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Biomedical subjects

M Manfredi

Publications and source records attributed to M Manfredi.

At least 37 records · Page 2Linked to original sources
PubMed2003

Abnormalities of motor cortex excitability preceding movement in patients with dystonia.

In patients with dystonia, abnormal movements are commonly triggered or made worse by voluntary action. By means of transcranial magnetic stimulation (TMS), we investigated changes in motor cortex excitability before the execution of wrist voluntary movements in patients with upper limb dystonia and normal control subjects. Magnetic stimulation was delivered by two Magstim 200 stimulators connected through a Bistim module to a figure-of-eight coil placed over the motor area of the forearm extensor muscles. A subthreshold (80% of the rest motor threshold) conditioning stimulus was delivered 3 ms before the suprathreshold (120% of the rest motor threshold) test stimulus and the degree of inhibition of the conditioned motor evoked potentials (MEPs) was taken as an indicator of intracortical inhibition. MEPs were recorded over the forearm extensor muscles of the right arm. To study MEP amplitudes and intracortical inhibition before the onset of wrist extension in the pre-movement condition, TMS pulses were delivered from 0 ms to 100 ms after the go-signal. Besides the pre-movement condition, intracortical inhibition and the unconditioned MEP size were also investigated at rest and during tonic wrist extension. In healthy subjects studied before the wrist movement, the unconditioned MEP amplitude increased progressively and intracortical inhibition decreased significantly. Before movement in dystonic patients, the unconditioned MEP amplitude remained significantly unchanged from resting values and intracortical inhibition decreased less than it did in healthy subjects. In both groups studied during contraction, the unconditioned MEP amplitude increased and intracortical inhibition decreased from values at rest. In conclusion, these findings from reaction time tasks in patients with primary dystonia provide evidence of abnormal pre-movement motor cortex excitability. This abnormality is due to an altered release or running of motor programmes.

Adult↗
PubMed2003

Multiple spinal meningiomas after tamoxifen therapy: a case report.

We describe a rare case of multiple spinal meningiomas and evaluate the possible relationship with tamoxifen treatment. We observed a 74-year-old woman who showed a spastic paraparesis gradually developed in the last year. The patient underwent left mastectomy for a breast cancer ten years earlier and was treated with tamoxifen for four years after surgical intervention. Magnetic resonance imaging revealed three spinal meningiomas at C6-C7, D6-D7 and D9 levels. Taking in account the tumor-inducing properties of tamoxifen and the extreme rarity of multiple spinal meningiomas, we suggest that tamoxifen may be the cause play a role in the genesis of the spinal meningiomatosis in the observed patient. Therefore, we propose the long-term clinical and neurological surveillance of patients who assumed tamoxifen, even for a short time, in order to survey the possible appearance of secondary tumours.

Aged↗
PubMed2003

Effects of transcranial magnetic stimulation on the H reflex and F wave in the hand muscles.

OBJECTIVE: In 14 healthy subjects, we studied the effects of transcranial magnetic stimulation (TMS) on the excitability of spinal motoneurons in the abductor pollicis brevis muscle (ABP), by testing the F wave and H reflex. METHODS: TMS pulses were delivered with the subjects at rest and at various motor threshold (Mth) intensities. Electrical stimuli were delivered to the median nerve at the wrist at two different intensities. High-intensity pulse was used to evoke an F wave and low-intensity paired pulse to evoke an H reflex in the ABP muscle. The effects of TMS were studied using a conditioning-test paradigm. The tests F wave and H reflex were conditioned by TMS (120% Mth) at various interstimulus intervals (ISIs) (30-100ms) and intensities (90-200% Mth). RESULTS: At 30ms but not at ISIs from 40 to 100ms, conditioning TMS (120% Mth) significantly increased the F-wave area. At the 30ms ISI, conditioning TMS at 120% Mth intensity significantly increased the F-wave area whereas higher intensities (140-180% Mth) did not. At 200% Mth intensity, the F-wave area decreased significantly. At 30 and 40ms ISIs, conditioning TMS at 120% Mth significantly reduced the H-reflex area. At 50-100ms ISIs, the H-reflex area almost matched the control value. At the 30ms ISI, conditioning TMS at >or=100% Mth intensity significantly decreased the H-reflex area. CONCLUSIONS: In conclusion, our findings suggest that the distinct changes in the TMS-conditioned F wave and H reflex reflect changing excitability in the motoneuronal populations activated by the cortical input.

Adult↗
PubMed2003

Infiltrating cells and related cytokines in lesional skin of patients with chronic idiopathic urticaria and positive autologous serum skin test.

In approximately one-third of patients with chronic idiopathic urticaria (CIU), autoantibodies against the high-affinity IgE receptor and/ or against IgE can be detected and a wheal-and-flare response can be provoked by the intradermal injection of autologous serum (ASST). In this study we aimed to further characterize the inflammatory response observed in the subgroup of CIU patients with positive ASST and serum-evoked histamine-release in vitro from basophils in comparison with unaffected skin and healthy donors. An immunohistochemical analysis of infiltrating cells (CD4, MPO, EG1, EG2, tryptase), cytokines (IL-4, IL-5, IFN-gamma), chemokines and chemokine receptors (IL-8, CCR3, CXCR3), and adhesion molecules (ICAM-1, VCAM-1, ELAM-1) was performed on seven selected patients (four males and three females; median age: 45 years; range: 22-57) and five healthy donors. Cytokine evaluation was also performed in five psoriatic patients to obtain an additional control. In spontaneous wheals we observed an increased number of CD4+ T lymphocytes when compared with the controls, and an increased number of neutrophils and eosinophils, whereas mast cells did not show a significant variation. A significant expression for IL-4 and IL-5 could only be observed in lesional skin, while IFN-gamma showed a slight expression in the same site. Chemokine receptors CCR3 and CXCR3 did not show a defined polarized response in either lesional or unaffected skin. An increased expression of all cellular adhesion molecules (CAMs) studied was detected in spontaneous wheals. The lack of a significant difference in the expression of tryptase + mast cells, T lymphocytes, IL-8, CXCR3 and CCR3, a few CAMs between the lesional and unaffected skin of CIU patients suggests a wide immunological activation that involves not only lesional tissues, but possibly extends to the whole of the skin's immune system.

Adult↗
PubMed2003

Evidence of a specific spinal pathway for the sense of warmth in humans.

While research on human sensory processing shows that warm input is conveyed from the periphery by specific, unmyelinated primary sensory neurons, its pathways in the central nervous system (CNS) remain unclear. To gain physiological information on the spinal pathways that convey warmth or nociceptive sensations, in 15 healthy subjects, we studied the cerebral evoked responses and reaction times in response to laser stimuli selectively exciting Adelta nociceptors or C warmth receptors at different levels along the spine. To minimize the conduction distance along the primary sensory neuron, we directed CO(2)-laser pulses to the skin overlying the vertebral spinous processes. Using brain source analysis of the evoked responses with high-resolution electroencephalography and a realistic model of the head based on individual magnetic resonance imaging scans, we also studied the cortical areas involved in the cerebral processing of warm and nociceptive inputs. The activation of C warmth receptors evoked cerebral potentials with a main positive component peaking at 470-540 ms, i.e., a latency clearly longer than that of the corresponding wave yielded by Adelta nociceptive input (290-320 ms). Spinal neurons activated by the warm input had a slower conduction velocity (2.5 m/s) than the nociceptive spinal neurons (11.9 m/s). Brain source analysis of the cerebral responses evoked by the Adelta input yielded a very strong fit for one single generator in the mid portion of the cingulate gyrus; the warmth-related responses were best explained by three generators, one within the cingulate and two in the right and left opercular-insular cortices. Our results support the existence of slow-conducting second-order neurons specific for the sense of warmth.

Adult↗
PubMed2003

[Pathogenesis of cyclosporine induced gingival overgrowth].

Several studies, during the last 20 years, tried to explain the pathogenetic mechanisms of the cyclosporine (CS) induced gingival overgrowth (and in general, of the drugs induced gingival overgrowth), but they are still poorly understood. The relationship between the drug and the different pharmacokinetic variables (dosage, duration of therapy, plasmatic and salivary Cs concentration) is still on discussion. It is accepted that a threshold concentration is necessary, in the gingival tissues, to begin or to enhance the morphostructural changes of the gums, but the total Cs weight, from the beginning of the therapy to the time of clinical examinations, has to be evaluated. The pharmacokinetic variables are associated with many other factors (first of all the oral hygiene score) that are probably connected with the developing of the gingival lesions. Gingival inflammation could be very important in the pathogenesis of gingival overgrowth. It has been shown by several cross-sectional studies a strong association between plaque and gingival lesions, but it is not yet clear if plaque accumulation is a causal factor or a consequence of the morphological gums changes. It would seem that the morphological alterations, in drug-induced gingival overgrowth, could be started by the plaque induced inflammation, and this would lead to an hyperemic and edematous gingival tissue. Oral hygiene (professional and at home) is more difficult and represents an irritation factor that makes the pathological cycle to go on. Other factors, probably connected with the cyclosporine induced gingival overgrowth, are represented by age, gender, genetic predisposition, alterations of gingival connective homeostasis and metabolism, inflammatory alterations, interactions with the growth factors and protective or synergic effects of other drugs.

Adolescent↗
PubMed2002

Transcranial magnetic stimulation techniques in clinical investigation.

Transcranial magnetic stimulation (TMS) is a technique that can activate cortical motor areas and the corticospinal tract without causing the subject discomfort. Since TMS was introduced, numerous applications of the technique have been developed for the evaluation of neurologic diseases. Standard TMS applications (central motor conduction time, threshold and amplitude of motor evoked potentials) allow the evaluation of motor conduction in the CNS. Conduction studies provide specific information in neurologic conditions characterized by clinical and subclinical upper motor neuron involvement. In addition, they have proved useful in monitoring motor abnormalities and the recovery of motor function. TMS also gives information on the pathophysiology of the processes underlying the various clinical conditions. More complex TMS applications (paired-pulse stimulation, silent period, ipsilateral silent period, input-output curve, and evaluation of central fatigue) allow investigation into the mechanisms of diseases causing changes in the excitability of cortical motor areas. These techniques are also useful in monitoring the effects of neurotrophic drugs on cortical activity. TMS applications have an important place among the investigative tools to study patients with motor disorders.

Brain↗
PubMed2002

Spread of electrical activity at cortical level after repetitive magnetic stimulation in normal subjects.

In normal subjects, focal repetitive transcranial magnetic stimulation (rTMS) of the hand motor area evokes muscle potentials (MEPs) from muscles in the hand (target muscles) and the arm (non-target muscles). In this study we investigated the mechanisms underlying the spread of MEPs induced by focal rTMS in non-target muscles. rTMS was delivered with a Magstim stimulator and a figure-of-eight coil placed over the first dorsal interosseus (FDI) motor area of the left hemisphere. Trains of 10 stimuli were given at a suprathreshold intensity (120% of motor threshold) and at frequencies of 5, 10 and 20 Hz at rest. Electromyographic (EMG) activity was recorded simultaneously from the FDI (target muscle) and the contralateral biceps muscle and from the FDI muscle ipsilateral to the side of stimulation (non-target muscle). rTMS delivered in trains to the FDI motor area of the left hemisphere elicited MEPs in the contralateral FDI (target muscle) that gradually increased in amplitude over the course of the train. Focal rTMS trains also induced MEPs in the contralateral biceps (non-target muscle) but did so only after the second or third stimulus; like target-muscle MEPs, in non-target muscle MEPs progressively increased in amplitude during the train. At no frequency did rTMS elicit MEPs in the FDI muscle ipsilateral to the site of stimulation. rTMS left the latency of EMG responses in the FDI and biceps muscles unchanged during the trains of stimuli. The latency of biceps MEPs was longer after rTMS than after a single TMS pulse. In conditioning-test experiments designed to investigate the cortical origin of the spread, a single TMS pulse delivered over the left hemisphere at an interstimulus interval (ISI) of 50, 100 and 150 ms reduced the amplitude of the test MEP evoked by a single TMS pulse delivered over the right hemisphere; and a conditioning rTMS train delivered over the left hemisphere increased the amplitude of the test MEP evoked by a single TMS pulse over the right hemisphere. A conditioning rTMS train delivered over the left hemisphere and paired magnetic shocks (test stimulus) at 3 and 13 ms ISIs over the right hemisphere reduced MEP inhibition at the 3-ms ISI but left the MEP facilitation at 13 ms unchanged. Using a control MEP size matched with that observed after a conditioning contralateral rTMS, we found that paired-pulse inhibition remained unchanged. Yet a single TMS conditioning pulse sufficiently strong to evoke a MEP in the contralateral FDI and biceps muscles simultaneously (as rTMS did) left paired-pulse inhibition unchanged. We conclude that the spread of EMG activity to non-target muscles depends on cortical mechanisms, mainly including changes in the excitability of the interneurones mediating intracortical inhibition.

Adult↗
PubMed2002

fMRI/EEG in paroxysmal activity elicited by elimination of central vision and fixation.

Using functional MRI (fMRI) with concurrent EEG monitoring the authors studied cortical activation associated with epileptiform discharges in three patients with fixation-off sensitivity. The EEG paroxysmal activity elicited by eliminating central vision correlated significantly with an increased blood oxygen level-dependent signal in the extrastriate cortex (Brodmann areas 19 and 37). fMRI provides a unique opportunity for localizing precisely the cortical areas generating paroxysmal activity in patients with fixation-off sensitivity.

Adult↗
PubMed2002

Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: implications for the pathophysiology of cortical function.

We investigated the neurophysiological and clinical effects of repetitive magnetic stimulation (rTMS) delivered to the cortical motor areas in healthy subjects and patients with Parkinson's disease. rTMS was delivered with a high speed magnetic stimulator (Cadwell, Kennewick, WA) through a figure-eight coil centred on the primary motor area at a stimulus intensity of 120% motor threshold. Trains of 10 stimuli were delivered at frequencies of 5 Hz while subjects were at rest and during a voluntary contraction of the contralateral first dorsal interosseous muscle. In normal subjects at rest, the muscle evoked responses (MEPs) to each stimulus in a train of magnetic stimuli progressively increased in size during the train. rTMS left the MEPs unchanged in patients off therapy and had a small facilitatory effect in those on therapy. In normal subjects and patients, 5-Hz rTMS trains delivered during a voluntary contraction of the target muscle left the MEP unchanged in size. MEPs were followed by a silent period that increased in duration during the course of the train. The silent period duration increased to a similar extent in patients and controls. The reduced rTMS-induced facilitation of MEPs in patients with Parkinson's disease reflects a decreased facilitation of the excitatory cells in the cortical motor areas.

Aged↗
PubMed2002

Bilateral spike-and-wave discharges in a hemi-deafferented cortex.

We studied a patient with a history of absence attacks in childhood in whom an absence status with bilateral spike-and-wave discharges developed after a top-of-the-basilar syndrome. Surprisingly, even though the ischemic lesion involved the left thalamus alone, spike-and-wave discharges were recorded from the two hemispheres. Three days after antiepileptic treatment (sodium valproate 500mg 3 times a day) began, electroenceplalographic recordings and consciousness became normal.

Action Potentials↗
PubMed2002

Molecular characterization of Candida spp. isolated from the oral cavities of patients from diverse clinical settings.

Infections by Candida spp. have increased in medical importance over the past few decades. Our understanding of species identification, commensalisms, pathogenicity, person-to-person spread, and the development of antifungal resistance within specific strains has been greatly enhanced by the utilization of molecular epidemiological methodology. The aim of the current research was to assess the quantity, species and molecular characterization of oral yeast isolates from well-defined cohorts of immunocompetent patients from a diverse range of clinical settings. Oral rinse samples were assessed for the growth of yeast and degree of colonization. Isolates were defined to the species level by both phenotypic and molecular methods and strains were further genotypically subtyped. Significant variation was shown to exist in the number, species and genotypic subgroups of yeast isolated from the oral cavity in different patient groups. This variation could be attributed to the local oral conditions unique to these patient groups.

Adult↗
PubMed2002

Nociceptive quality of the laser-evoked blink reflex in humans.

Laser radiant-heat pulses selectively excite the free nerve endings in the superficial layers of the skin and activate mechano-thermal nociceptive afferents; when directed to the perioral or supraorbital skin, high-intensity laser pulses evoke a blink-like response in the orbicularis oculi muscle (the laser blink reflex, LBR). We investigated the functional properties (startle or nociceptive origin) of the LBR and sought to characterize its central pathways. Using high-intensity CO(2)-laser stimulation of the perioral or supraorbital regions and electromyographic (EMG) recordings from the orbicularis oculi muscles, we did five experiments in 20 healthy volunteers. First, to investigate whether the LBR is a startle response, we studied its habituation to expected rhythmic stimuli and to unexpected arrhythmic stimuli. To assess its possible nociceptive quality, we studied changes in the LBR and the R2 component of the electrical blink reflex after a lidocaine-induced supraorbital nerve block and after intramuscular injection of the opiate fentanyl and the opiate-antagonist naloxone. To characterize the central pathways for the LBR, we investigated the interaction between the LBR and the three components of the blink reflex (R1, R2, and R3) by delivering laser pulses to the perioral or supraorbital regions before or after electrical stimulation of the supraorbital nerve at various interstimulus intervals. Finally, to gain further information on the central LBR pathways, using two identical CO(2)-laser stimulators, we studied the LBR recovery curves with paired laser pulses delivered to adjacent forehead points at interstimulus intervals from 250 ms to 1.5 s. The LBR withstood relatively high-frequency rhythmic stimulations, and unexpected laser pulses failed to evoke larger responses. When lidocaine began to induce hypoalgesia (about 5 min after the injection), the LBR was abolished, whereas R2 was only partly suppressed 10 min after the injection. Fentanyl injection induced strong, naloxone-reversible, LBR suppression (the response decreased to 25.3% of predrug values at 10 min and to 4% at 20 min), whereas R2 remained appreciably unchanged. Whether directed to the perioral or supraorbital regions, preceding laser pulses strongly suppressed R2 and R3 though not R1. Conversely, preceding electrical stimuli to the supraorbital nerve suppressed the LBR. In response to paired stimuli, the LBR recovered significantly faster than R2. These findings indicate that the LBR is a nociceptive reflex, which shares part of the interneuron chain mediating the nonnociceptive R2 blink reflex, probably in the medullary reticular formation. The LBR may prove useful for studying the pathophysiology of orofacial pain syndromes.

Adult↗
PubMed2001

Small-fiber dysfunction in trigeminal neuralgia: carbamazepine effect on laser-evoked potentials.

BACKGROUND: In patients with trigeminal neuralgia, results of clinical examination of sensory function are normal. Reflex and evoked potential studies have already provided information on large-afferent (non-nociceptive) function. Using laser-evoked potentials (LEP), the authors sought information on small-afferent (nociceptive) function. METHODS: The brain potentials evoked by CO(2)-laser pulses directed to the perioral and supraorbital regions were studied in 67 patients with idiopathic or symptomatic trigeminal neuralgia and 30 normal subjects. Of the 67 patients, 49 were receiving carbamazepine. RESULTS: All patients with symptomatic and 51% of those with idiopathic trigeminal neuralgia had frankly abnormal LEP on the painful side. The mean latency was significantly higher and mean amplitude lower on the painful than the nonpainful side. However, even on the nonpainful side, the mean latency was significantly longer than that of the age-matched controls. The nonpainful-side latency correlated significantly with the carbamazepine dose. CONCLUSIONS: LEP detect severe impairment of the nociceptive afferent system on the painful side of patients with idiopathic as well as symptomatic trigeminal neuralgia. A dysfunction of small-myelinated afferents may play an important role in the pathophysiology of neuralgic pain. Carbamazepine markedly dampens these brain potentials. The authors propose that this effect may result from inhibition of nociceptive transmission in the cingulate gyrus.

Afferent Pathways↗
PubMed2001

Extracellular matrix-derived peptide binds to alpha(v)beta(3) integrin and inhibits angiogenesis.

Angiogenesis is associated with several pathological disorders as well as with normal physiological maintenance. Components of vascular basement membrane are speculated to regulate angiogenesis in both positive and negative manner. Recently, we reported that tumstatin (the NC1 domain of alpha 3 chain of type IV collagen) and its deletion mutant tum-5 possess anti-angiogenic activity. In the present study, we confirm that the anti-angiogenic activity of tumstatin and tum-5 is independent of disulfide bond requirement. This property of tum-5 allowed us to use overlapping synthetic peptide strategy to identify peptide sequence(s) which possess anti-angiogenic activity. Among these peptides, only the T3 peptide (69-88 amino acids) and T7 peptide (74-98 amino acids) inhibited proliferation and induced apoptosis specifically in endothelial cells. The peptides, similar to tumstatin and the tum-5 domain, bind and function via alpha(v)beta(3) in an RGD-independent manner. Restoration of a disulfide bond between two cysteines within the peptide did not alter the anti-angiogenic activity. Additionally, these studies show that tumstatin peptides can inhibit proliferation of endothelial cells in the presence of vitronectin, fibronectin, and collagen I. Anti-angiogenic effect of the peptides was further confirmed in vivo using a Matrigel plug assay in C57BL/6 mice. Collectively, these experiments suggest that the anti-angiogenic activity of tumstatin is localized to a 25-amino acid region of tumstatin and it is independent of disulfide bond linkage. Structural features and potency of the tumstatin peptide make it highly feasible as a potential anti-cancer drug.

Alkylation↗
PubMed2001

Identification of the anti-angiogenic site within vascular basement membrane-derived tumstatin.

Components of vascular basement membrane are involved in regulating angiogenesis. Recently, tumstatin (the NC1 domain of alpha3 chain of type IV collagen) was identified as possessing anti-angiogenic activity. In the present study, the anti-angiogenic activity of tumstatin was localized to the putative 54-132-amino acid Tum-5 domain, and the activity mediated by alpha(v)beta(3) integrin interaction in an RGD-independent manner. The recombinant Tum-5 produced in Escherichia coli and Pichia Pastoris specifically inhibited proliferation and caused apoptosis of endothelial cells with no significant effect on nonendothelial cells. Tum-5 also inhibited tube formation of endothelial cells on Matrigel and induced G1 endothelial cell cycle arrest. Moreover, anti-angiogenic effect of Tum-5 was also examined in vivo using both a Matrigel plug assay in C57BL/6 mice and human prostate cancer (PC-3) xenografts in nude mice. The in vivo results demonstrate that Tum-5 at 1 mg/kg significantly inhibited growth of PC-3 tumors in association with a decrease in CD31 positive vasculature. These in vivo studies also show that, at molar equivalents, human Tum-5 is at least 10-fold more active than human endostatin. In addition, these studies for the first time suggest that through the action of endogenous inhibitors, alpha(v)beta(3) integrin may also function as a negative regulator of angiogenesis. Taken together, these findings demonstrate that Tum-5, a domain derived from tumstatin, is an effective inhibitor of tumor-associated angiogenesis and a promising candidate for the treatment of cancer.

Angiogenesis Inhibitors↗