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Biomedical subjects

Ana Ramos

Publications and source records attributed to Ana Ramos.

At least 19 recordsLinked to original sources
PubMed2006

Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CKD.

BACKGROUND: Silent cerebral white matter lesions are observed on magnetic resonance imaging (MRI) scans in elderly people, and they are related to vascular risk factors, particularly hypertension. No data on the prevalence and risk factors of white matter lesions in patients with chronic kidney disease (CKD) are available. The aim is to analyze the prevalence of white matter lesions and their determinants in this population. METHODS: We studied 52 patients without diabetes with CKD (stage 3 or 4) aged 30 to 60 years (average, 49 years) and a group of 32 normotensive control subjects. MRI studies were performed and subcortical and periventricular white matter lesions were evaluated by using semiquantitative measures. Patients were classified into 2 groups depending on the presence or absence of white matter lesions. Echocardiographic studies and measures of markers of systemic inflammation (C-reactive protein and interleukin 6) also were performed. RESULTS: White matter lesions were more prevalent in patients with CKD than controls (33% versus 6%; P = 0.008). Patients with CKD who had white matter lesions were older; had a greater history of cardiovascular disease and vascular nephropathy as a primary cause of renal disease and greater levels of systolic blood pressure, pulse pressure, left ventricular mass index, and C-reactive protein; and were administered more antihypertensive drugs than patients with CKD without white matter lesions. Stage and duration of CKD were not related to the presence of white matter lesions. After adjusting for several factors, only vascular nephropathy (odds ratio, 15.6; 95% confidence interval, 1.27 to 191.54; P = 0.03) independently predicted an increased risk for white matter lesions. CONCLUSION: One third of middle-aged patients with CKD have silent cerebral white matter lesions. Vascular nephropathy seems to be the most important factor related to the presence of these lesions, suggesting that white matter lesions reflect ischemic brain damage caused by generalized vascular damage.

Adult↗
PubMed2006

Adrenomedullin: a new and promising target for drug discovery.

Adrenomedullin (AM) is a 52 amino acid peptide that plays a critical role in several diseases such as hypertension, cancer, diabetes, cardiovascular and renal disorders, among others. Interestingly, AM behaves as a protective agent against some pathologies, yet is a stimulating factor for other disorders. Thus, AM can be considered as a new and promising target for the design of non-peptidic modulators that could be useful for the treatment of those pathologies, by regulating AM levels or the activity of AM. A full decade on from its discovery, much more is known about AM molecular biology and pharmacology, but this knowledge still needs to be applied to the development of clinically useful drugs.

Adrenomedullin↗
PubMed2005

Pannus resolution after occipitocervical fusion in a non-rheumatoid atlanto-axial instability.

Periodontoid pseudotumor or pannus is considered to be an inflammatory mass most frequently associated with rheumatoid arthritis. Transoral resection of the pannus has been the treatment of choice for patients with associated myelopathy, followed in many instances by posterior stabilization. However, some authors have reported resolution of pannus associated with rheumatoid arthritis and other forms of chronic atlanto-axial instability only after posterior stabilization. We report a case of a 69-year-old man who presented with a rapidly progressing myelopathy due to a retro-odontoid mass produced by chronic atlanto-axial instability associated with an occipital assimilation of C1 and tight posterior fossa. An urgent posterior fossa craniectomy followed by occipitocervical fixation was performed. After surgery, the patient's clinical condition improved and 1 year after surgery was asymptomatic, walked without any help and had normal strength. Control MR showed complete resolution of the retro-odontoid pannus.

Aged↗
PubMed2005

Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.

Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.

Adenosine Triphosphate↗
PubMed2005

Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.

Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator with a bistriazole structure has been identified.(1) In this work, a new series of structurally related compounds has been synthesized by reaction of phenoxyacetic acid with the corresponding dihydrazide, followed by treatment of the formed bisoxadiazoles with benzylamine. The affinity toward AM of the lead compound, and a structurally related family obtained from the small-molecule NCI library together with the synthesized series, has been determined. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study and conformational and molecular dynamics simulations have shown that the presence of a free NH and a phenyl group is essential for the interaction of these compounds with AM.

Adrenomedullin↗
PubMed2005

Adrenomedullin: a new target for the design of small molecule modulators with promising pharmacological activities.

Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies.

Adrenomedullin↗
PubMed2005

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome treated with microvascular decompression of the trigeminal nerve: case report.

OBJECTIVE AND IMPORTANCE: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome is a very rare disorder characterized by short-lasting neuralgiform unilateral pain affecting the orbital-periorbital area and associated with autonomic phenomena consisting mainly of conjunctival injection, tearing, and rhinorrhea. Treatment of this condition is difficult; many drugs and surgical procedures have been tried with variable results. In the literature, two cases have been described with short-term response to microvascular decompression of the trigeminal root. We present the case of a patient with short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome who remains asymptomatic 2 years after microvascular decompression. CLINICAL PRESENTATION: A 56-year-old woman was referred to our clinic because she had experienced pain in the distribution of the first left trigeminal branch during the previous 2 years. She experienced paroxysms lasting from a few seconds to 1 to 2 minutes superimposed over a dull sensation of pain involving the same territory. The paroxysms had no refractory period and were triggered by touching the eye or the left side of the face, chewing, yawning, washing her hair, and even by light. Although the paroxysms were triggered by light touch or chewing, she was able to talk or touch herself while having the paroxysm. During pain attacks, she experienced tearing and ipsilateral conjunctival injection, eyelid edema and rhinorrhea, as well as intense photophobia. A magnetic resonance imaging scan revealed a vascular structure distorting and compressing the trigeminal root. INTERVENTION: The patient underwent microvascular decompression of the trigeminal root. At surgery, there was clear compression of the trigeminal root by a superior cerebellar artery loop that was resolved by interposing a Teflon patch. The patient awoke from the operation without pain, and all the accompanying signs and symptoms, such as photophobia, disappeared. The postoperative course was uneventful, and 2 years after treatment, the patient remains asymptomatic. CONCLUSION: Microvascular decompression could be an alternative therapeutic approach to this rare syndrome.

Conjunctival Diseases↗
PubMed2004

Synthesis and biological evaluation of analogues of butyrolactone I and molecular model of its interaction with CDK2.

A series of analogues of butyrolactone I, a natural product isolated from Aspergillus terreus that selectively inhibits the CDK2 and CDK1 kinases and that has been found to exhibit an interesting antiproliferative activity, have been synthesized. Its antitumor activity has been tested. Molecular models of the complex between butyrolactone I and the CDK2 active site have been built using a combination of conformational search and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues are rationalized based on the molecular models.

4-Butyrolactone↗
PubMed2004

New analogues of amonafide and elinafide, containing aromatic heterocycles: synthesis, antitumor activity, molecular modeling, and DNA binding properties.

Amonafide- and elinafide-related mono and bisintercalators, modified by the introduction of a pi-excedent furan or thiophene ring fused to the naphthalimide moiety, have been synthesized. These compounds have shown an interesting antitumor profile. The best compound, 9, was 2.5-fold more potent than elinafide against human colon carcinoma cells (HT-29). Molecular dynamic simulations and physicochemical experiments have demonstrated that these compounds are capable of forming stable DNA complexes. These results, together with those previously reported by us for imidazo- and pyrazinonaphthalimide analogues, have prompted us to propose that the DNA binding process does not depend on the electronic nature of the fused heterocycle.

Adenine↗
PubMed2004

Enhancement of trehalose production in dairy propionibacteria through manipulation of environmental conditions.

We have shown that the ability to produce trehalose is widespread within the genus Propionibacterium. Eighteen strains isolated from dairy sources were screened for trehalose synthesis; the effect of environmental conditions on trehalose production was evaluated in Propionibacterium freudenreichii ssp. shermanii NIZO B365, a strain that accumulated high amounts of this disaccharide. Lactose was the best carbohydrate source for trehalose production, whereas lactate, the substrate that led to the highest specific growth rate, was a poor precursor. Trehalose was consumed after exhaustion of the carbon source in the medium, suggesting its role as a reserve compound. The production of trehalose was not affected by lowering the growth temperature from 30 to 20 degrees C. On the other hand, the maximum trehalose accumulation increased from about 200 to 400 mg of trehalose/g of cell protein upon decreasing the pH from 7.0 to 4.7, by increasing the concentration of NaCl to 2% (w/v), or during growth under aerobic conditions (50% air saturation, 24 microM O(2), pH 7.0). In the absence of NaCl, trehalose accumulated concomitantly with growth, but an increase in salinity triggered a high trehalose production already in the early exponential growth phase. The data provide evidence for a dual function of trehalose as a reserve compound and as a stress-response metabolite. Moreover, P. freudenreichii ssp. shermanii NIZO B365 was able to produce high levels of trehalose in skim milk, which is promising for the implementation of fermented dairy products.

Cultured Milk Products↗
PubMed2004

Effect of pyruvate kinase overproduction on glucose metabolism of Lactococcus lactis.

Lactococcus lactis strain NZ9000(pNZpyk), which overproduces pyruvate kinase (PK), was constructed. The pNZpyk plasmid carries the P(nisA)-pyk transcriptional fusion, and the overexpression of its pyk gene was accomplished by using the nisin-inducible expression system of the NZ9000 strain. In vivo (13)C- and (31)P-NMR spectroscopy was used to evaluate the effect of this modification on the metabolism of glucose in non-growing cells. A detailed description of the kinetics of glucose, end products, glycolytic intermediates, NAD(+) and NADH was obtained. A 15-fold increase in the level of PK did not increase the overall glycolytic flux, which, on the contrary, was slightly reduced. Significant differences were observed in (i) the level of 3-phosphoglycerate (3-PGA) and phosphoenolpyruvate (PEP), metabolites associated with starvation; (ii) the rate of fructose 1,6-bisphosphate (FBP) depletion upon glucose exhaustion; and (iii) the NAD(+)/NADH ratio during glucose catabolism. In the mutant, the rate of FBP consumption after glucose depletion was notably accelerated under anaerobic conditions, whereas 3-PGA and PEP decreased to undetectable levels. Furthermore, the level of NAD(+) decreased steadily during the utilization of glucose, probably due to the unanticipated reduction in the lactate dehydrogenase activity in comparison with the control strain, NZ9000(pNZ8020). The results show that PK is an important bottleneck to carbon flux only when glucose becomes limiting; in the overproducer this constriction was no longer present, as evidenced by the faster FBP consumption and lack of accumulation of 3-PGA and PEP in anaerobic as well as aerobic conditions. Despite these clear changes, the PK-overproducing strain showed typical homolactic metabolism under anaerobic conditions, as did the strain harbouring the vector plasmid without the pyk insert. However, under an oxygen atmosphere, there was increased channelling of carbon to the production of acetate and acetoin, to the detriment of lactate production.

Adenosine Triphosphate↗
PubMed2004

Venous angioma associated with atypical ophthalmoplegic migraine.

BACKGROUND: Ophthalmoplegic migraine is a rare syndrome in which episodic headaches are associated with ophthalmoplegia. Several recent reports emphasize the possibility, especially in atypical cases, of a heterogeneous type of ophthalmoplegic migraine. METHODS: We describe the case of an 18-year-old woman with recurrent episodic headache accompanied by binocular diplopia due to left third cranial nerve palsy. The symptoms resolve in hours. A diagnosis of atypical ophthalmoplegic migraine was established. RESULTS: Digital angiography revealed a venous angioma draining into the left cavernous sinus. CONCLUSIONS: This case reveals the importance of differential diagnosis in atypical migraine in which the symptomatology could be secondary to intracranial lesions. We propose venous stasis as a cause of symptoms.

Adolescent↗
PubMed2004

Engineering Lactococcus lactis for production of mannitol: high yields from food-grade strains deficient in lactate dehydrogenase and the mannitol transport system.

Mannitol is a sugar polyol claimed to have health-promoting properties. A mannitol-producing strain of Lactococcus lactis was obtained by disruption of two genes of the phosphoenolpyruvate (PEP)-mannitol phosphotransferase system (PTS(Mtl)). Genes mtlA and mtlF were independently deleted by double-crossover recombination in strain L. lactis FI9630 (a food-grade lactate dehydrogenase-deficient strain derived from MG1363), yielding two mutant (Delta ldh Delta mtlA and Delta ldh Delta mtlF) strains. The new strains, FI10091 and FI10089, respectively, do not possess any selection marker and are suitable for use in the food industry. The metabolism of glucose in nongrowing cell suspensions of the mutant strains was characterized by in vivo (13)C-nuclear magnetic resonance. The intermediate metabolite, mannitol-1-phosphate, accumulated intracellularly to high levels (up to 76 mM). Mannitol was a major end product, one-third of glucose being converted to this hexitol. The double mutants, in contrast to the parent strain, were unable to utilize mannitol even after glucose depletion, showing that mannitol was taken up exclusively by PEP-PTS(Mtl). Disruption of this system completely blocked mannitol transport in L. lactis, as intended. In addition to mannitol, approximately equimolar amounts of ethanol, 2,3-butanediol, and lactate were produced. A mixed-acid fermentation (formate, ethanol, and acetate) was also observed during growth under controlled conditions of pH and temperature, but mannitol production was low. The reasons for the alteration in the pattern of end products under nongrowing and growing conditions are discussed, and strategies to improve mannitol production during growth are proposed.

Base Sequence↗
PubMed2003

Chromophore-modified bisnaphthalimides: DNA recognition, topoisomerase inhibition, and cytotoxic properties of two mono- and bisfuronaphthalimides.

Bisnaphthalimides represent a promising group of DNA-targeted anticancer agents. In this series, the lead compounds elinafide and bisnafide have reached clinical trials, and the search for more potent analogues remains a priority. In the course of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the naphthalimide skeleton, different dimeric molecules containing two tetracyclic neutral DNA intercalating chromophores were synthesized. The naphthalimide unit has been fused to a benzene ring (azonafide derivatives), an imidazole, a pyrazine, or, as reported here, a furan ring which increases the planar surface of the chromophore and enhances its stacking properties. We report a detailed investigation of the DNA binding capacity of the dimeric molecule MCI3335 composed of two furonaphthalimide units connected by a 12 A long amino alkyl linker [(CH(2))(2)-NH-(CH(2))(3)-NH-(CH(2))(2)] identical to that of elinafide. Qualitative and quantitative binding studies, in particular using surface plasmon resonance, establish that the dimer binds considerably more tightly to DNA (up to 1000 times) than the corresponding monomer and exhibits a higher sequence selectivity for GC-rich sequences. DNase I footprinting experiments attest that the dimer, and to a lesser extent the monomer, preferentially intercalate at GC sites. The strong binding interaction between the drugs and DNA perturbs the relaxation of supercoiled DNA by topoisomerases, but the test compounds do not promote DNA cleavage by topoisomerase I or II. Despite the lack of poisoning effect toward topoisomerase II, MCI3335 displays a very high cytotoxicity toward CEM human leukemia cells, with an IC(50) in the low nanomolar range, approximately 4 times inferior to that of the reference drug elinafide. Confocal microscopy observations indicate that the monomer shows a stronger tendency to accumulate in the cell nuclei than the dimer. The extremely high cytotoxic potential of MCI3335 is attributed to its enhanced capacity to bind to DNA and to inhibit DNA synthesis, as evidenced by flow cytometry experiments using the BrdU assay. The results provide novel mechanistic information that furthers the understanding of the structure-activity relationships in the bisnaphthalimide series and identify MCI3335 as a novel lead compound for further preclinical investigations.

Base Sequence↗
PubMed2003

Synthesis, biological evaluation and DNA binding properties of novel mono and bisnaphthalimides.

A novel series of mono and bisnaphthalimides was synthesized and their antiproliferative activities were evaluated against three tumor cell lines. Bisnaphthalimides 3 and 4, bearing a pyrazine ring fused to the naphthalimide system, showed activities in the order of 10(-8) microM, similar to elinafide. DNA binding properties and the ability to induce DNA damage were studied for some of the most active compounds.

Antineoplastic Agents↗
PubMed2003

Comparison between perimesencephalic nonaneurysmal subarachnoid hemorrhage and subarachnoid hemorrhage caused by posterior circulation aneurysms.

OBJECT: Some authors have questioned the need to perform cerebral angiography in patients presenting with a benign clinical picture and a perimesencephalic pattern of subarachnoid hemorrhage (SAH) on initial computerized tomography (CT) scans, because the low probability of finding an aneurysm does not justify exposing patients to the risks of angiography. It has been stated, however, that ruptured posterior circulation aneurysms may present with a perimesencephalic SAH pattern in up to 10% of cases. The aim of the present study was twofold: to define the frequency of the perimesencephalic SAH pattern in the setting of ruptured posterior fossa aneurysms, and to determine whether this clinical syndrome and pattern of bleeding could be reliably and definitely distinguished from that of aneurysmal SAH. METHODS: Twenty-eight patients with ruptured posterior circulation aneurysms and 44 with nonaneurysmal perimesencephalic SAH were selected from a series of 408 consecutive patients with spontaneous SAH admitted to the authors' institution. The admission unenhanced CT scans were evaluated by a neuroradiologist in a blinded fashion and classified as revealing a perimesencephalic SAH or a nonperimesencephalic pattern of bleeding. Of the 28 patients with posterior circulation aneurysms, five whose grade was I according to the World Federation of Neurosurgical Societies scale were classified as having a perimesencephalic SAH pattern on the initial CT scan. The data show that the likelihood of finding an aneurysm on angiographic studies obtained in a patient with a perimesencephalic SAH pattern is 8.9%. Conversely, ruptured aneurysms of the posterior circulation present with an early perimesencephalic SAH pattern in 16.6% of cases. CONCLUSIONS: This study supports the impression that there is no completely sensitive and specific CT pattern for a nonaneurysmal SAH. In addition, the authors believe that there is no specific clinical syndrome that can differentiate patients who have a perimesencephalic SAH pattern caused by an aneurysm from those without aneurysms. Digital subtraction angiography continues to be the gold standard for the diagnosis of cerebral aneurysms and should be performed even in patients who have the characteristic perimesencephalic SAH pattern on admission CT scans.

Adult↗
PubMed2002

Synthesis, antitumor activity, molecular modeling, and DNA binding properties of a new series of imidazonaphthalimides.

A series of mono and bisintercalators based on the 5,8-dihydrobenz[de]imidazo[4,5-g]isoquinoline-4,6-dione system were synthesized and evaluated for growth inhibitory properties in several human cell lines. All target compounds showed activity in the micromolar range. Representative compounds were evaluated using UV--vis spectroscopy and viscosimetric determinations, showing that they behave as DNA intercalators. Molecular modeling techniques were used in order to rationalize the moderate activity observed for bisnaphthalimides.

Antineoplastic Agents↗