver inhibitory signals that determine decreased CTL function. Their expression on CD8+ CTL may be induced by IL-15 or TGFP in vitro, and may represent an important regulatory function for the fine-tuning of the antigen-specific T cell response against tumors and intracytoplasmic pathogens. In HIV-1 infected patients, relevant proportions of peripheral blood CD8+ T lymphocytes express iNKRs belonging to the Ig superfamily (p58/p70/p140) and CD94/NKG2A. Presence of iNKRs on CD8+ CTLs impairs HIV-1-specific cytolytic activity in vitro and may allow uncontrolled viral replication and spread following functional inhibition of CTL effectors in infected patients.