Biomedical subjects
Publications and source records attributed to R Granados.
Metarrhizium anisopliae is a common insect pathogen that rarely causes infection in animals and humans. We report the first case of a disseminated skin infection in an immunocompromised adult patient. To date, only five cases of the disease in humans have been reported. There is no standard treatment for this infection.
Although structural and functional changes of resistance arteries have been proposed to participate in arterial hypertension (HTA) outcome, not all therapies may correct these alterations, even if they normalize the blood pressure (BP). The aim of this study was to investigate the mechanisms of the protection afforded by the angiotensin receptor antagonist losartan in resistance arteries from patients with essential HTA. In all, 22 untreated hypertensive patients were randomized to receive losartan or amlodipine for 1 year and the morphological characteristics of resistance vessels from subcutaneous biopsies were evaluated. Protein expression of connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta), and collagens III and IV was detected by immunohistochemistry. In comparison with normotensive subjects, resistance arteries from hypertensive patients showed a significant media:lumen (M/L) ratio increment and a higher protein expression of CTGF, TGF-beta, and collagens. After 1 year of treatment, both losartan and amlodipine similarly controlled BP. However, M/L only decreased in patients under losartan treatment, whereas in the amlodipine-treated group this ratio continued to increase significantly. The administration of losartan prevented significant increments in CTGF, TGF-beta, and collagens in resistance arteries. By contrast, amlodipine-treated patients showed a higher vascular CTGF, TGF-beta, and collagen IV staining than before treatment. Our results show that the administration of losartan, but not amlodipine, to hypertensive patients improves structural abnormalities and prevents the production of CTGF and TGF-beta in small arteries, despite similar BP lowering. These data may explain the molecular mechanisms of the better vascular protection afforded by drugs interfering with the renin-angiotensin system.
There are many helpful cytological criteria for the diagnosis of liver fine-needle aspiration biopsies (FNABs), but none of them are pathognomonic of primary or metastatic tumors. We analyzed the diagnostic value and reproducibility of 28 cytological parameters in FNABs from 140 hepatic masses, including 29 benign lesions, 49 hepatocellular carcinomas (HCCs), and 62 metastatic tumors, encompassing 48 adenocarcinomas (ACAs). Five different observers evaluated each sample, and the interobserver and intraobserver agreement was studied. Multivariable analysis showed that the criteria more closely associated with malignancy were irregular nuclear contour, three-dimensional cell groups, and atypical naked nuclei. Capillaries separating tumor cells and granular cytoplasm were strongly associated with HCCs, while eccentrically placed nuclei and necrosis were most commonly seen in ACAs and in metastatic tumors. The intraobserver and interobserver agreement was excellent for the final cytological diagnosis, and there was fair to very good interobserver agreement for 22 of the 28 criteria studied. Architectural features were less reproducible than pure cytological criteria. Intraobserver variability was not influenced by the years of experience in the field. A precise and strict definition of terminology rendered a better reproducibility of the cytological criteria.
BACKGROUND: Some cirrhotic patients with tense ascites who undergo paracentesis develop a circulatory dysfunction syndrome, manifested by an increase in plasma renin activity. Recently, a significant inverse correlation between postparacentesis changes in plasma renin activity and systemic vascular resistance has been demonstrated in these patients, suggesting that peripheral arterial vasodilatation could be responsible for this circulatory dysfunction, but the mechanisms by which tense ascites removal induces such changes are unknown AIM: To investigate the role of a decrease in intra-abdominal pressure (IAP) in the development of early postparacentesis haemodynamic changes METHODS: Eleven cirrhotic patients with tense ascites received a large volume paracentesis. A specially designed pneumatic girdle was used to compress the abdomen to avoid a decrease in IAP during ascites removal. Haemodynamic studies were performed before paracentesis, one hour after ascites flow stopped, and 30 minutes after pneumatic girdle deflation RESULTS: When IAP was maintained at its original level, no haemodynamic changes were observed, despite large volume paracentesis. However, a significant decrease in systemic vascular resistance was seen immediately after pneumatic girdle deflation CONCLUSIONS: Early haemodynamic changes after paracentesis are avoided if IAP is maintained at its original level. The abrupt decrease in IAP could be the trigger for the development of the initial haemodynamic changes that eventually produce postparacentesis circulatory dysfunction.
Administration of a dose of 15 mg/kg of the recreationally used drug 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") to Dark Agouti rats resulted in an acute hyperthermic response which was followed 7 days later by a marked (approximately 45%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [3H]-paroxetine binding in cortex. These losses reflect the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. Administration of pentobarbitone (40 mg/kg) concurrently with MDMA produced a significant attenuation of the neurotoxic damage, but also acute hypothermia. When the temperature of the MDMA plus pentobarbitone-treated group was kept elevated to that of the MDMA-treated group by the use of a homeothermic blanket, the neuroprotective effect of pentobarbitone was lost. These data demonstrate that pentobarbitone appears to possess no intrinsic neuroprotective activity and the previously reported activity is due to a hypothermic action of the drug.
Clomethiazole is an effective neuroprotective agent against the degeneration of 5-HT neurones that follows administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). Since there is good evidence that free radical formation resulting from auto-oxidation of MDMA metabolites is responsible for the degeneration we have examined whether clomethiazole is a free radical scavenger. MDMA (15 mg/kg i.p.) increased the formation of 2,3- and 2,5-dihydroxybenzoic acids (2,3-DHBA and 2,5-DHBA) from salicylic acid perfused through a microdialysis tube implanted in the hippocampus, indicating increased free radical formation. Clomethiazole (50 mg/kg i.p.) administered 5 min prior and 55 min post MDMA prevented both the acute MDMA-induced hyperthermia and the rise in 2,3- and 2,5-DHBA. However, when the temperature of the MDMA + clomethiazole treated rats was kept elevated to that of the MDMA treated rats with a homeothermic blanket there was no inhibition of the MDMA-induced increase in 2,3-DHBA or 2,5-DHBA. These data suggest firstly that free radical formation is inhibited when the acute MDMA-induced hyperthermia is prevented. Secondly the data further indicate that clomethiazole has no free radical scavenging activity since the drug produces substantial neuroprotection when MDMA + clomethiazole treated rats are kept hyperthermic. This conclusion was strengthened by our observation that clomethiazole is a weak inhibitor (IC50 > 1 mM) of lipid peroxidation in synaptosomes when it had been induced by addition of FeCl2 + ascorbic acid.
1. We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration. 2. Haloperidol (2 mg kg(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA + haloperidol treated rats was kept elevated, this protective effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) failed to induce neurodegeneration. 4. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5. The neuroprotective drug clomethiazole (50 mg kg(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.
Administration of a single dose of the recreationally used drug 3,4-methylenedioxyethamphetamine (MDEA or "eve") to Dark Agouti rats resulted in an acute dose-dependent hyperthermic response. The peak effect and duration of hyperthermia of a dose of MDEA of 35 mg/kg intraperitoneally was similar to a dose of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") of 15 mg/kg intraperitoneally. Seven days later this dose of MDMA produced a marked (approximately 50%) loss of 5-HT and its metabolite 5-HIAA in cortex, hippocampus and striatum and a similar loss of [3H]-paroxetine binding in cortex: these losses reflecting the MDMA-induced neurotoxic degeneration of 5-HT nerve endings. In contrast, administration of MDEA (15, 25 or 35 mg/kg), even at the highest dose, produced only a 20% loss in cortex and hippocampus and no decrease in striatum. The neurotoxic effect of MDEA was only weakly dose-dependent. Neither MDEA (35 mg/kg) nor MDMA (15 mg/kg) altered striatal dopamine content 7 days later. MDEA appeared to have about half the potency of MDMA in inducing acute hyperthermia and 25% of the potency in inducing degeneration of cerebral 5-HT neurones. However since higher doses of MDEA (compared to MDMA) are probably necessary to induce mood changing effects, these data do not support any contention that this compound is a "safer" recreational drug than MDMA in terms of either acute toxicity or long term neurodegeneration.
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The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [3H]paroxetine binding in regions of the brain 7 days later, with a dose of 4 mg/kg having no degenerative effect. This dose was also without effect when given once daily for 4 days, but produced a marked loss of [3H]paroxetine binding and indole concentration ( approximately 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorectic effect of the drug being seen. These data demonstrate that MDMA-induced neurodegeneration is related to both the dose and frequency of administration and indicate that damage to 5-HT neurones can occur in the absence of a hyperthermic response to the drug. We suggest that damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted.
1. The immediate effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on rectal temperature and the effect of putative neuroprotective agents on this change has been examined in rats. The influence of the temperature changes on the long term MDMA-induced neurodegeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals was also examined. 2. The novel low affinity N-methyl-D-aspartate (NMDA) receptor channel blocker AR-R15896AR (20 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1), i.p.) did not prevent the MDMA-induced hyperthermia and did not alter either the MDMA-induced neurodegenerative loss of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, striatum and hippocampus or loss of [3H]-paroxetine binding in cortex 7 days later. 3. The neuroprotective agent clomethiazole (50 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1)) abolished the MDMA-induced hyperthermic response and markedly attenuated the loss of 5-HT, 5-HIAA and [3H]-paroxetine binding in the brain regions examined 7 days later. 4. When rats treated with MDMA plus clomethiazole were kept at high ambient temperature for 5 h post-MDMA, thereby keeping their body temperature elevated to near that seen in rats given MDMA alone, the MDMA-induced loss of 5-HT, 5-HIAA and [3H]-paroxetine was still attenuated. However, the protection (39%) afforded by the clomethiazole administration was less than seen in rats kept at normal ambient temperature (75%). 5. These data support the proposals of others that NMDA receptor antagonists are neuroprotective against MDMA-induced degeneration only if they induce hypothermia and further suggest that increased glutamate activity may not be involved in the neurotoxic action of MDMA. 6. These data further demonstrate that a proportion of the neuroprotective action of clomethiazole is due to an effect on body temperature but that, in addition, the compound protects against MDMA-induced damage by an unrelated mechanism.
1. It is well established that 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is neurotoxic and produces long term degeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals in many species. Since MDMA is used extensively as a recreational drug by young people, it is being ingested by many women of child bearing age. We have therefore examined the effect of administering high doses of MDMA to rats during pregnancy on the cerebral content of both the dams and the neonates. 2. MDMA (20 mg kg-1, s.c.) was injected twice daily on days 14-17 of the gestation period. The initial dose produced a marked hyperthermic response in the dam which was progressively attenuated in both peak height and area under the curve following further doses of the drug. The body weight of the dams decreased during the period of treatment. 3. There was a modest decrease in litter size (-20%) of the MDMA-treated dams. 4. The concentration of 5-HT and its metabolite 5-HIAA was decreased by over 65% in the hippocampus and striatum and 40% in the cortex of the dams 1 week after parturition. In contrast, the content of 5-HT and 5-HIAA in the dorsal telencephalon of the pups of the MDMA-treated dams was the same as that seen in tissue from pups born to control animals. 5. Administration of MDMA (40 mg kg-1, s.c.) to adult rats increased thiobarbituric acid reacting substances (TBARS) in cortical tissue 3 h and 6 h later, indicating increased lipid peroxidation. No increase in TBARS was seen in the cortical tissue of 7-10 day neonates injected with this dose of MDMA 3 h or 6 h earlier. 6. The data suggest that exposure to MDMA in utero during the maturation phase does not produce damage to 5-HT nerve terminals in the foetal rat brain, in contrast to the damage seen in the brains of the mothers. This may be due to MDMA being metabolized to free radical producing entities in the adult brain but not in the immature brain or, alternatively, to more effective or more active free radical scavenging mechanisms being present in the immature brain.
1. Administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') to several species results in a long lasting neurotoxic degeneration of 5-hydroxytryptaminergic neurones in several regions of the brain. We have now investigated whether this degeneration is likely to be the result of free radical-induced damage. 2. Free radical formation can be assessed by measuring the formation of 2,3- and 2,5-dihydroxybenzoic acid (2,3-DHBA and 2,5-DHBA) from salicylic acid. An existing method involving implantation of a probe into the hippocampus and in vivo microdialysis was modified and validated. 3. Administration of MDMA (15 mg kg-1, i.p.) to Dark Agouti (DA) rats increased the formation of 2,3-DHBA (but not 2,5-DHBA) for at least 6 h. Seven days after this dose of MDMA, the concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) was reduced by over 50% in hippocampus, cortex and striatum, reflecting neurotoxic damage. There was no change in the concentration of dopamine or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. 4. p-Chloroamphetamine (PCA), another compound which produces a neurotoxic loss of cerebral 5-HT content, when given at a dose of 5 mg kg-1 also significantly increased the formation of 2.3-DHBA (but not 2,5-DHBA) in the dialysate for over 4.5 h. post-injection starting 2 h after treatment. 5. In contrast, fenfluramine administration (15 mg kg-1, i.p.) failed to increase the 2,3-DHBA or 2,5-DHBA concentration in the dialysate. A single fenfluramine injection nevertheless also markedly decreased the concentration of 5-HT and 5-HIAA in the hippocampus, cortex and striatum seven days later. 6. When rats pretreated with fenfluramine (15 mg kg-1, i.p.) seven days earlier were given MDMA (15 mg kg-1, i.p.) no increase in 2,3-DHBA was seen in the dialysate from the hippocampal probe. This indicates that the increase in free radical formation following MDMA is occurring in 5-HT neurones which have been damaged by the prior fenfluramine injection. 7. Administration of the free radical scavenging agent alpha-phenyl-N-tert-butyl nitrone (PBN; 120 mg kg-1, i.p.) 10 min before and 120 min after an MDMA (15 mg kg-1, i.p.) injection prevented the acute rise in the 2,3-DHBA concentration in the dialysate and attenuated by 30% the long term damage to hippocampal 5-HT neurones (as indicated by a smaller MDMA-induced decrease in both the concentration of 5-HT and 5-HIAA and also the binding of [3H]-paroxetine). 8. These data indicate that a major mechanism by which MDMA and PCA induce damage to 5-hydroxytryptaminergic neurones in rat brain is by increasing the formation of free radicals. These probably result from the degradation of catechol and quinone metabolites of these substituted amphetamines. In contrast, fenfluramine induces damage by another mechanism not involving free radicals; a proposal supported by some of our earlier indirect studies. 9. We suggest that these different modes of action render untenable the recent suggestion that MDMA will not be neurotoxic in humans because fenfluramine appears safe at clinical doses.
Fifty-five cervicovaginal smears from women with squamous intraepithelial lesions (SILs) were independently evaluated on two separate occasions by four cytopathologists using a binary classification system (the Bethesda system). Smears were categorized as low-grade (LSIL) or high-grade (HSIL) using previously published criteria. All women had subsequent cervical biopsies containing human papillomavirus (HPV) DNA amplified with the polymerase chain reaction and typed by restriction fragment polymorphism analysis. Three or more observers agreed on classification in 49 of 55 cases (87%); unanimous diagnoses were rendered in 31 cases (56%). Interobserver and intraobserver reproducibility ranged from fair to near-excellent (kappa values 0.40 to 0.63; 0.63 to 0.74, respectively). HPV types included HPV 16 (27%), 18 (7%), 31 (9%), 35 (4%), 39 (4%), 6 (10%), 11 (2%), novel types (30%), and multiple types (4%). High-risk HPV types (16, 18, 31, 35, and 39) were significantly associated (P = .03) with consensus HSIL diagnoses (agreement of three or more observers). This was primarily because of the strong association of HPV 16 with HSIL (P = .001). After excluding HPV 16, the other high-risk HPV types (18, 31, 35, and 39) were no longer significantly associated with consensus HSIL diagnoses (P > .5). Conversely, LSIL diagnoses were significantly associated with non-high-risk HPV types (all HPV types except 16, 18, 31, 35, and 39; P = .006). Binary cytological classification of cervicovaginal SILs is reproducible among cytopathologists. Such classification correlates well with most low-risk HPV types and with the prototypic high-risk HPV 16 but not with other high-risk HPV types.
BACKGROUND & AIMS: Uncontrolled studies suggest that placement of a transjugular intrahepatic portosystemic shunt (TIPS) could be useful in the treatment of variceal bleeding. The aim of this study was to evaluate the efficacy and safety of TIPS in the elective treatment of hemorrhage from esophageal varices in a randomized controlled study that compared the effects of TIPS with those of endoscopic sclerotherapy (ES). METHODS: Sixty-three consecutive cirrhotic patients with hemorrhage from esophageal varices were included. Thirty-two patients were randomly allocated to ES and 31 to TIPS groups. RESULTS: One patient in each group died before the therapeutic procedure could be performed. During a mean follow-up period of 15 months, variceal rebleeding occurred in 51.6% of the patients in the ES group and 23% of those in the TIPS group. Uncontrolled rebleeding occurred in 10 of 31 patients in the ES group, whereas rebleeding did not occur in any patient of the TIPS group. Hepatic encephalopathy was more frequent in TIPS patients (33.3%) than in those treated by ES (13%). However, mortality was similar in both treatment groups. CONCLUSIONS: These preliminary results suggest that TIPS is more effective than ES in the prevention of variceal rebleeding in cirrhotic patients, even though no difference in survival was observed.
A transverse rectus abdominis musculocutaneous free flap was electively performed for reconstructing the cutaneous cover in a patient during the early puerperium (12 hr after delivery). This flap was chosen because of the natural expansion achieved by pregnancy, and because it would cover the entire area to be reconstructed. During surgery, considerable vasodilation and continuous bleeding were encountered, as well as severe spasm of the arteries and veins both in the flap pedicle and at the recipient site. This spasm eased when local papaverine was used, and blood flow was interrupted but recurred as soon as the artery or vein had contact with the patient's blood. The administration of systemic papaverine caused dilation of flap and recipient vessels, but also of uterine vessels, with severe hemorrhage. Under such circumstances, the systemic use of papaverine was interrupted and systemic oxytocin was administered, with subsequent decrease in tissue perfusion and necrosis of the transplanted flap.
Trichilemmal keratosis (TK) is an uncommon epidermal tumor that exhibits a keratinizing surface with the formation of a cutaneous horn and that clinically resembles a hyperkeratotic actinic keratosis. Histologically, there is verrucous hyperplasia of the epidermis with orthokeratotic hyperkeratosis. TK is characterized by abrupt keratinization without formation of a granular cell layer, in the same manner as that in which the outer root sheath keratinizes (trichilemmal keratinization). The epidermis is acanthotic and contains pale-staining keratinocytes. Epithelial lobules and small trichilemmal cysts are connected to the thickened epidermis. We describe the clinical, histologic, and immunohistochemical findings of two cases of TK.