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Biomedical subjects

R Martini

Publications and source records attributed to R Martini.

At least 19 recordsLinked to original sources
PubMed2002

Impaired sensory function in heterozygous P0 knockout mice is associated with nodal changes in sensory nerves.

Mice heterozygously deficient in the major myelin component P0 are an established model of an inherited neuropathy and show signs of myelin degeneration in motor nerves. Unlike the case in patients, the sensory nerves are only mildly affected in the mouse mutants and do not show features indicative of myelin degeneration. Unexpectedly, by applying established behavioral tests, we found sensory deficits, as reflected by raised withdrawal thresholds to mechanical and thermal stimuli, whereas behavioral signs of a painful neuropathy were not detectable. By electron microscopy of longitudinal sections of sensory nerves, we found abnormalities in nodes of Ranvier comprising enlarged nodal gaps and poorly developed nodal Schwann cell microvilli. These alterations might be causally linked to the sensory deficits in the absence of profound myelin degeneration in the sensory nerves of the mutants.

Animals↗
PubMed2002

[Evaluation of cutaneous necrosis risk in peripheral arterial diseases].

BACKGROUND: In the last years the surgical and pharmacological treatment of critical limb ischaemia has been significantly modified, increasing the reduction of amputation and/or the increase of limbs recovery. However, neither survival nor incidence of amputations changed. This, probably has been related to an inadequate therapy after revascularization procedures or to an increase of complications. The assessment of cutaneous necrosis risk and of the recovery possibility of the ischemic limb can positively influence the therapeutic strategy, in these patients. The aim of this paper is to identify the reference parameters that can represent objectively the limit for cutaneous ischemic suffering, improving the physiological knowledges of critical limb ischemia. METHODS: In the first phase of our study 56 patients, in different stages of peripheral arterial disease have been, submitted to microcirculatory assessment measuring the pattern of TcPO2 and TcPCO2 in correlation with walking performance expressed as ACD at treadmill test (2.5 Km/h gradient 12.5%). The second phase assesses the clinical outcome after three months of 12 among 19 patients with critical limb ischemia, measuring the changes of TcPO2 and TcPCO2 with postural test and after infusion with prostanoids of two weeks. RESULTS: A reduction of the TcPO2 and an increase of the acidosis from stable to invalidant claudication have been observed, with a progressive loss of direct correlation between ACD and TcPO2, and an increase of the inverse correlation of the ACD with TcPCO2. In the CLI we found a very low TcPO2 levels with a TcPCO2 levels ( about 120 mmHg) with no correlation of ACD with TcPO2 and TcPCO2. The good clinical outcome was related to an increase of the TcPO2 and to a reduction of the TcPCO2 after postural stimulation and after therapy. In the patients with a bad response to the postural test, a possibility of recovery was observed only in those with a positive answer to therapeutic treatment. CONCLUSIONS: The invalidant claudication phase can be considered a point of physiopathological change from relative to absolute ischemia that is clinically equivalent to early sign of ischemia. The identification of recoverable patients seems to be related to postural test and pharmacological treatment with an increased values. Viceversa, it is still difficult to identify as non-responders, those patients with a bad postural test, or with a little improvement after pharmacological treatment, as those with an indication to primary amputation. More observations, evaluation data will contribute to a better definition of a negative trend.

Acute Disease↗
PubMed2001

Caspr1/Paranodin/Neurexin IV is most likely not a common disease-causing gene for inherited peripheral neuropathies.

Contactin associated protein 1 (Caspr1/Paranodin/Neurexin IV) is an axonal transmembrane molecule mainly localised at the paranodal junction. Since molecular alterations in septate-like junctions at the paranodes might have important consequences for the function of the nerve fiber, we considered that Caspr1 could be involved in the pathogenesis of inherited peripheral neuropathies. In this study, we physically mapped the Caspr1 gene on chromosome 17q21.1 and determined its genomic structure. We performed a mutation analysis of the Caspr1 gene in a cohort of 64 unrelated patients afflicted with distinct inherited peripheral neuropathies. Since no disease causing mutations were found, we suggest that Caspr1 is probably not a common cause of inherited peripheral neuropathies.

Cell Adhesion Molecules, Neuronal↗
PubMed2001

The role of macrophages in demyelinating peripheral nervous system of mice heterozygously deficient in p0.

Mice heterozygously deficient in the p0 gene (P0(+/-)) are animal models for some forms of inherited neuropathies. They display a progressive demyelinating phenotype in motor nerves, accompanied by mild infiltration of lymphocytes and increase in macrophages. We have shown previously that the T lymphocytes are instrumental in the demyelination process. This study addresses the functional role of the macrophage in this monogenic myelin disorder. In motor nerves of P0(+/)- mice, the number of macrophages in demyelinated peripheral nerves was increased by a factor of five when compared with motor nerves of wild-type mice. Immunoelectron microscopy, using a specific marker for mouse macrophages, displayed macrophages not only in the endoneurium of the myelin mutants, but also within endoneurial tubes, suggesting an active role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.

Animals↗
PubMed2001

The effect of myelinating Schwann cells on axons.

Myelinating Schwann cells control the number of neurofilaments and elevate the phosphorylation state of neurofilaments in the axon, eventually leading to the typical large axon caliber. Conversely, absence of myelin leads to lower amounts of neurofilaments, reduced phosphorylation levels, and smaller axon diameters. In addition, myelinating Schwann cells mediate the spacing of Na(+) channel clusters during development of the node of Ranvier. When axons are associated with mutant Schwann cells in inherited neuropathies, their calibers are reduced and their neurofilaments are less phosphorylated and more closely spaced. Also, axonal transport is reduced and axons degenerate at the distal ends of long nerves. Myelin-associated glycoprotein may mediate some aspects of Schwann cell-axon communication, but much remains to be learned about the molecular bases of Schwann cell-axon communication.

Animals↗
PubMed2001

Bone marrow transfer from wild-type mice reverts the beneficial effect of genetically mediated immune deficiency in myelin mutants.

Inherited demyelinating neuropathies are chronically disabling human disorders caused by various genetic defects, including deletions, single site mutations, and duplications in the respective myelin genes. We have shown in a mouse model of one distinct hereditary demyelinating neuropathy (heterozygous P0-deficiency, P0+-) that an additional null mutation in the recombination activating gene-1 (RAG-1--) leads to a substantially milder disorder, indicating a disease modifying role of T-lymphocytes. In the present study, we addressed the role of lymphocytes in the mouse model by reconstituting bone marrow of P0+-/RAG-1-- mice with bone marrow from immunocompetent wild-type mice. We compared the pathology and nerve conduction in double mutant mice (P0+-/RAG-1-- on a C57BL/6 background) with that in double mutants after receiving a bone marrow transplant. We found that the milder demyelination seen in the lymphocyte-deficient P0+-/RAG-1-- mutants was reverted to the more severe pathology by reestablishing a competent immune system by bone marrow transfer. These data corroborate the concept that the immune system contributes substantially to the pathologic process in this mouse model and may open new avenues to ameliorate human hereditary neuropathies by exploiting immunosuppressive treatments.

Animals↗
PubMed2001

Miller Fisher syndrome: immunofluorescence and immunoelectron microscopic localization of IgG at the mouse neuromuscular junction.

In vitro electrophysiological experiments have demonstrated that IgG antibodies from patients with Miller Fisher syndrome (MFS) impair neuromuscular transmission by a fast and completely reversible combined pre- and postsynaptic blockade. In this study we investigated the cellular and subcellular binding sites of IgG from four MFS patients at the mouse hemidiaphragm by immunofluorescence and immunoelectron microscopy. IgG from all patients produced significant immunostaining at the neuromuscular junction, whereas sera from healthy volunteers or from patients with other neurological diseases did not stain neuromuscular junction. Immunoelectron microscopy revealed that, when living hemidiaphragms were incubated with IgG from MFS patients, labeling was found on both pre- and postsynaptic membranes of the neuromuscular junction, whereas terminal Schwann cells and the basal lamina covering the synaptic membranes were not labeled. These findings demonstrate that IgG from MFS patients binds to synaptic membranes of the neuromuscular junction where it might interfere with the function of both the pre- and postsynaptic activities.

Animals↗
PubMed2001

Anxiety and depression in mothers of children undergoing bone marrow transplant: symptom prevalence and use of the Beck depression and Beck anxiety inventories as screening instruments.

This study examined anxiety and depressive symptoms among 115 mothers of children undergoing bone marrow transplant and evaluated the ability of the Beck Anxiety Inventory (BAI; A. T. Beck, N. Epstein, et al., 1988) and the Beck Depression Inventory (BDI; A. T. Beck, 1978) to serve as screening tools for assessing generalized anxiety disorder (GAD), panic disorder (PD), and major depressive disorder (MDD). Mothers with BAI or BDI scores greater than or equal to 14 were administered a structured clinical interview. An additional 20% was randomly selected for interview to determine whether the scale cutoff was an accurate screening method. Among the 64 mothers interviewed, 20% received at least I of the 3 diagnoses. Although the BAI did not demonstrate predictive accuracy in assessing GAD and PD, the BDI did in assessing MDD. The results suggest that a subset of mothers may have an anxiety or depressive disorder and that investigators should use caution before using the BAI as a screening instrument for anxiety disorder.

Adolescent↗
PubMed2001

[Klinefelter's syndrome: diagnosis and treatment. Case report].

Klinefelter's syndrome affects 1 in 500 men across all ethnic groups but the diagnosis is often delayed because of substantial variations in clinical presentation. A 26 year-old male came to observation for chronic fatigue. His laboratory data and radiological examination were negative. Examination showed eunuchoidal body habitus with sparse facial hair, small and firm testes and no gynecomastia. The patient had heterosexual orientation with regular sexual intercourses but diminished libido. Serum gonadotropin concentrations were raised while serum testosterone concentration was low-normal level. Serum PRL concentration and thyroid function were normal. Seminal analysis revealed azoospermia and peripheral lymphocyte karyotyping showed a 47,XXY karyotype, confirming diagnostic suspicion. Patient was given testosterone enanthate 200 mg intramuscularly every 2 weeks. He noted improvements in fatigue and libido and increase of muscle mass. Since the true prevalence of Klinefelter's syndrome is very high, the diagnosis of this disease should be considered in every men with complaints related to hypogonadism (fatigue, weakness, gynecomastia, infertility, erectile dysfunction, small testis and osteoporosis). Testosterone replacement therapy should be started early to minimize the physical and psychological effects of androgen deficiency. There have been recent advances in the options for the treatment of infertility in patients with Klinefelter's syndrome: however findings that this syndrome may be transmitted by the new assisted reproductive techniques is cause for concern.

Adult↗
PubMed2001

[Adolescent health care in pediatric departments of Tuscany].

BACKGROUND: Admission to Pediatric Departments for 0/18- year-old patients is an important issue for the best organization of pediatric hospital assistance. Aim of the study. To locate adolescent health care and identify the percentage of adolescent admissions to Pediatric Departments in an Italian region (Tuscany). METHODS: Adolescent health care in pediatric departments and pediatric admissions (0-18 years old) in 1999 into the reference hospital of Pisa and into 5 other regional hospitals in Tuscany are reported. The percentages of patients, subdivided by age, hospitalyzed in Pediatric Departments have been determined. RESULTS: In 1999 the admissions for subjects aged 0 to 18 years were 12573 of which 4966 adolescents (39.6 %). The percentage of adolescent admissions is not smaller than children's admissions (aged 0 to 1 year: 16.2%; aged 2 to 5 years: 26.2%; aged 6 to 9 years: 17.8%; aged 10 to 14 years: 20.4%; aged 15 to 18 years: 19.2%). Analysis by age demonstrated a continuous decrease of patient percentages admitted to Pediatric Departments with the increased age. A minority of 15/18- year-old subjects has been admitted to Pediatric Departments. CONCLUSIONS: The percentage of adolescent admissions is similar to there of children. Most adolescents are admitted to structures unsuitable for assistance to subjects aged 0 to 18 years. These data underline the necessity for a strong recovery of adolescent admissions to pediatric structures also equipping suitable nursing rooms.

Adolescent↗
PubMed2000

Animal models for inherited peripheral neuropathies: chances to find treatment strategies?

Mutations in four identified genes (peripheral myelin protein 22, P(0), connexin 32, and the early growth response 2 zinc finger protein) are the cause for several forms of inherited peripheral neuropathies that are still incurable disorders. Some forms of these disorders are well mimicked by engineered or spontaneous rodent mutants that might be instrumental for developing treatment strategies. This review focusses on common pathways of pathogenesis of the disorders and emphasizes strategies that might be suitable to ameliorate disease expression.

Animals↗
PubMed2000

P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves.

We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy.

Animals↗
PubMed2000

Immune deficiency in mouse models for inherited peripheral neuropathies leads to improved myelin maintenance.

The adhesive cell surface molecule P(0) is the most abundant glycoprotein in peripheral nerve myelin and fulfills pivotal functions during myelin formation and maintenance. Mutations in the corresponding gene cause hereditary demyelinating neuropathies. In mice heterozygously deficient in P(0) (P(0)(+/-) mice), an established animal model for a subtype of hereditary neuropathies, T-lymphocytes are present in the demyelinating nerves. To monitor the possible involvement of the immune system in myelin pathology, we cross-bred P(0)(+/-) mice with null mutants for the recombination activating gene 1 (RAG-1) or with mice deficient in the T-cell receptor alpha-subunit. We found that in P(0)(+/-) mice myelin degeneration and impairment of nerve conduction properties is less severe when the immune system is deficient. Moreover, isolated T-lymphocytes from P(0)(+/-) mice show enhanced reactivity to myelin components of the peripheral nerve, such as P(0), P(2), and myelin basic protein. We hypothesize that autoreactive immune cells can significantly foster the demyelinating phenotype of mice with a primarily genetically based peripheral neuropathy.

Animals↗
PubMed2000

Neuromyotonia in mice with hereditary myelinopathies.

The purpose of this study was to further characterize neuromyotonia in mice with deletions and point mutations of myelin protein genes. Clinical observation showed irregular stretching of the hindlimbs, tremor and generalized myokymia in mice with targeted deletions of the genes encoding myelin protein zero (P0-/-) or peripheral myelin protein 22 (Pmp22-/-), and Trembler mice, which carry a point mutation of Pmp22. By electromyography (EMG), we found irregular high-frequency bursts of spontaneous motor unit activity and rhythmic doublet or multiplet discharges of motor units in these mouse models of human hereditary neuropathies. The EMG signs are typical for neuromyotonia and myokymia, respectively. The activity persisted after a proximal nerve section in many cases, localizing the generator to the peripheral nerve or the muscle. We now show that blocking neuromuscular transmission with suxamethonium abolished the spontaneous activity, ruling out a muscle origin. Phenytoin ameliorated the motor behavior. Taken together, our study shows that neuromyotonia develops in different mouse models of hereditary myelinopathies. This indicates that spontaneous motor unit activity may underlie neuromyotonia, which is occasionally observed in Charcot-Marie-Tooth disease. These animal models will be useful to study the pathogenesis of neuromyotonia.

Animals↗
PubMed2000

Varicose symptoms without varicose veins: the hypotonic phlebopathy, epidemiology and pathophysiology. The Acireale project.

Ever since 1982 the authors have been interested in varicose symptoms without varicose veins. Carrying out several pilot studies with infrared photoplethysmography (PPG) and strain gauge plethysmography they suggest that the pathophysiology of this behaviour could be caused by the reduction of the venous wall tone. They propose the name of Hypotonic Phlebopathy (HP). The diagnosis criteria are focused by symptoms (heavy legs in upright position, restless leg syndrome, sub-oedema and/or evening oedema) and signs detected by PPG, s.g plethysmography and duplex scanning (reduction of the muscle-venous calf pump and increase of the venous wall compliance). Epidemiology, assessed between 1989 and 1992 (Acireale Project), showed a 15.90% morbidity, with higher prevalence in females; the most important risk factors are pregnancy and family history. HP is not rare in males; the principal risk factor is work involving standing for long periods. These behaviours have been independently confirmed by two studies carried out in France in 1992, which showed a 15% prevalence in a similar group of subjects with functional venous insufficiency. The authors suggest the introduction of the term of Hypotonic Phlebopathy, the symptoms of which are significantly improved by phlebotonic drugs, especially when they are stronger. CEAP classification: C(0-S); E(P); A(0); P(unclassifiable); Clinical score (1-2); Anatomical score (0); Disability score (1).

Adult↗