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Biomedical subjects

M Farias

Publications and source records attributed to M Farias.

At least 19 recordsLinked to original sources
PubMed2007

Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse.

Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd), with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a-deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a(-/-) and Rab3a(+/+) mice were represented by genes from the 129/Sv-derived chromosomal region surrounding the Rab3a gene. These results showed that differences in genetic background have a stronger effect on gene expression than the mutations in the Rab3a gene. In behavioral tests, the Ebd/Ebd mice showed a more pronounced mutant phenotype than the null mice; Ebd/Ebd have reduced anxiety-like behavior in the elevated zero-maze test, reduced response to stress in the forced swim test and a deficit in cued fear conditioning (FC), whereas Rab3a(-/-) showed only a deficit in cued FC. Our data implicate Rab3A in learning and memory as well as in the regulation of emotion. A combination of forward and reverse genetics has provided multiple alleles of the Rab3a gene; our studies illustrate the power and complexities of the parallel analysis of these alleles at the biochemical, molecular and behavioral levels.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Bimodal delta-opioid receptors regulate vagal bradycardia in canine sinoatrial node.

Methionine-enkephalin-arginine-phenylalanine (MEAP) introduced into the interstitium of the canine sinoatrial (SA) node by microdialysis interrupts vagal bradycardia. In contrast, raising endogenous MEAP by occluding the SA node artery improves vagal bradycardia. Both are blocked by the same delta-selective antagonist, naltrindole. We tested the hypothesis that vagal responses to intranodal enkephalin are bimodal and that the polarity of the response is both dose- and opioid receptor subtype dependent. Ultralow doses of MEAP were introduced into the canine SA node by microdialysis. Heart rate frequency responses were constructed by stimulating the right vagus nerve at 1, 2, and 3 Hz. Ultralow MEAP infusions produced a 50-100% increase in bradycardia during vagal stimulation. Maximal improvement was observed at a dose rate of 500 fmol/min with an ED50 near 50 fmol/min. Vagal improvement was returned to control when MEAP was combined with the delta-antagonist naltrindole. The dose of naltrindole (500 fmol/min) was previously determined as ineffective vs. the vagolytic effect of higher dose MEAP. When MEAP was later reintroduced in the same animals at nanomoles per minute, a clear vagolytic response was observed. The delta1-selective antagonist 7-benzylidenenaltrexone (BNTX) reversed the vagal improvement with an ED50 near 1 x 10-21 mol/min, whereas the delta2-antagonist naltriben had no effect through 10-9 mol/min. Finally, the improved vagal bradycardia previously associated with nodal artery occlusion and endogenous MEAP was blocked by the selective delta1-antagonist BNTX. These data support the hypothesis that opioid effects within the SA node are bimodal in character, that low doses are vagotonic, acting on delta1-receptors, and that higher doses are vagolytic, acting on delta2-receptors.

Animals↗
PubMed2001

Transient arterial occlusion raises enkephalin in the canine sinoatrial node and improves vagal bradycardia.

The C-terminal proenkephalin sequence, Methionine-enkephalin-arginine-phenylalanine (MEAP), is abundant in the myocardium and when delivered into the sinoatrial (SA) node by microdialysis, the peptide had significant vagolytic activity. The study that follows was conducted to determine if an increase in endogenous nodal MEAP could be demonstrated during reduced nodal blood flow and was endogenous MEAP similarly vagolytic. Microdialysis probes were placed in the canine SA node and perfused at 5 microl per min. The SA node artery was occluded and released four times at 10-min intervals. The intermittent occlusions were followed by one or two prolonged occlusions (30 min). Vagally mediated bradycardia was compared before, during, and after occlusion of the artery. An increase in recovered MEAP (70-220 fmol) was recorded during each of the initial 10-min occlusions. MEAP returned to baseline during each subsequent 10-min reperfusion. There was a sustained increase in MEAP (110-150 fmol) during longer occlusions. Contrary to the hypothesis, the increased MEAP during arterial occlusion was coincident with improved vagal bradycardia. The improvement in vagally mediated bradycardia was highly reproducible and was observed again during a second 30-min occlusion. The improved vagal function was reversed or reduced, respectively, when naltrindole or glibenclamide was included in the microdialysis inflow during arterial occlusion. Although these observations suggested that opioid receptors and ATP-sensitive K+ channels might have been involved, only a single dose of each agent was practical. Therefore, the specificity of these two responses remains to be confirmed. In summary, the recovery of endogenous opioids from the sinoatrial node increased during reduced arterial perfusion of the node. Contrary to expectations, the increase in recovered endogenous opioids was accompanied byimproved rather than impaired vagal bradycardia.

Animals↗
PubMed2001

Local opiate receptors in the sinoatrial node moderate vagal bradycardia.

Met-enkephalin-arg-phe (MEAP) interrupts vagal bradycardia when infused into the systemic circulation. This study was designed to locate the opiate receptors functionally responsible for this inhibition. Previous observations suggested that the receptors were most likely located in either intracardiac parasympathetic ganglia or the pre-junctional nerve terminals innervating the sinoatrial node. In this study 10 dogs were instrumented with a microdialysis probe inserted into the sinoatrial node. The functional position of the probe was tested by briefly introducing norepinephrine into the probe producing an increase in heart rate of more than 30 beats/min. Vagal stimulations were conducted at 0.5, 1.2 and 4 Hz during vehicle infusion (saline ascorbate). Cardiovascular responses during vagal stimulation were recorded on-line. MEAP was infused directly into the sinoatrial node via the microdialysis probe. The evaluation of vagal bradycardia was repeated during the nodal application of MEAP, diprenorphine (opiate antagonist), and diprenorphine co-infused with MEAP. MEAP introduced into the sinoatrial node via the microdialysis probe reduced vagal bradycardia by more than half. Simultaneous local nodal blockade of these receptors with the opiate antagonist, diprenorphine, eliminated the effect of MEAP demonstrating the participation by opiate receptors. Systemic infusions of MEAP produced a reduction in vagal bradycardia nearly identical to that observed during nodal administration. When local nodal opiate receptors were blocked with diprenorphine, the systemic effect of MEAP was eliminated. These data lead us to suggest that the opiate receptors responsible for the inhibition of vagal bradycardia are located within the sinoatrial node with few, if any, participating extra-nodal or ganglionic receptors.

Animals↗
PubMed2001

Delta opioid receptors inhibit vagal bradycardia in the sinoatrial node.

BACKGROUND: Methionine-enkephalin-arginine-phenylalanine (MEAP) is an endogenous opiate derived from the C-terminal sequence of the larger precursor molecule proenkephalin. This heptapeptide is abundant in the myocardium and has significant vagolytic activity when infused systemically. MEAP interrupted vagal bradycardia when it was delivered directly into the sinoatrial node by local microdialysis. This study was conducted to determine the opioid receptor responsible for the vagolytic effect of MEAP. METHODS AND RESULTS: Microdialysis probes were placed in the sinoatrial node of mongrel dogs and perfused at 5 microL/min. Increasing doses of MEAP were included in the nodal perfusate and approximately two thirds of the vagal bradycardia was inhibited with a maximal effect at 0.3 nmoles/microL and a half-maximal response near 0.1 nmoles/microL. When deltorphin II (a delta opioid receptor agonist) was infused into the sinoatrial node, more than 95% of the vagal bradycardia was eliminated at 0.3 nmoles/microL with the half-maximal response near 0.1 nmoles/microL, indicating that deltorphin II was more efficacious than MEAP. The maximal deltorphin II and MEAP effects were both similarly reversed by the paired infusion of increasing doses of the delta opiate receptor antagonist, naltrindole. Selected mu (endomorphin, super DALDA) and kappa (dynorphin, U50488) receptor agonists and mu (CTAP) and kappa (norBNI) receptor antagonists were completely ineffective in this system. CONCLUSIONS: These data suggest that the vagolytic effect of MEAP involves the activation of delta opiate receptors within the sinoatrial node.

Animals↗
PubMed1993

[Diabetic foot. A clinical case].

Diabetic neuropathy may cause an alteration of the function of the muscles of the sole of the foot. This is at the origin of the chronic dislocation of the articular heads, mainly of the little metatarsal bones (neuro diabetes arthropathy), with formation of areas of pathological pressure. The tissues below being chronically under pressure are affected by trophic lesions called "plantar perforating disease". Recovery may be obtained by not exposing the injured area of the foot to pressure and through careful local therapy. This doesn't prevent disease from appearing again, even though some specially conceived soles are being used, aiming at a correct weight redistribution on the sole of the foot. The clinical case we are describing applies to a man affected by insulin dependent diabetes mellitus, with relapsing diabetic foot ulcers, in spite of him using a specifically designed sole. Such lesion is aggravated by a serious infection which, by gradually penetrating in depth, leads to osteomyelitis, affecting the 5th Metatarsal head. The bone area, dislocated by neuroarthropathy, was presumably responsible for the persisting plantar lesion. The amputation of this infected necrotic structure, has led to the overcoming of the serious septic problem. By eliminating the bone link responsible for the transmission of the pathological pressure, the plantar lesion the patient had been suffering from for a long time, has consequently disappeared.

Abscess↗
PubMed1990

Prevention of adult respiratory distress syndrome with plasminogen activator in pigs.

Death from traumatic shock has been associated with loss of blood externally or internally. However, many patients die after trauma, even though blood volume restoration is adequate. Death is often due to pulmonary failure (adult respiratory distress syndrome [ARDS]). Death and ARDS have been associated with disseminated intravascular coagulation (DIC) and microclots in the lungs. Dissolution of the microclots after trauma can be achieved by activation of endogenous plasmin. Nine pigs were anesthetized for 48 h. Trauma was administered by 60 standard blows to each thigh resulting in a bruise of muscle but no skin, bone, or major vessel injury. Nutrition and respiration were maintained at normal levels. All nine pigs died with severe lung pathology and low PaO2. Ten other traumatized pigs were treated with a plasminogen activator iv 4 h after trauma. Five of these were treated with tissue plasminogen activator (tPA) and five with urokinase. All treated pigs survived 48 h and maintained a normal PaO2. Autopsy showed minimal lung pathology.

Animals↗
PubMed1989

[Clinical aspects of hyperthyroidism in aged patients].

Hyperthyroidism is difficult to diagnose in the elderly because at this age thyroid disorders are often insidious and atypical with non-specific symptoms. The diagnosis of thyroid disease may be particularly difficult in the presence of a multiple age-associated pathology which may mask the signs or symptoms of thyroid disease. The paper presents the clinical findings in 18 patients in whom the diagnosis of thyrotoxicosis was established at the age of 65 or later.

Age Factors↗
PubMed1988

Histochemical and electromyographic analysis of craniomandibular muscles in the rhesus monkey, Macaca mulatta.

The range of fiber composition was analyzed in four regions of the temporalis muscle of four normal rhesus monkeys. The middle region of the temporalis muscle contained significantly fewer type I fibers than the anterior region. Comparison of the same region between left and right temporalis muscles showed that a bilateral symmetry existed in the composition at the different comparable levels of the muscle except for the deep anterior temporalis. Biopsies were also taken from three muscles, the superficial anterior temporalis, superficial masseter, and the digastric muscles, of ten normal adult monkeys to determine the fiber composition. Both adult male and female monkeys demonstrated a low percentage of type I fibers in the anterior temporalis (less than 25%), and twice as many type I fibers in the masseter and digastric muscles (40 to 50%). The effect of applying a constant touch-pressure to the dorsal surface of the tongue using an acrylic wedge was studied subsequently in these ten animals. Behaviorally, the animals lowered their mandible more during the first 3 months of adapting to the tactile stimulus, and lowering of the mandible was accompanied by increased electromyographic activity (EMG) of the digastric muscle, but not of the anterior temporalis or masseter muscles. In fiber composition, only the anterior temporalis demonstrated a significant shift in percentage of type I fibers with a decrease during the first 3 months. In cross-sectional area, both the anterior temporalis and digastric muscles demonstrated a significant decrease for type I fibers during the 12 month period. Lowering the postural position of the mandible had more effect on the cross-sectional area of the individual fibers than on the metabolic activity of the muscles.

Animals↗
PubMed1987

Changes in zygomatic arch position following experimental lateral displacement.

In order to obtain information about the stability of augmentation procedures in the area of the zygomatic arch, the zygomatic arch on one side was displaced laterally in eight rhesus monkeys by an osteotomy of the anterior portion of the arch and placement of an 8 mm bone graft obtained from the supraorbital ridge. The other side served as a control. The post-operative changes were studied on submento-vertex head films during a 24 month follow-up period. Three months post-operatively the amount of lateral displacement was reduced by 55%. During the next 9 months of follow-up only small changes occurred in the individual animals, and the mean values remained predominantly unchanged. Between 12 and 24 months the distance from the zygomatic arch to the midline increased with growth. On the control side this distance increased from three months on. At 24 months only 18% of the difference in width that was created by the surgical repositioning remained.

Animals↗
PubMed1986

Factors affecting long-term results in hemifacial microsomia.

Mandibular malformations in patients with hemifacial microsomia are described and six phases of treatment outlined. Growth of the malformed mandibular ramus in response to functional appliance treatment was studied in 15 subjects with type I mandibular malformations. It was found that length increase of the affected side during the treatment period was not significantly different from the growth of the other side. Changes in length of the affected side of the mandible following surgical repositioning and bonegrafting was assessed in 25 consecutive cases. In 10 of these subjects, the surgical procedure was done during the growth period and in 15 of them after growth had ceased. In the still growing subjects, there was additional length increase of the reconstructed mandibular ramus, but on an average, less than on the side which had normal temporomandibular joint structures. In seven cases, the length increase was similar on the two sides ( +/- 2 mm) or greater on the affected side, and the established symmetry was maintained. In three subjects, there was recurrence of asymmetry, which in two individuals was corrected by a second surgical lengthening of the mandible. There was minimal loss in length of the reconstructed mandibular ramus in the nongrowing subjects and the established mandibular position was maintained.

Activator Appliances↗