Biomedical subjects

N Perez

Publications and source records attributed to N Perez.

At least 19 recordsLinked to original sources

PubMed2006

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies.

Muscular dystrophies are a genetically and phenotypically heterogeneous group of degenerative muscle diseases. A subset of them are due to genetic deficiencies in proteins which form the dystrophin-associated complex at the membrane of the myofibers. In this report, we utilized recombinant adeno-associated virus containing a U7 cassette carrying an antisense sequence aimed at inducing exon skipping of the dystrophin gene or containing the alpha-sarcoglycan gene to alleviate the dystrophic phenotype of the mdx and Sgca-null mice, respectively. As these diseases are characterized by cycle of degeneration/regeneration, we postulated that a reporter gene coadministered at the time of the treatment would make it possible to follow the extent of muscle repair. We observed that the murine secreted alkaline phosphatase (muSeAP) level was very much lower in these animal models than in normal mice. Upon treatment of the dystrophic muscle by gene transfer, the level of muSeAP was restored and correlated with the expression of the therapeutic transgene and with the level of muscle improvement. The system described here provides a simple and noninvasive procedure for monitoring the outcome of a therapeutic strategy involving cell survival.

Alkaline Phosphatase↗

PubMed2005

Adeno-associated virus pseudotype 5 vector improves gene transfer in arthritic joints.

The potential for gene delivery to joints, using recombinant adeno-associated virus (rAAV) vectors for the treatment of rheumatoid arthritis (RA), has received much attention. Different serotypes have different virion shell proteins and, as a consequence, vary in their tropism for diverse tissues. The aim of this study was to compare the transduction efficiency of different AAV serotypes encoding murine secreted alkaline phosphatase (mSEAP) or Escherichia coli beta-galactosidase for intraarticular gene delivery in an experimental model of arthritis. The vectors contained AAV2 terminal repeats flanking the reporter gene in an AAV1, AAV2, or AAV5 capsid, producing the pseudotypes rAAV-2/1, rAAV-2/2, and rAAV-2/5. Left knee joints of mice with collagen-induced arthritis were injected and transgene expression was analyzed by chemiluminescence or direct in situ staining of frozen sections. We show for the first time that intraarticular gene transfer with AAV- 2/5 was far more efficient than with the other serotypes tested. Transgene expression was detectable as early as 7 days after injection, reached a maximum at 21 days, and was stably expressed for at least 130 days, whereas AAV-2/1- and AAV-2/2-mediated expression levels were barely detectable. These findings provide a practical application for future local AAV-mediated gene therapy trials in RA.

Alkaline Phosphatase↗

PubMed2005

A report of two cases of unilateral vestibulopathie after systemic ototoxic treatment.

PURPOSE OF THE STUDY: To present the cases of two patients that developed unilateral vestibular hypofunction after systemic treatment with ototoxic agents, although they manifested symptoms more typical of bilateral vestibular hypofunction. MATERIAL AND METHODS: The patients were seen after having recovered from their initial illnesses, and both of them denied suffering any spells of vertigo, loss of hearing during the treatment or tinnitus. RESULTS: In both patients, oscillopsia and vestibular ataxia were of varying intensity. Bedside vestibular examination, caloric and rotatory chair testing, and vestibular evoked myogenic potentials were congruent with a complete unilateral loss of vestibular function. Audiometry was normal in one case whereas in the other, there was a moderate bilateral sensorineural loss of hearing that was present before treatment and that did not change during the course of the treatment. CONCLUSION: The existence of unilateral vestibular loss was an unsuspected finding but after careful bedside examination, it was confirmed through extensive vestibular testing. However, this infrequent finding responded very well to vestibular rehabilitation. Different mechanisms are proposed to explain this phenomenon, although there is still no clear evidence of which may account for the responses observed.

Adult↗

PubMed2005

The subjective visual vertical in benign paroxysmal positional vertigo. A preliminary study.

In Benign Paroxysmal Positional Vertigo (BPPV), the existence of otoconial debris in the cupula or canal explains most of the symptoms and signs characteristic of this common inner ear disorder. We have studied the ability of patients with BPPV to correctly determine the subjective visual vertical, as this is a good test to evaluate utricular function. Only 1 of 10 patients with BPPV displayed a clearly abnormal response, and there was no correlation between the side of the lesion and the perceived tilt. This might imply that the limited damage induced by the dislodged otoconia does not disrupt utricular function or that the saccule is the source of the problem.

Adult↗

PubMed2004

HLA-A*0201-restricted cytolytic responses to the rtTA transactivator dominant and cryptic epitopes compromise transgene expression induced by the tetracycline on system.

The tetracycline-controlled transcription system (Tet-on) is widely used to regulate gene expression in mammalian cells. In gene therapy applications, immune responses to Tet-on proteins such as the rtTA transcription factor have been reported, raising concerns about their occurrence in humans. To monitor the HLA class I cytolytic responses against Tet-on regulators, we characterized the immunogenic CD8+ epitopes within rtTA and tTS regulators using HLA-A*0201 class I transgenic mice. Epitope prediction programs, HLA-A*0201 binding assays, and peptide immunization were used to select a set of immunogenic peptides within rtTA and tTS sequences. To identify further the rejection epitopes, we expressed Tet-on protein components in vivo and found a single dominant rtTA186 CTL epitope in the rtTA tetracycline repressor domain. Target cells expressing rtTA were susceptible to CTL lysis, and rtTA expression compromised muscle transgene engraftment. To reduce the occurrence of immune responses to rtTA protein, we mutated the dominant rtTA186 epitope and found that this leads to the appearance of subdominant epitopes. As a result, we think that an epitope modification strategy is not applicable to blunt the immune response in this model. Moreover, the identification of HLA-A*0201 rtTA epitopes allowed us to demonstrate here that the delivery of the Tet-on system with weakly immunogenic rAAV vectors does not trigger primary CTL responses in mice, in contrast to DNA transfer. Altogether, the existence of HLA-A*0201 rtTA epitopes may lead to the occurrence of immune responses depending on vectors and local inflammation in gene therapy applications involving rtTA-based regulatory systems.

Alkaline Phosphatase↗

PubMed2004

[Long term survival in metastatic colorectal cancer treated with leucovorin and 5-fluoro-uracil chemotherapy].

PURPOSE: Median survival in advanced colorectal cancer patients treated with 5-fluoro-uracil (5FU) and leucovorin (LV) is between 12 and 18 months. The aim of this study was to evaluate long term survival in this disease. METHODS: We report here, retrospectively, the survival of 445 patients who entered in first-line prospective studies with LV-5FU-based regimen chemotherapy, between 1985 and 1995. RESULTS: Median survival was 18 months. The 3, 5 and 10 year survival were respectively 17.9%, 4.5% and 2.4%. Seventy-five patients survived more than 3 years, among them, 10 achieved a complete and 34 a partial response, 12 had curative liver or lung surgery. Fifteen patients lived more than 5 years, 2 achieved a complete and 7 a partial response. Seven had curative surgery. Eleven patients were still alive in 2002, among them 7 in complete remission at 5 years, including 3 who did not have surgery. CONCLUSION: This study shows that some patients with metastatic colorectal cancer can achieve long survival, especially when secondary curative surgery can be performed. However, 1% of the patients can be cured with LV-5FU chemotherapy alone. These results will be probably improve with the use of the new drugs: oxaliplatin and irinotecan.

Aged↗

PubMed2004

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment.

The suppression levels induced by gentamicin on premature stop codons, caused by primary nonsense mutations found in muscular dystrophy patients, were assessed using a very sensitive dual reporter gene assay. Results show that: (i) the effect of gentamicin on readthrough is similar in cultured cells and in vivo in murine skeletal muscle; (ii) a wide variability of readthrough efficiency is obtained, depending on the mutation tested; (iii) due to the complexity of readthrough regulation, efficiency cannot be predicted by the nucleotide context of the stop codon; (iv) only a minority of premature stop codons found in patients show a significant level of readthrough, and would thus be amenable to this pharmacological treatment, given our present understanding of the problem. These results probably provide an explanation for the relative failure of clinical trials reported to date using gentamicin to treat diseases due to premature stop codons, and emphasize that preliminary assays in cell culture provide valuable information concerning the potential efficiency of pharmacological treatments.

3T3 Cells↗

PubMed2003

Vibration induced nystagmus in normal subjects and in patients with dizziness. A videonystagmography study.

OBJECTIVE: To analyze the incidence and characteristics of vibration-induced nystagmus in normal subjects and in patients with vertigo. STUDY DESIGN AND SETTING: This is a prospective analysis of the effect of vibration on several points of the skull in 38 normal subjects, 10 patients who had undergone labyrinthectomy and 125 consecutive patients with dizziness referred to a tertiary care center. Nystagmus was documented and its corresponding slow phase velocity measured with a videonystagmography system. RESULTS: In 81.6% of normal subjects and 80.8% of all patients, nystagmus could be provoked by stimulation of at least one of the points on the skull to which the vibrator was applied. In normals, however, no subject had nystagmus greater than 2.8 degrees s-1 whereas 35.2% of patients did. CONCLUSION/SIGNIFICANCE: The value of the slow-phase velocity of vibration-induced nystagmus can be used to identify a sizeable proportion of patients with a vestibular disorders. Vibration-induced nystagmus is a frequent sign in patients with dizziness and can provide complimentary information about vestibular system function.

Adult↗

PubMed2002

Mismatch negativity to single and multiple pitch-deviant tones in regular and pseudo-random complex tone sequences.

OBJECTIVES: To determine whether the process responsible for the mismatch negativity (MMN) might be involved in the analysis of temporal sound patterns for information. METHODS: Synthesized musical instrument tones of 'clarinet' timbre were delivered in a continuous sequence at 16 tones/s, such that there was virtually no N1 potential to each individual tone. The standard sequence comprised 4 or 5 adjacent notes of the diatonic scale, presented either as a regularly repeated, rising pattern or pseudo-randomly. The deviant stimuli were 1-5 consecutive tones of higher pitch than the standards. RESULTS: A MMN was evoked by a single deviant tone, 1 or 5 semitones above the pitch range of the standards. The response to the 5-semitone deviant was significantly larger (mean of 7.3 microV) when the standard pattern was regular as compared with pseudo-random. The MMN latency, on the other hand, was only influenced by the magnitude of pitch deviation. A second MMN was evoked by a second deviant tone, immediately (SOA 62.5 ms) following the first. Further consecutive MMNs were not consistently evoked. CONCLUSIONS: The large amplitude of these MMNs can be attributed to the use of complex tones, continuous presentation and a rapid rate of pitch changes, such that no waveform subtraction was required. Over and above the probability with which each individual tone occurs in the standard sequence, the mismatch process is influenced by its temporal structure, i.e. can be regarded as a temporal pattern analyzer. Contrary to the findings of some other groups, we found that two consecutive deviants can evoke an MMN, even at high rates of presentation such that both occur within the postulated 'temporal window of integration' of ca. 170 ms. These findings suggest that the mismatch process might be involved in the extraction of sequential information from repetitive and non-repetitive sound patterns.

Acoustic Stimulation↗

PubMed2002

The auditory C-process of spectral profile analysis.

OBJECTIVES: We here review the findings of several experiments, aimed at clarifying the functional role of the human auditory cortex in the processing of complex sound mixtures. METHODS: Long-latency auditory evoked potentials were recorded to abrupt changes in the pitch or timbre of continuous complex tones (synthesized musical instrument sounds). Changes were made at intervals of 0.5-4.5 s while the subjects read a magazine. RESULTS: The main response was a P1/N1/P2 complex which was maximal at the vertex and symmetrically distributed, consistent with origin in the supratemporal cortices of both hemispheres. To distinguish them from the conventional responses to brief pure tones, the potentials were named CP1 (c. 55 ms), CN1 (90 ms) and CP2 (165 ms). Responses to changes of pitch, where all the spectral components changed frequency, and to changes of timbre, where the frequencies remained the same but their energy levels changed, were very similar to one another. The response amplitudes were little affected by the magnitude of frequency changes in the range 6-100%, but were strongly influenced by the rate at which changes occurred (requiring at least 4 s for full recovery) and by the breadth of the changing frequency spectrum (the upper partials of the tone in sum contributing more than the fundamental). When the C-potentials were made refractory by a high rate of pitch changes (16/s) within a narrow frequency range, responses could still be elicited by infrequently interspersed changes of timbre. When the tones were split into their high and low partials, the responses to change in the two frequency bands combined roughly algebraically. CONCLUSIONS: The responses appear to represent a cortical process concerned with analysing the distribution of sound energy across the frequency spectrum ('spectral profile analysis'). This may be an important stage in the analysis of complex sound mixtures and in the perception of sound quality.

Adult↗

PubMed2001

Can laparoscopy reduce hospital stay in the treatment of Crohn's disease?

PURPOSE: The aim of this article was to investigate the safety, outcome, length of stay, and cost of hospital admission in patients with Crohn's disease who underwent laparoscopy compared with open surgery. METHODS: Among 51 consecutive patients with inflammatory bowel disease (1996-2000), 46 with Crohn's disease were included in this nonrandomized prospective study. Of these, 20 patients underwent laparoscopic surgery and 26 underwent open surgery. Data collected included the following information: age, gender, body mass index, diagnosis, duration of disease, preoperative medical treatment, previous abdominal surgery, present indication for surgery, and procedure performed (comparability measures), as well as conversion to open surgery, operating time, time to resolution of ileus, morbidity, duration of hospital stay, and cost of hospital admission (outcome measures). RESULTS: There was no significant difference with respect to comparability measures between the laparoscopic and the open-surgery groups. There was no mortality. There was no intraoperative complication in either group and no conversion in the laparoscopic group. Operating time was significantly longer in the laparoscopic group (302 minutes) vs. the open group (244.7 minutes) (P < 0.05), but this difference disappeared when data were adjusted for the extra time required to perform the laparoscopic hand-sewn anastomoses (288.2 minutes vs. 244.7 minutes). Bowel function returned more quickly in the laparoscopic group vs. the open group in terms of passage of flatus (3.7 vs. 4.7 days) (P < 0.05) and resumption of oral intake (4.2 vs. 6.3 day) (P < 0.01). There were significantly fewer postoperative complications in the laparoscopic group (9.5 percent) vs. the open group (18.5 percent) (P < 0.05); the length of stay was significantly shorter in the laparoscopic group (8.3 days) vs. the open group (13.2 days) (P < 0.01); and the cost of hospital admission was significantly lower in the laparoscopic group ($6106, United States dollars) vs. the open group ($9829, United States dollars) (P < 0.05). CONCLUSION: There is a reduction in the postoperative ileus, length of stay, cost of hospital admission, and postoperative complication rate in the laparoscopic group. Laparoscopic surgery for Crohn's disease is safe, and it is potentially more cost-effective than traditional open surgery.

Adult↗

PubMed2001

The auditory 'C-process': analyzing the spectral envelope of complex sounds.

OBJECTIVE: To examine the hypothesis that auditory evoked potentials (AEPs) to pitch and timbre change of complex harmonic tones reflect a process of spectral envelope analysis. METHODS: AEPs were recorded to: (1) continuous tones of 'clarinet' timbre whose pitch abruptly rose or fell by 1 or 7 semitones every 0.5 or 1.5 s; (2) a cycle of 6 pitches changing every 0.5 s; (3) tones of constant pitch whose timbre (spectral envelope shape) changed periodically; (4) pitch change of high- and low-pass filtered 'clarinet' tones. RESULTS: The amplitudes of the 'change-N1' (CN1) potential peaking at ca. 90 ms and the following CP2 were influenced to a far greater degree by the time interval between changes, than by the magnitude of the change or by the time interval between occurrences of the same pitch. Amplitudes were also strongly dependent on the number of partials present, irrespective of whether they were increasing or decreasing in energy. The algebraic sum of the responses to pitch change of high- and low-pass filtered tones closely approximated the response to the unfiltered tone. CONCLUSION: The rate-sensitivity of the responses cannot be explained by the refractoriness of frequency-specific 'feature detector' neurones, but rather of a process (termed 'C-process') which analyzes amplitude modulations across the spectral envelope, the contribution of different frequency bands combining linearly in the scalp-recorded activity. On-going computation of the spectral envelope shape may be an important factor in maintaining the perceptual constancy of timbre.

Adult↗

PubMed2001

Influence of canal paresis and compensation on gain and time constant of nystagmus slow-phase velocity to yaw-axis rotation.

In order to assess the influence of canal paresis and compensation on the yaw-axis rotatory chair test parameters gain and time constant, a study was conducted in 435 patients diagnosed with unilateral peripheral vestibulopathy. Patients were grouped according to the amount of canal paresis found in the caloric test and by the result of a bedside examination of the vestibulo-ocular reflex (VOR). The time constant of the VOR diminishes as canal paresis increases and, when using a high-velocity sinusoidal test, there is a similar reduction in gain. Mean time constant was reduced when rotations were to the side of the lesion (ipsilesional) and to the normal (contralesional) and differences between both rotations were found for 21-80%, canal paresis. Ipsilesional gain was significantly less than contralesional gain, which had a normal result independent of the amount of canal paresis; differences between them were significant when canal paresis was > 41%. Spontaneous nystagmus significantly influenced the appearance of asymmetries in gain and time constant in the tests performed while, with high-velocity sinusoidal rotation, gain was found to be significantly different for ipsilesional and contralesional rotations in non-acute symptomatic patients.

Adolescent↗

PubMed2001

Factor analysis and correlation between Dizziness Handicap Inventory and Dizziness Characteristics and Impact on Quality of Life scales.

In order to assess the different dimensions of disability and handicap analyzed in the Dizziness Handicap Inventory (DHI) and Dizziness Characteristics and Impact on Quality of Life (UCLA-DQ) questionnaires a factor analysis study was done. The instruments used were the corresponding transculturally adapted versions of the originals into Spanish. The study included 337 patients with dizziness, independent of location and etiology, who were able to respond to all the items in the questionnaires given before vestibular testing. Factor analysis was used to determine the structure of both scales; a principal components analysis with orthogonal rotation (Varimax) was conducted on data collected from the patients. A three-factor solution was obtained in the DHI and a two-factor solution for the UCLA-DQ. The factors obtained from the DHI were related to vestibular handicap, vestibular disability and visuo-vestibular disability; the factors from the UCLA-DQ were related to frequency and severity of dizziness. There was no coincidence between the items in each of the factor obtained in the DHI questionnaire and the items in the subscales provided in the original version. The main relation between factors was found between vestibular handicap and frequency. The DHI and UCLA-DQ questionnaires are multidimensional questionnaires for the assessment of the impact of dizziness and provide a model for vestibular disability and handicap.

Adolescent↗

PubMed2001

Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture.

PURPOSE: To report the demographics and clinical features of a large series of patients with orbital metastasis. METHODS: Retrospective chart review on 100 consecutive patients and a literature review on orbital metastasis. RESULTS: Of 100 patients, the primary tumor site was breast in 53 (53%), prostate gland in 12 (12%), lung in 8 (8%), skin (melanoma) in 6 (6%), kidney in 5 (5%), gastrointestinal tract in 5 (5%), choroid (melanoma) in 2 (2%), parotid gland in 1 (1%), and adrenal gland (neuroblastoma) in 1 (1%). Of patients in whom a detailed history was available, there was no history of cancer at the time of presentation in 19%. In 10%, the primary tumor remained undetected despite systemic evaluation. There were 36 male patients and 64 female patients whose mean age at diagnosis was 62 years (median 60 years, range 5 to 91 years). Both the right and left orbits were affected equally, and 4 cases (4%) were bilateral. The most frequent clinical findings were limited ocular motility (54%), proptosis (50%), and palpable mass (43%). The diagnoses were established by history, systemic survey, imaging studies, and biopsy. Treatment included chemotherapy, hormone therapy, irradiation, surgical excision, or observation, depending on clinical circumstances. Among patients with sufficient follow-up, 95% died of metastasis, with overall mean survival of 15 months (median 15 months; range 3 to 96 months) after orbital diagnosis. CONCLUSIONS: The most common primary cancers that metastasize to the orbit are breast, prostate gland, and lung cancer. In 19%, there is no history of cancer when the patient presents with ophthalmic symptoms and in 10% the primary site remains obscure despite systemic evaluation. The systemic prognosis is generally poor.

Adolescent↗

PubMed2001

[Medullary extradural hematoma revealing a coarctation of the aorta].

The authors report a spontaneous, unusual complication of coarctation of the aorta. An 11 year old child was admitted for investigation of chest pain. Cardiovascular examination revealed typical clinical signs of coarctation of the aorta. Neurological examination found neck stiffness without headache or deficit. The presumptive diagnosis of dissection of the aorta was infirmed by echocardiography and MRI. The latter investigation, with views of the spinal cord, revealed a compressive medullary extradural haematoma. Antihypertensive therapy and corticosteroids with strict bed rest resulted in complete regression of the haematoma and the coarctation was operated 6 months later. Medullary complications of coarctation of the aorta are usually postoperative. Spontaneous complications are exceedingly rare but very serious: medullary compression by the dilated anterior spinal artery or rupture of an aneurysmal collateral vessel. In this case, magnetic resonance imaging led to diagnosis and effective early treatment of this complication before the patient developed a neurological deficit and the coarctation was treated surgically thereafter.

Aortic Coarctation↗

PubMed2000

A functional assay in Escherichia coli to detect non-assisted interaction between galactose repressor dimers.

Among the Escherichia coli operons repressed from multiple sites on DNA, the galactose operon is unique: its repression requires an auxiliary protein, HU, to assist cooperative repressor binding to two distant DNA sites. Here we show that GalR can still mediate repression from distant sites in an artificial and simplified regulatory region which totally disturbs the organisation of the natural interactions. This simple and unexpected cooperation of a protein incapable of self-association in solution might be involved in regulation of the gal operon. Furthermore, the assay may be generalised to detection of rather weak cooperative interactions between DNA-bound proteins.

Bacterial Proteins↗

PubMed2000

Functional MRI in double cortex: functionality of heterotopia.

A 12-year-old boy with epilepsy and subcortical laminar heterotopia (band heterotopia) underwent a functional MRI protocol to study voluntary motor activity in the hand. Finger tapping produced an activation of a contralateral limited and focused frontal cortical area both in the subcortical band heterotopia and the overlying cortex. Despite its epileptogenic activity, subcortical laminar heterotopia seems to be responsible for part of the functional activity of the brain. This has to be pointed out for epilepsy surgery resecting cortical dysplasia.

Action Potentials↗