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Biomedical subjects

J J Martin

Publications and source records attributed to J J Martin.

At least 91 records · Page 5Linked to original sources

Cervical myelopathy due to rheumatoid arthritis. Case report and review of the literature.

We present the case report of a 62 year-old female suffering from destructive rheumatoid arthritis (RA) for more than 20 years. She had complaints of progressive gait impairment and numbness in hands and feet. Neurological examination showed an unstable gait and pyramidal tract signs. Anterior atlantoaxial subluxation with pannus formation and cervical myelopathy were demonstrated using conventional X-ray studies and MRI. She was conservatively treated with a soft collar. Treatment with methotrexate and an intensive gait revalidation program were started. RA commonly involves the cervical spine, usually in advanced systemic disease after a mean delay of 16 years. Subluxations of the cervical spine are found in 43 to 86%, 50% of these patients are asymptomatic. The reported rate of neurological impairment due to cervical instability ranges from 7 to 58%. The three most common lesions resulting from cervical RA are atlantoaxial subluxation (50 to 70%), subaxial subluxation (15 to 25%) and cranial settling (20%). It is important to differentiate between cranial settling and atlantoaxial instability, as the latter may have a more benign history with less than 20% showing progressive instability. Cranial settling progresses in 35 to 50% of patients. The commonest presenting features of rheumatoid cervical myelopathy are isolated sensory symptoms. Most patients were found to have multiple neurological deficits once the myelopathy was diagnosed. A mean delay of 31 weeks between the first symptom and the diagnosis of the myelopathy is reported. The sensory symptoms are often misinterpreted as being due to entrapment neuropathy or rheumatoid peripheral neuropathy. Radiographic analysis indicates that the posterior atlantoodontoid interval (< or = 14 mm) is an important parameter that shows excellent correlation with the severity of paralysis.

Aged↗

Proteolytic processing of presenilin-1 (PS-1) is not associated with Alzheimer's disease with or without PS-1 mutations.

Cerebral presenilin-1 protein (PS-1) is normally composed of the amino-terminal fragment (NTF) with Mr 28 kDa and the carboxy-terminal fragment (CTF) with 18 kDa. We analyzed human PS-1 in brains with early-onset familial Alzheimer's disease (FAD) with and without PS-1 mutations to study whether mutated PS-1 was abnormally metabolized. Cerebral PS-1 were found to be cleaved into two fragments of NTF and CTF independently of the occurrence of PS-1 mutation in human brains. A small portion of PS-1 was recently found to suffer another processing by caspase-3, an apoptosis-related cysteine protease. In contrast to the recent finding that the Volga-German mutation on presenilin-2 (PS-2) affects the increasing caspase-3 PS-2 fragment, the PS-1 mutation did not cause a significant change in PS-1 fragmentation. We conclude that PS-1 fragmentation and other (probably caspase-3-mediated) digestion following apoptosis occur independently of PS-1 mutations.

Alzheimer Disease↗

Interleukin 1-dependent and -independent mouse melanoma metastases.

BACKGROUND: The adhesion of cancer cells to the endothelial lining of blood vessels, which is important for metastasis, is promoted by the action of interleukin 1 (IL-1) and other cytokines. PURPOSE: IL-1-producing melanoma cells were used to induce metastases in mice to test whether melanoma metastasis--wherever it occurs--depends on the action of IL-1. METHODS: We used the following experimental designs in this study: 1) Male C57BL/6J mice were inoculated in the left cardiac ventricle with 5 x 10(4) murine B16 melanoma cells, and no treatment was given (control animals). 2) Mice received an intraperitoneal injection of either saline (control animals) or recombinant human IL-1 receptor antagonist (rHuIL-1Ra) 2 hours before the injection of cancer cells; thereafter, they received an additional injection of saline or rHuIL-1Ra daily for 20 days. 3) Mice received an intravenous injection of either saline or rHuIL-1Ra; 15 minutes later, mice that received saline were given either a second injection of saline (control animals) or an injection of bacterial lipopolysaccharide (LPS) to stimulate host IL-1 production and endothelial cell activation. The mice that received rHuIL-1Ra were also given an injection of LPS at this time. Six hours later, all mice were inoculated with cancer cells, followed by no further treatment. In all experiments, the mice were killed 20 days after the injection of cancer cells, and metastases were counted in multiple organs and bones. Metastasis incidence values (relating to the frequency that a given site was positive for metastasis) and metastasis development index values (relating to the extent of metastasis at a given site) were calculated. A hierarchical cluster analysis was performed to determine whether groups of organs exhibited characteristic changes in their metastasis development index values in response to the three treatments given (i.e., rHuIL-1Ra, LPS, or rHuIL-1Ra plus LPS). Reported P values are two-sided. RESULTS AND CONCLUSIONS: Treatment with rHuIL-1Ra alone significantly (P<.05) reduced the occurrence of metastasis in the bone marrow, spleen, liver, lung, pancreas, skeletal muscle, adrenal gland, and heart, indicating that host- and/or melanoma-derived IL-1 promoted metastasis in these organs; treatment with rHuIL-1Ra had no effect on metastasis in the kidney, testis, brain, skin, and gastrointestinal tract, suggesting that metastasis in these latter organs was IL-1 independent. Treatment with LPS alone significantly (P<.05) enhanced metastasis in the same organs for which rHuIL-1Ra treatment reduced metastasis, except for the heart and the adrenal gland. Treatment with rHuIL-1Ra 15 minutes before LPS treatment abrogated the LPS-mediated enhancement of metastasis. Two independent organ groups for which IL-1 promoted melanoma metastasis were identified in the cluster analysis.

Animals↗

Processing of presenilin 1 in brains of patients with Alzheimer's disease and controls.

Mutations in the presenilin genes are involved in the aetiology of the majority of familial early-onset Alzheimer disease (AD) cases. Presenilin 1 (PS1) is proteolytically processed in vivo, resulting in the accumulation of N-terminal approximately 27-28 kDa and C-terminal approximately 18 kDa derivatives. To examine the metabolism of PS1 in brains of patients with AD harbouring PS1 mutations I143T and G384A, we performed immunoblot analyses of brain homogenates using well characterized antibodies. We document that approximately 27-28 kDa N-terminal and approximately 18 kDa C-terminal PS1 proteolytic fragments accumulate in brain of these individuals, and that in large part the accumulation pattern is indistinguishable from that observed in brains from individuals with sporadic AD or controls. Notably, little, if any, full-length PS1 was detected in brain tissue of patients carrying PS1 mutations or in those with sporadic AD, indicating that failed proteolysis of PS1 is not a central feature of pathogenesis in these patients.

Adult↗

Mutation analysis of the human pancreatic phospholipase A2 gene in a family with distal hereditary motor neuropathy type II linked to 12q24.

Molecular genetic analysis in a Belgian family with distal hereditary motor neuropathy type II (distal HMN II), demonstrated significant linkage of markers located at chromosome 12q24. The candidate region, extending from D12S86 to D12S340, includes the gene encoding pancreatic phospholipase A2 (PPLA2). PPLA2 is a candidate gene for distal HMN II in this family since it is expressed in the peripheral nervous system during nerve degeneration. We analyzed the sequences of the four coding exons of the PPLA2 gene in two patients affected with distal HMN II and in two unrelated healthy individuals of the pedigree. Two rare polymorphisms in exon 3 and one intronic three-base pair insertion were observed in both the patients as well as the control individuals. However, no disease specific mutation within the coding region of PPLA2 could be identified, suggesting that the PPLA2 gene is most likely not the disease causing gene for distal HMN II in this Belgian family.

Chromosomes, Human, Pair 12↗

Focal myopathy associated with chronic intramuscular injection of piritramide.

We report a patient in whom chronic intramuscular piritramide led to a focal fibrotic myopathy. Since piritramide myotoxicity has never been reported, we have studied its effect on rat skeletal muscle. Chronic intramuscular piritramide led to fibrous connective tissue replacement of rat skeletal muscle, similar to that found in the patient's muscle. Although the pathogenetic mechanism of piritramide myopathy is unclear, we caution against prolonged intramuscular use of piritramide to prevent this potentially debilitating adverse effect.

Adult↗

Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice.

The hepatic sinusoidal endothelium (HSE) releases large amounts of reactive oxygen species (ROS) in response to endotoxins and interleukin-1 (IL-1). Such pro-inflammatory mediators have been shown to promote hepatic metastasis. We have investigated the involvement of ROS released by IL-1-stimulated HSE in this promoting effect. Recombinant human interleukin-1 beta (rHuIL-1 beta) (5 micrograms/kg) was intravenously injected into C57BL/6J mice, and the hepatic metastasizing ability of B16 melanoma cells following intrasplenic injection was studied in the presence of ROS scavengers. rHuIL-1 beta-promoted hepatic metastases were significantly (P < .01) reduced by catalase (1 mg/kg) and enhanced by recombinant human superoxide dismutase (rHuSOD) (5 mg/kg). rHuIL-1 beta-stimulated HSE-conditioned medium (HSE-CM) significantly (P < .01) enhanced B16 melanoma cell adhesion to HSE compared with unstimulated HSE-CM, which in turn also significantly (P < .01) increased with melanoma cell adherence compared with basal medium. The addition of catalase completely abrogated proadhesive effects induced by rHuIL-1 beta-stimulated HSE-CM with respect to unstimulated HSE-CM, but did not affect the proadhesive effects induced by unstimulated HSE-CM over basal medium. The rat monoclonal antibody to mouse vascular cell adhesion molecule-1 (VCAM-1) significantly (P < .01) inhibited the enhanced melanoma cell adherence effects of both unstimulated and rHuIL-1 beta-stimulated HSE-CM, indicating that adherence was very late antigen-4 (VLA-4)-mediated. Not surprisingly, the percentage of VLA-4 expressing B16 melanoma cells significantly (P < .05) increased in response to unstimulated (21% of controls) and rHuIL-1 beta-stimulated (32% of controls) HSE-CM. Catalase addition abrogated these effects of rHuIL-1 beta-stimulated-HSE-CM. Melanoma cell damage was observed from the second hour of adhesion to HSE and significantly (P < .01) increased when the cells adhered to rHuIL-1 beta-stimulated HSE. This increase was abrogated by catalase. Cytolysis of the HSE was not observed during melanoma cell adhesion. Neither was the enhancement of B16 melanoma hydrogen peroxide production observed in response to rHuIL-1 beta. Thus, the effects of IL-1 in the liver may consist of a balance between the prometastatic effect of enhanced adherence to the HSE and the antimetastatic effect of H2O2-mediated cytotoxicity. Our results suggest that the enhancement of H2O2 production by the rHuIL-1 beta-stimulated HSE may contribute to the hepatic metastasis progression of ROS-resistant melanoma cells. Results in vitro indicate that this progression is associated with a H2O2-mediated increase in melanoma cell adhesion to HSE.

Animals↗

Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible individuals assessed by 31P-MR spectroscopy.

Our aim was to develop an exercise protocol using 31P-magnetic resonance spectroscopy (31P-MRS), which can discriminate between malignant hyperthermia-susceptible (MHS) individuals and controls. MRS spectra of the forearm muscles were recorded at rest, during and after a standardized exercise protocol in 10 MHS patients and compared with spectra obtained in 10 controls. There was no difference in resting intracellular pH (pHi) or PCr/(Pi+PCr) ratio between the groups (PCr = phosphocreatine, Pi = inorganic phosphorus). At the end of the exercise and during the initial recovery phase, the pHi and PCr/(Pi+PCr) ratio were significantly lower in the MHS group ([pHi: 6.37 (0.07) for MHS vs 6.70 (0.05) for controls, P < 0.005; PCr/(Pi+PCr): 0.784 (0.017) for MHS vs 0.954 (0.020) for controls, P < 0.0005]). For PCr/(Pi+PCr), complete separation between the two groups was observed during the initial recovery phase. The mean recovery time of PCr/(Pi+PCr) was 0.57 min for the control group and 1.28 min for the MHS group. The slower recovery of PCr/(Pi+PCr) is likely to be caused by a combination of several factors, including the lower pHi in MHS subjects at the start of recovery (inhibiting ATP production) and excessive sarcoplasmic calcium overload (causing continued enzyme activation and ATP consumption). Our exercise protocol can be a valuable adjunct to discriminate between MHS and non susceptible subjects.

Adult↗

Refinement of the locus for autosomal dominant cerebellar ataxia type II to chromosome 3p21.1-14.1.

We have previously mapped the gene for autosomal dominant cerebellar ataxia type II (ADCAII) to chromosome 3p12-p21.1 in a region of 33 cM by using four families of different geographic origin. In this study, we analysed the families with nine additional simple tandem repeat markers located in the ADCAII candidate region. An extensive clinical evaluation was also performed in the Belgian family CA-1 on two probably affected and seven at-risk individuals by means of ophthalmological examination and magnetic resonance imaging. Based on informative recombinants, we were able to reduce the ADCAII candidate region to the 12-cM region between D3S1300 and D3S1285. Furthermore, haplotype analysis among the families suggested that the most likely location of the ADCAII gene is within the 6.2-cM interval between D3S3698 and D3S1285. Because of the documented anticipation in ADCAII families, we also analysed family CA-1 with six polymorphic triplet repeat markers located on chromosome 3. None of these markers showed expanded alleles.

Cerebellar Ataxia↗

Pearls, pitfalls, and updates for pain management.

Pain management is one of the most challenging areas we encounter as emergency physicians. However, many of us fail to adequately meet this challenge. This article discusses frequently encountered pain syndromes and pain management options.

Adult↗

On a dominantly inherited myopathy with tubular aggregates.

A 19-year-old patient presented with exercise-related myalgia, fatigue and elevated creatine kinase levels. Histology of a muscle biopsy was characterized by the presence of very large amounts of tubular aggregates. Both his father and paternal grandfather had elevated creatine kinase and large amounts of tubular aggregates in their muscle biopsies. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with one to several smaller tubules. Disorders with tubular aggregates in the muscle fibres such as hyperornithinaemia with gyrate atrophy of the retina, hypokalaemic periodic paralysis, hyperkalaemic periodic paralysis, myotonia congenita, alcoholism, osteomalacic myopathy etc. have been excluded. Tubular aggregates can be found in muscle disorders characterized by exercise-induced cramps, pain and stiffness. They also represent the predominant histological feature of some familial myopathies due to a yet unidentified genetic defect. In our family, there was male-to-male transmission, confirming dominant inheritance.

Adult↗

Genetic linkage analysis of a variant of juvenile onset neuronal ceroid lipofuscinosis with granular osmiophilic deposits.

A number of variant forms of the neuronal ceroid lipofuscinoses (NCL) have been described and remain unmapped. The genes for infantile (CLN1), juvenile (CLN3) and Finnish-variant late-infantile (CLN5) have previously been mapped to chromosome regions 1p32, 16p12 and 13q21.1-32 respectively. The locus for a variant form of juvenile onset NCL characterised by cytosomal granular osmiophilic deposits (GROD) has been excluded from the CLN3 region of chromosome 16. This study describes the outcome of genetic linkage analysis in four families with this variant at the loci for the CLN1 and CLN5 genes. Using highly informative microsatellite markers tightly linked to the CLN5 locus we have excluded the JNCL variant with GROD from this region. Marker typing across the CLN1 region suggests that JNCL with GROD may be an allelic variant of infantile NCL.

Adolescent↗

Quantitative chromatin pattern description in Feulgen-stained nuclei as a diagnostic tool to characterize the oligodendroglial and astroglial components in mixed oligo-astrocytomas.

The oligoastrocytoma, as a mixed glioma, represents a nosologic dilemma with respect to precisely defining the oligodendroglial and astroglial phenotypes that constitute the neoplastic cell lineages of these tumors. In this study, cell image analysis with Feulgen-stained nuclei was used to distinguish between oligodendroglial and astrocytic phenotypes in oligodendrogliomas and astrocytomas and then applied to mixed oligoastrocytomas. Quantitative features with respect to chromatin pattern (30 variables) and DNA ploidy (8 variables) were evaluated on Feulgen-stained nuclei in a series of 71 gliomas using computer-assisted microscopy. These included 32 oligodendrogliomas (OLG group: 24 grade II and 8 grade III tumors according to the WHO classification), 32 astrocytomas (AST group: 13 grade II and 19 grade III tumors), and 7 oligoastrocytomas (OLGAST group). Initially, image analysis with multivariate statistical analyses (Discriminant Analysis) could identify each glial tumor group. Highly significant statistical differences were obtained distinguishing the morphonuclear features of oligodendrogliomas from those of astrocytomas, regardless of their histological grade. When compared with the 7 mixed oligoastrocytomas under study, 5 exhibited DNA ploidy and chromatin pattern characteristics similar to grade II oligodendrogliomas, I to grade III oligodendrogliomas, and I to grade II astrocytomas. Using multifactorial statistical analyses (Discriminant Analysis combined with Principal Component Analysis). It was possible to quantify the proportion of "typical" glial cell phenotypes that compose grade II and III oligodendrogliomas and grade II and III astrocytomas in each mixed glioma. Cytometric image analysis may be an important adjunct to routine histopathology for the reproducible identification of neoplasms containing a mixture of oligodendroglial and astrocytic phenotypes.

Adult↗

Detection of the CMT1A/HNPP recombination hotspot in unrelated patients of European descent.

Charcot-Marie-Tooth type 1 disease (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are common inherited disorders of the peripheral nervous system. The majority of CMT1 patients have a 1.5Mb tandem duplication (CMT1A) in chromosome 17p11.2 while most HNPP patients have a deletion of the same 1.5 Mb region. The CMT1A duplication and HNPP deletion are the reciprocal products of an unequal crossing over event between misaligned flanking CMT1A-REP elements. We analysed 162 unrelated CMT1A duplication patients and HNPP deletion patients from 11 different countries for the presence of a recombination hotspot in the CMT1A-REP sequences. A hotspot for unequal crossing over between the misaligned flanking CMT1A-REP elements was observed through the detection of novel junction fragments in 76.9% of 130 unrelated CMT1A patients and in 71.9% of 32 unrelated HNPP patients. This recombination hotspot was also detected in eight out of 10 de novo CMT1A duplication and in two de novo HNPP deletion patients. These data indicate that the hotspot of unequal crossing over occurs in several populations independently of ethnic background and is directly involved in the pathogenesis of CMT1A and HNPP. We conclude that the detection of junction fragments from the CMT1A-REP element on Southern blot analysis is a simple and reliable DNA diagnostic tool for the identification of the CMT1A duplication and HNPP deletion in most patients.

Blotting, Southern↗

Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family.

BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) or hereditary motor and sensory neuropathy type II (HMSN II) is an inherited axonal neuropathy of the peripheral nervous system. Three autosomal dominant CMT2 loci have been located on chromosomes 1p35-p36 (CMT2A), 3q13-q22 (CMT2B), and 7p14 (CMT2D) indicating that CMT2 is a genetically heterogeneous disorder. METHODS: A CMT2 family was examined for linkage to the CMT2A, CMT2B, and CMT2D loci using short tandem repeat polymorphisms. RESULTS: Suggestive evidence for linkage to 3q13-q22 was found. Recombinations occurred with markers D3S1769 and D3S1267 indicating that the CMT2B locus is located distal to D3S1267 and resides in an interval of 25 cM. Some patients in this family have pronounced sensory disturbances leading to poorly healing ulcerations. CONCLUSIONS: These unusual sensory signs for CMT were also noted in the only other CMT2B family reported so far, suggesting a distinct clinical phenotype for CMT2B. Exclusion of the locus for hereditary sensory neuropathy type I (HSN I) on chromosome 9q22 indicates that HSN I with mild motor symptoms and CMT2 with prominent sensory abnormalities are not allelic.

Adult↗

Charcot-Marie-Tooth disease and related peripheral neuropathies.

Soon after the description of Charcot-Marie-Tooth disease (CMT) in 1886, it became apparent that this syndrome is clinically and genetically heterogeneous. Neuropathological and electrophysiological studies have further dissected this syndrome into distinct categories that are now classified in a complex nosology of the inherited peripheral neuropathies. The recent advent of molecular genetics has dramatically increased our understanding of the underlying disease mechanisms. Genetic linkage studies have identified at least 17 genetic loci for different types of inherited neuropathies although most genes involved still remain to be found. The application of molecular genetics has already had an important impact on clinical practice and genetic counselling. Three genes responsible for hereditary motor and sensory neuropathy type I (HMSNI) or CMT1 have been identified: peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ) for the autosomal dominant form and connexin 32 (Cx32) for the X-linked dominant variant. The PMP22 gene is also involved in the majority of families with hereditary neuropathy with liability to pressure palsies (HNPP). The observation of a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene, in CMT1 and the reciprocal deletion in the same region in HNPP has provided a novel disease paradigm for autosomal dominant disorders, i.e. the gene dosage mechanism. The study of phenotype-genotype correlations in transgenic animal models for PMP22, MPZ and Cx32 mutations will help elucidate the underlying disease mechanisms and will provide a basis for gene therapy and/or other therapeutic approaches such as treatment with neurotrophic growth factors.

Charcot-Marie-Tooth Disease↗

Prolonged and atypical course in some cases of subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a persistent viral infection of the central nervous system due to a defective measles virus. Beginning with progressive cognitive malfunctioning, myoclonus and other less specific neurologic signs and symptoms, it usually evolves to a vegetative, decorticated state and death. Disease course and characteristics can be highly variable. Since the widespread measles vaccination in the Western countries started in the late seventies and early eighties, the incidence of SSPE has dropped significantly. Also adult onset is more frequently seen which changes the field of differential diagnosis. In this article 3 atypical cases of SSPE are described with peculiarities such as adult onset, pronounced extrapyramidal involvement, remission and prolonged disease course. Common features of the disease are emphasized to enable accurate diagnosis which is based on clinical features, presence of high titers of serum and cerebrospinal fluid (CSE) measles antibodies, MRI and EEG.

Adolescent↗