Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism.

BACKGROUND: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. METHODS: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. RESULTS: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. CONCLUSION: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.

Caffeine and cerebral palsy: A systematic review of randomized controlled trials and cohort studies.

OBJECTIVE: To systematically review the effects of caffeine on the development of cerebral palsy (CP). DESIGN: Systematic review. SETTING: A search of five databases was performed to identify randomized controlled trials (RCT) or cohort studies published through May 2022. Studies conducted on newborns at risk of developing CP upon receiving caffeine in the first days of life were included as well. Two independent researchers assessed the screening, data extraction, and methodological quality assessment. MAIN OUTCOME MEASURES: Percentage of children with CP. RESULTS: Four studies met our inclusion criteria. The only RCT found a decreased risk (approximately 40 %) of developing CP with 20 mg/kg caffeine citrate (OR 0.59, 95 % CI 0.39, 0.89). In addition, when comparing the period over which caffeine citrate was administered, one retrospective cohort study reported that infants who received caffeine up to the second day of life were also less likely to develop CP. Some methodological issues should be highlighted: in the RCT, the differences between the groups with respect to loss to follow-up were not explored. Similarly, intention-to-treat analyses were not performed. Most cohort studies have not adequately identified the primary confounding factors. CONCLUSIONS: Caffeine could be an important intervention in preventing CP. However, few studies have assessed the effects of caffeine on the risk of CP development. Due to methodological differences, no recommendation regarding its use can be safely made. The findings suggest a positive effect of caffeine citrate in the early stages of life with approximately 20 mg/kg of weight; however, well-designed RCTs with adequate sample size and power, randomization process, outcome measurement, and data analysis are still required.

Friction ridge analysis in disaster victim identification (DVI): Brazilian case studies.

Depending on the magnitude and nature of a disaster, identifying the victims can be a complex task that requires coordinated work by disaster victim identification (DVI) teams based on pre-established protocols. Thus, the analysis of fingerprints has been presented as a method to establish, when possible, the identity of the victims during the DVI process. This study discusses the importance of this primary method of identification and the results obtained in four different disasters in which Brazilian DVI teams were involved: the Air France Flight AF447 plane crash in the Atlantic Ocean, floods and mudslides in the State of Rio de Janeiro, Brazil, the LaMia Flight 2933 plane crash in Colombia, and the tailings dam collapse in Brumadinho, Brazil. Here, we also report the use of the automatic fingerprint capture and identification system, called Alethia, developed by the Federal Police of Brazil and used in the victim identification process in the two latter events mentioned above.Key pointsThis article presents four different disasters that occurred in Brazil and overseas and involved Brazilian DVI teams in the identification process, focusing on fingerprint identification (Air France Flight AF447, floods and mudslides in the State of Rio de Janeiro, Brazil, LaMia Flight 2933, and the Brumadinho tailings dam collapse).This article also describes the evolution of the DVI process in Brazil, including a description of the technology currently used by Brazilian fingerprint experts (Alethia).This article reports how the Alethia System was used in the disasters and how it optimized the human identification process when compared to traditional methods.

Bradykinin induces peripheral antinociception in PGE2-induced hyperalgesia in mice.

BACKGROUND: Bradykinin (BK) is an endogenous peptide involved in vascular permeability and inflammation. It has opposite effects (inducing hyperalgesia or antinociception) when administered directly in the central nervous system. The aim of this study was to evaluate whether BK may also present this dual effect when injected peripherally in a PGE2-induced nociceptive pain model, as well as to investigate the possible mechanisms of action involved in this event in mice. METHODS: Male Swiss and C57BL/6 knockout mice for B1 or B2 bradykinin receptors were submitted to a mechanical paw pressure test and hyperalgesia was induced by intraplantar prostaglandin E2 (2 µg/paw) injection. RESULTS: Bradykinin (20, 40 and 80 ng/paw) produced dose-dependent peripheral antinociception against PGE2-induced hyperalgesia. This effect was antagonized by bradyzide (8, 16 and 32 µg/paw), naloxone (12.5, 25 and 50 µg/paw), nor-binaltorphimine (50, 100 and 200 µg/paw) and AM251 (20, 40 and 80 µg/paw). Bestatin (400 µg/paw), MAFP (0.5 µg/paw) and VDM11 (2.5 µg/paw) potentiated the antinociception of a lower 20 ng BK dose. The knockout of B1 or B2 bradykinin receptors partially abolished the antinociceptive action of BK (80 ng/paw), bremazocine (1 µg/paw) and anandamide (40 ng/paw) when compared with wild-type animals, which show complete antinociception with the same dose of each drug. CONCLUSION: The present study is the first to demonstrate BK-induced antinociception in peripheral tissues against PGE2-induced nociception in mice and the involvement of κ-opioid and CB1 cannabinoid receptors in this effect.

Recommendations for procedures related to the evidence chain of custody in forensic anthropology in Brazil.

Forensic anthropologists perform specialised analysis, mainly involving skeletonised human remains, cadavers in advanced stages of decomposition, disassociated elements from the human body, and human remains in extreme carbonisation. The main objectives of the forensic anthropology expertise are human identification and assisting in determining the cause and manner of death. Estimating the time since death is also a priority for some cases, especially ones involving missing persons. This science works on individual cases, violent deaths, missing persons, mass disasters, suspected violations of human rights, and crimes against humanity. Forensic anthropological evidence is, in general, very sensitive. Thus, it is important to detail aspects relevant to the maintenance of the chain of custody at all phases of the investigation, as well as standardise the actions of the individuals involved. This aims to preserve the evidence integrity and sameness (Sameness: free translation of the Portuguese word "mesmidade", derived from a Spanish word that does not possess a translation to Portuguese. Sameness of evidence is understood as the guarantee that the evidence under valuation (or under analysis of its probative value) is exactly and integrally the same one which was collected, corresponding, therefore, to "the same" (and not "part of", "derived from"), safeguarding its value. Brazil Law No. 13.964 of 14 December 2019 establishes and lists 10 phases related to the evidence chain of custody that must be followed. These newly introduced requirements resulted in the need for adaptation of the forensic, investigative, and legal actors involved in an investigation, and in the detailed description of the procedures for the different areas related to criminalistics, including forensic anthropology. The information provided in this article should be interpreted as recommendations, even though their non-compliance may weaken the investigative and forensic analysis processes in whole or in part.

PnAn13, an antinociceptive synthetic peptide inspired in the Phoneutria nigriventer toxin PnTx4(6-1) (δ-Ctenitoxin-Pn1a).

Animal venoms are an almost inexhaustible source for promising molecules with biological activity and the venom of Phoneutria nigriventer spider is a good example of this. Among several other toxins obtained from this venom, PnTx4(6-1), also called δ-Ctenitoxin-Pn1a, was isolated and initially described as an insect toxin that binds to the site 3 of sodium channels in cockroach nerve cord synaptosomes (Periplaneta americana) and slows down sodium current inactivation in isolated axons of this animal. This toxin did not cause any apparent toxicity to mice when intracerebroventricularly injected (30 µg). Subsequently, it was demonstrated that PnTx4(6-1) has an antinociceptive effect in three different pain models: inflammatory, induced by carrageenan; nociceptive, induced by prostaglandin E2 and neuropathic, induced by sciatic nerve constriction. Using diverse antagonists from receptors, it was shown that the cannabinoid system, via the CB1 receptor, and the opioid system, through the µ and δ receptors, are both involved in the antinociceptive effect of PnTx4(6-1). In the present work, it was synthesized a peptide, named PnAn13, based on the amino acid sequence of PnTx4(6-1) in order to try to reproduce or increase the analgesic effect of the toxin. As it was seen for the toxin, PnAn13 had antinociceptive activity, when intrathecally injected, and this effect involved the cannabinoid and opioid systems. In addition, when it was evaluated the peripheral effect of PnAn13, via intraplantar administration, this peptide was able to reverse the hyperalgesic threshold, evoked by prostaglandin E2. Therefore, using different pharmacological tools, it was shown the participation of cannabinoid and opioid systems in this effect.

Evidence for the involvement of opioid and cannabinoid systems in the peripheral antinociception mediated by resveratrol.

Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception. Paw withdrawal method was used and hyperalgesia was induced by carrageenan (200 µg/paw). All drugs were given by intraplantar injection in male Swiss mice (n = 5). RES (100 µg/paw) administered in the right hind paw induced local antinociception that was antagonized by naloxone, non-selective opioid receptor antagonist, and clocinnamox, µOR selective antagonist. Naltrindole and nor-binaltorfimine, selective antagonists for δOR and kOR, respectively, did not reverse RES-induced peripheral antinociception. CB1R antagonist AM251, but not CB2R antagonist AM630, antagonized RES-induced peripheral antinociception. Peripheral antinociception of RES intermediate-dose (50 µg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of µOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through µOR and CB1R activation by endogenous opioid and endocannabinoid releasing.

TNF-α mediated upregulation of NaV1.7 currents in rat dorsal root ganglion neurons is independent of CRMP2 SUMOylation.

Clinical and preclinical studies have shown that patients with Diabetic Neuropathy Pain (DNP) present with increased tumor necrosis factor alpha (TNF-α) serum concentration, whereas studies with diabetic animals have shown that TNF-α induces an increase in NaV1.7 sodium channel expression. This is expected to result in sensitization of nociceptor neuron terminals, and therefore the development of DNP. For further study of this mechanism, dissociated dorsal root ganglion (DRG) neurons were exposed to TNF-α for 6 h, at a concentration equivalent to that measured in STZ-induced diabetic rats that developed hyperalgesia. Tetrodotoxin sensitive (TTXs), resistant (TTXr) and total sodium current was studied in these DRG neurons. Total sodium current was also studied in DRG neurons expressing the collapsin response mediator protein 2 (CRMP2) SUMO-incompetent mutant protein (CRMP2-K374A), which causes a significant reduction in NaV1.7 membrane cell expression levels. Our results show that TNF-α exposure increased the density of the total, TTXs and TTXr sodium current in DRG neurons. Furthermore, TNF-α shifted the steady state activation and inactivation curves of the total and TTXs sodium current. DRG neurons expressing the CRMP2-K374A mutant also exhibited total sodium current increases after exposure to TNF-α, indicating that these effects were independent of SUMOylation of CRMP2. In conclusion, TNF-α sensitizes DRG neurons via augmentation of whole cell sodium current. This may underlie the pronociceptive effects of TNF-α and suggests a molecular mechanism responsible for pain hypersensitivity in diabetic neuropathy patients.

Peripheral Antinociception Induced by Aripiprazole Is Mediated by the Opioid System.

BACKGROUND: Aripiprazole is an antipsychotic drug used to treat schizophrenia and related disorders. Our previous study showed that this compound also induces antinociceptive effects. The present study aimed to assess the participation of the opioid system in this effect. METHODS: Male Swiss mice were submitted to paw pressure test and hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2 µg). Aripiprazole was injected 10 min before the measurement. Naloxone, clocinnamox, naltrindole, nor-binaltorphimine, and bestatin were given 30 min before aripiprazole. Nociceptive thresholds were measured in the 3rd hour after PGE2 injection. RESULTS: Aripiprazole (100 µg/paw) injected locally into the right hind paw induced an antinociceptive effect that was blocked by naloxone (50 µg/paw), a nonselective opioid receptor antagonist. The role of µ-, δ-, and κ-opioid receptors was investigated using the selective antagonists, clocinnamox (40 µg/paw), naltrindole (15, 30, and 60 µg/paw), and nor-binaltorphimine (200 µg/paw), respectively. The data indicated that only the δ-opioid receptor antagonist inhibited the peripheral antinociception induced by aripiprazole. Bestatin (400 µg), an aminopeptidase-N inhibitor, significantly enhanced low-dose (25 µg/paw) aripiprazole-induced peripheral antinociception. CONCLUSION: The results suggest the participation of the opioid system via δ-opioid receptor in the peripheral antinociceptive effect induced by aripiprazole.

Peltatoside Isolated from Annona crassiflora Induces Peripheral Antinociception by Activation of the Cannabinoid System.

Peltatoside is a natural compound isolated from leaves of Annona crassiflora Mart., a plant widely used in folk medicine. This substance is an analogue of quercetin, a flavonoid extensively studied because of its diverse biological activities, including analgesic effects. Besides, a previous study suggested, by computer structure analyses, a possible quercetin-CB1 cannabinoid receptor interaction. Thus, the aim of this work was to assess the antinociceptive effect of peltatoside and analyze the cannabinoid system involvement in this action. The mouse paw pressure test was used and hyperalgesia was induced by intraplantar injection of carrageenan (200 µg/paw). All used drugs were administered by intraplantar administration in Swiss male mice (n = 6). Peltatoside (100 µg/paw) elicited a local inhibition of hyperalgesia. The peripheral antinociceptive action of peltatoside was antagonized by the CB1 cannabinoid antagonist AM251 (160 µg/paw), but not by CB2 cannabinoid antagonist AM630 (100 µg/paw). In order to assess the role of endocannabinoids in this peripheral antinociceptive effect, we used (i) [5Z,8Z,11Z,14Z]-5,8,11,14-eicosatetraenyl-methyl ester phosphonofluoridic acid, an inhibitor of anandamide amidase; (ii) JZL184, an inhibitor for monoacylglycerol lipase, the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol; and (iii) VDM11, an endocannabinoid reuptake inhibitor. MAFP, JZL184, and VDM11 did not induce antinociception, respectively, at the doses 0.5, 3.8, and 2.5 µg/paw, however, these three drugs were able to potentiate the peripheral antinociceptive effect of peltatoside at an intermediary dose (50 µg/paw). Our results suggest that this natural substance is capable of inducing analgesia through the activation of peripheral CB1 receptors, involving endocannabinoids in this process.

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP-sensitive K(+) channels pathway activation in mice.

Substances derived from plants play an important role in the development of new analgesic drugs, among them, triterpenoids. The connection between the participation of L-arginine/NO/cGMP pathway and the activation of ATP-sensitive K(+) channels (KATP) has been established on the peripheral antinociception induced by various drugs. The study assessed the involvement of L-arginine/NO/cGMP/KATP pathway in the antinociceptive effect induced by tingenone, from Maytenus imbricata, against the hyperalgesia evoked by prostaglandin E2 (PGE2) in peripheral pathway. The paw pressure test was used, with hyperalgesia induced by intraplantar injection of PGE2 (2 µg). Tingenone (200 µg/paw) administered into the right hind paw induced a local antinociceptive effect, that was antagonized by l-NOArg, nonselective nitric oxide synthase (NOS) inhibitor and by L-NPA, selective neuronal NOS (nNOS) inhibitor. The L-NIO, selective inhibitor of endothelial (eNOS), and the L-NIL, selective inhibitor of inducible (iNOS), did not alter the peripheral antinociceptive effect of the tingenone. The ODQ, selective soluble guanylyl cyclase inhibitor, prevented the antinociceptive effect of tingenone, and zaprinast, inhibitor of the phosphodiesterase that is cyclic guanosine monophosphate (cGMP) specific, intensified the peripheral antinociceptive effect of the smaller dose of tingenone. Glibenclamide, ATP-sensitive K(+) channels (KATP) blocker, but not tetraethylammonium chloride, voltage-dependent K(+) channel blocker; dequalinium dichloride, blocker of the small conductance Ca(2+)-activated K(+) channel, and paxilline, a potent blocker of high-conductance Ca(2+)-activated K(+) channels, respectively, prevented the peripheral antinociceptive effect of tingenone. The results demonstrate that tingenone induced a peripheral antinociceptive effect by L-arginine/NO/cGMP/KATP pathway activation, with potential for a new analgesic drug.

Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to opioidergic activation.

Plants belonging to the genus Maytenus are routinely used in folk medicine for the treatment of pain diseases. Our previous phytochemical study of the roots of Maytenus imbricata resulted in the isolation and characterization of tingenone, a pentacyclic triterpene. Natural triterpenoids are of growing interest because they have several biological activities, including analgesic properties. The present study assessed the involvement of the opiodergic pathway in the tingenone-induced antinociceptive effect against hyperalgesia induced by prostaglandin E2 (2 µg) in the peripheral pathway. We evaluated the effect of several antagonists to opioid receptors using the mouse paw pressure test. Tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to µ, δ, and κ receptors, respectively, which reverted the peripheral antinociception induced by tingenone. Bestatine acts as an inhibitor of aminopeptidase, an enzyme that degrades endogenous opioid peptides, and was shown to intensify the antinociceptive effect of tingenone. The results suggest that the opioidergic system participates in the peripheral antinociception induced by tingenone.

Oocyte morphology does not affect post-warming survival rate in an egg-cryobanking donation program.

PURPOSE: To evaluate whether oocyte dysmorphisms affect oocyte survival rates in an egg-cryobanking donation program. METHODS: This study included 54 patients undergoing intracytoplasmic sperm injection. A total of 415 metaphase II oocytes were vitrified using the Cryotop method. Oocyte morphology was assessed immediately prior to oocyte vitrification under 400× magnification. The influence of dysmorphisms on post-thaw survival rates was assessed using regression analysis. Results were considered to be significant at the 5% critical level. RESULTS: Oocyte survival rate was not affected by the presence of the following analysed oocyte abnormalities: increased cytoplasmic granularity, vacuoles in the ooplasm, aggregates of smooth endoplasmic reticulum in the ooplasm, large perivitelline space size, perivitelline space granularity, fragmented first polar body and zona pellucida abnormalities. CONCLUSIONS: Oocyte morphology, observed prior to vitrification, does not predict post-warming survival. The non-invasive identification of predictive markers for oocyte survival potential remains a difficult task.

Intracytoplasmic sperm injection outcome versus intracytoplasmic morphologically selected sperm injection outcome: a meta-analysis.

The development of a modified intracytoplasmic sperm injection (ICSI), called intracytoplasmic morphologically selected sperm injection (IMSI), demonstrated that a profound morphological investigation of the spermatozoon, under the magnification of 6600 x, enables outcome improvement. The aim of this study was to compare ICSI outcome with IMSI outcome. The meta-analysis results demonstrated no significant difference in fertilization rate between ICSI and IMSI groups. However, a significantly improved implantation (odds ratio (OR) 2.72; 95% confidence interval (CI) 1.50-4.95) and pregnancy rate (OR 3.12; 95% CI 1.55-6.26) was observed in IMSI cycles. Moreover, the results showed a significantly decreased miscarriage rate (OR 0.42; 95% CI 0.23-0.78) in IMSI cycles as compared with ICSI cycles. This is the first meta-analysis of published data to evaluate the potential benefits of IMSI. The pooled data of IMSI cycles demonstrate a statistically significant improvement in implantation and pregnancy rates and a statistically significant reduction in miscarriage rates. However, more randomized controlled trials are needed to confirm these results.

Physical activity, obesity and eating habits can influence assisted reproduction outcomes.

OBJECTIVE: To determine if eating habits, physical activity and BMI can influence assisted reproduction outcomes. MATERIAL AND METHODS: This study analyzed 436 patients undergoing intracytoplasmic sperm injection cycles. Patients answered a questionnaire and regression analysis examined the relationship between lifestyle and BMI with the intracytoplasmic sperm injection cycles outcomes. RESULTS: No influence of lifestyle and obesity was observed on the number of oocytes recovered. Obesity reduced the normal fertilization rate (coefficient [Coef.]: -16.0; p = 0.01) and increased the risk of miscarriage (OR: 14.3; p = 0.03). Physical activity positively affected implantation (Coef.: 9.4; p = 0.009), increased the chance of pregnancy (OR: 1.83; p = 0.013) and tended to decrease the risk of miscarriage (OR: 0.30; p = 0.068). In addition, an inverse correlation was found between physical activity and BMI, and a direct correlation was found between soft-drink consumption and BMI. CONCLUSIONS: Eating habits, physical activity and obesity could affect clinical outcomes of assisted reproduction.

Contribution of in-vitro maturation in ovarian stimulation cycles of poor-responder patients.

This cohort study evaluated whether rescue spontaneous maturation (RSM) could be a valid method to increase the number of embryos available for transfer and whether transfers with RSM-derived embryos would contribute to clinical outcomes of poor-responder patients in ovarian stimulation cycles. The study included 440 patients undergoing intracytoplasmic sperm injection cycles in which fewer than five metaphase II (MII) oocytes and at least one immature oocyte were retrieved after follicle aspiration. Patients were allocated into two groups based on the injected oocytes' nuclear maturation status: MII group (n=330), in which only embryos derived from MII oocytes were transferred, and RSM group (n=110), in which at least one embryo derived from an RSM oocyte was transferred. No differences between the MII and RSM groups were observed for pregnancy (16.7% versus 16.5%) or miscarriage (25.5% versus 29.4%) rates, respectively. The RSM group had a higher number of transferred embryos (1.87+/-1.24 versus 2.35+/-1.22; P<0.001), a lower embryo transfer cancellation rate (14.5% versus 6.36%; P=0.025) and lower implantation rate (15.4+/-31.5% versus 10.5+/-22.3%; not significant). These findings suggest that RSM did not contribute to the outcomes in poor-responder cycles.

Negative influence of paternal age on clinical intracytoplasmic sperm injection cycle outcomes in oligozoospermic patients.

OBJECTIVE: To evaluate the effect of male age on clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles, according to sperm concentration. DESIGN: Retrospective, observational study. SETTING: Assisted reproduction center. PATIENT(S): The study included 1,024 couples undergoing ICSI cycles with fresh spermatozoa. INTERVENTION(S): The influence of paternal age on ICSI outcomes of oligozoospermic and normozoospermic patients was evaluated. MAIN OUTCOME MEASURE(S): Rates of high-quality embryos, pregnancy, implantation, and miscarriage were evaluated through linear logistic regression analyses. RESULT(S): When the sperm concentration was abnormal, paternal age influenced implantation (regression coefficient value = -0.7009) and pregnancy rates (odds ratio = 0.95, 95% confidence interval 0.91-0.99). However, in normozoospermic patients, no influence of paternal age was observed on implantation (regression coefficient value = 0.0566) or pregnancy rates (odds ratio = 1.00, 95% confidence interval 0.97-1.03). CONCLUSION(S): For couples in which the men are oligozoospermic, the implantation rate could be impaired by increased paternal age. In these couples, the chance of pregnancy decreased 5% for each year of paternal age. When men are normozoospermic, this effect is not observed.

Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/"indeterminate" and Chagas disease cardiomyopathy patients.

We compared plasma tumor necrosis factor-alpha (TNF-alpha) levels among asymptomatic/"indeterminate" Chagas disease patients (ASY) and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC). Idiopathic dilated cardiomyopathy (DCM) patients and normal controls (NC) were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-alpha levels than NC. TNF-alpha levels among severe CCC patients with significant left ventricular (LV) dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-a production prior to heart failure may play a role in CCC progression.

Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/"indeterminate" and Chagas disease cardiomyopathy patients

We compared plasma tumor necrosis factor-alpha (TNF-alpha) levels among asymptomatic/"indeterminate" Chagas disease patients (ASY) and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC). Idiopathic dilated cardiomyopathy (DCM) patients and normal controls (NC) were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-alpha levels than NC. TNF-alpha levels among severe CCC patients with significant left ventricular (LV) dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-a production prior to heart failure may play a role in CCC progression