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K J Jones

Publications and source records attributed to K J Jones.

At least 19 recordsLinked to original sources
PubMed2003

Deficiency of the syntrophins and alpha-dystrobrevin in patients with inherited myopathy.

The syntrophins and dystrobrevins are members of the dystrophin-associated protein complex, and are thought to function as modular adaptors for signalling proteins recruited to the sarcolemmal membrane. We have characterised the expression of the syntrophins (alpha-, beta1-, and beta2-) and alpha-dystrobrevin by immunohistochemistry in normal human muscle and in biopsies from 162 patients with myopathies of unknown aetiology (with normal staining for dystrophin and other dystrophin-associated proteins). Unlike mice, beta2-syntrophin is expressed at the sarcolemma in post-natal human skeletal muscle. Deficiency of alpha-dystrobrevin +/- beta2-syntrophin was present in 16/162 (10%) patients, compared to age-matched controls. All patients presented with congenital-onset hypotonia and weakness, although there was variability in clinical severity. Two major clinical patterns emerged: patients with deficiency of beta2-syntrophin and alpha-dystrobrevin presented with severe congenital weakness and died in the first year of life, and two patients with deficiency of alpha-dystrobrevin had congenital muscular dystrophy with complete external ophthalmoplegia. We have sequenced the coding regions of alpha-dystrobrevin and beta2-syntrophin in these patients, and identified a new isoform of dystrobrevin, but have not identified any mutations. This suggests that disease causing mutations occur outside the coding region of these genes, in gene(s) encoding other components of the syntrophin-dystrobrevin subcomplex, or in gene(s) responsible for their post-translational modification and normal localisation.

Adult↗
PubMed2002

Primary gamma-sarcoglycanopathy (LGMD 2C): broadening of the mutational spectrum guided by the immunohistochemical profile.

An important step in the diagnostic evaluation of a patient with recessive limb-girdle muscular dystrophy is the immunohistochemical analysis of the components of the sarcoglycan complex in a muscle biopsy specimen. Even though a primary mutation in any of the four sarcoglycan genes (alpha-, beta-,gamma-, delta-sarcoglycan) may cause secondary deficiencies in all the other sarcoglycan proteins, more specific immunohistochemical patterns have emerged with the potential to guide and abbreviate the necessary molecular genetic investigations. In gamma-sarcoglycan mutations, the pattern consists of absent or prominently reduced gamma-sarcoglycan immunoreactivity in combination with reduced but detectable immunoreactivity for the other components, with preservation of delta-sarcoglycan. In five consecutive patients, this pattern was able to predict primary gamma-sarcoglycan mutations. Five different mutations were found, including a recurrent novel splice mutation, a large deletion of the entire gene and a novel missense mutation (Leu90Ser). The mutation Cys283Tyr, previously restricted to Gypsy populations was found in compound heterozygosity with del521T, common in north Africa. The variety of known and novel mutations found indicates that the immunohistochemical profile of gamma-sarcoglycan mutations is not restricted to a particular mutation or type of mutation, but rather is a general reflection of the effect of gamma-sarcoglycan mutations on the composition of the sarcoglycan complex. Complete immunohistochemical analysis with all available sarcoglycan antibodies, therefore, is a useful tool to guide the molecular genetic investigations that are necessary to arrive at the correct genetic diagnosis in a given case.

Adolescent↗
PubMed2001

Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study.

The authors report a case of congenital muscular dystrophy with mild nonprogressive muscle weakness, white matter hypodensity, and absence of the laminin alpha2 chain in muscle fibers with two antibodies, but not with four others. They identified mutations in LAMA2, which explain the partial laminin alpha2 deficiency. Analysis of this case and two others allows us to refine the epitopes of two of the commercial antibodies, and illustrate the importance of using antibodies directed against different domains of the protein.

Antibodies, Monoclonal↗
PubMed2001

Neurotrophic and migratory properties of an olfactory ensheathing cell line.

Olfactory ensheathing cells (OECs) are a unique type of macroglia required for normal olfactory axonal regeneration throughout the lifetime of an individual. Recent evidence in the literature suggests that OECs transplanted into injured spinal cords may facilitate axonal regeneration. In this study, we evaluated the neurotrophic properties of OECs using a homogeneous clonal cell line (nOEC), which does not contain contaminating cell types found in all primary OEC cultures. The results indicate that nOECs express mRNA for NGF, BDNF, NT-4/5, and neuregulins, but not for NT-3 or CNTF. In addition, nOECs secrete NGF, BDNF, and neuregulin, but retain NT-4/5 intracellularly. Finally, prelabeled nOECs derived from rat survived transplantation into a dorsal hemisected region of the hamster spinal cord and migrated only in the injured, dorsal portion of the spinal cord. This migratory pattern suggests that the nOECs are viable in vivo and respond to signals originating from the injured neuronal cells and their processes.

Animals↗
PubMed2001

Neuroprotective effects of gonadal steroids on regenerating peripheral motoneurons.

In this review, the neuroprotective actions of testosterone on three different populations of injured rat peripheral motoneurons, i.e. facial (FMN), spinal (SMN) and pudendal (PMN), will be discussed. We have extrapolated concepts from the neuroendocrine field regarding the trophic effects of gonadal steroids on target neural tissue to the nerve regeneration field. Exogenous administration of testosterone immediately after nerve injury impacts positively on functional recovery through actions mediated by the androgen receptor. The mechanism by which steroidal enhancement of the regenerative properties of injured motoneurons occurs may involve pre-existing androgen receptors, heat shock proteins, and modulation of the cellular stress response.

Animals↗
PubMed2001

Detection of retrogradely transported WGA-HRP in axotomized adult hamster facial motoneurons occurs after initiation of the axon reaction.

We have previously shown that facial nerve transection at the stylomastoid foramen activates ribosomal RNA transcription in injured facial motoneurons (FMN) of the adult hamster within 30 minutes postoperative. The signal for the initiation of the nerve cell body response to injury in vertebrates is currently unknown. It has been hypothesized that the signal for initiating the injury response is dependent on retrograde transport, where the signal itself is either the loss of a repressor substance from the periphery or the loss of retrogradely transported target-derived factors. To examine if a retrograde transport-mediated signal would be sufficient to produce the rapid ribosomal effects observed in hamster FMN following injury, adult hamsters were subjected to right facial nerve axotomies, with the neuronal tracer wheat germ agglutinin horseradish peroxidase (WGA-HRP; M.W. 80,000) applied at the proximal stump of the transected nerve. At time points ranging from 0.5 to 24 hours postoperative (hpo), the animals were killed and brainstem sections containing bilateral facial nuclei processed for WGA-HRP label using the TMB method. The earliest time point at which WGA-HRP was detected in the axotomized facial nucleus occurred at 3 hpo. To eliminate molecular weight as a confounding factor, an additional retrograde transport study was performed using the smaller tracer, Fluoro-Gold (M.W. 532.59). Fluoro-Gold was not detected until well after the 3 hpo time point. Thus, it appears that initiation of the axon reaction in hamster FMN is likely to be independent of the retrograde transport properties of the injured neuron.

Animals↗
PubMed2001

The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.

Age of Onset↗
PubMed2001

Preinduction cervical ripening. A randomized trial of intravaginal misoprostol alone vs. a combination of transcervical Foley balloon and intravaginal misoprostol.

OBJECTIVE: To determine if the addition of a mechanical ripening agent (transcervical Foley balloon) to a pharmacologic agent (intravaginal misoprostol) improves the efficiency of preinduction cervical ripening. STUDY DESIGN: Singleton patients with an indication for delivery, unfavorable cervix (Bishop score < or = 5) and no contraindication to labor were randomly assigned to two groups: misoprostol alone (25 micrograms intravaginally every 3 hours for no more than 12 hr) or combination therapy (25-French transcervical Foley balloon inflated to 50 mL of sterile water with identical intravaginal misoprostol dosing). All patients received a history and physical examination (including Bishop score), preripening ultrasound, electronic fetal heart rate and contraction monitoring (to rule out spontaneous labor and document fetal well-being). Multiple variables of perinatal outcome were analyzed, including the main outcome variables of ripening-to-delivery time and cesarean section rate. RESULTS: During August 1998 to August 1999, 81 patients were randomized, 40 to misoprostol alone and 41 to combination therapy. There were no differences between the groups with respect to maternal demographics, preripening Bishop score, maternal complications, intrapartum intervention or neonatal outcome. The misoprostol group spent longer periods of time in active labor, and there was a trend for the combination group to require oxytocin for longer intervals. These findings did not significantly affect the total ripening-to-delivery time or cesarean section rate which were similar for both groups. CONCLUSION: The addition of mechanical ripening with a transcervical Foley balloon to intravaginal misoprostol did not improve the efficiency of preinduction cervical ripening. Mechanical and pharmacologic cervical ripening agents appear to act independently rather than synergistically.

Administration, Intravaginal↗
PubMed2001

Androgenic enhancement of betaII-tubulin mRNA in spinal motoneurons following sciatic nerve injury.

PURPOSE: We have previously demonstrated that systemic administration of testosterone propionate (TP) can accelerate the functional recovery from hind limb paralysis following sciatic nerve injury in the rat. In this study, we looked at the molecular mechanisms underlying this phenomenon. METHODS: Castrated adult male rats received a right side sciatic nerve crush at the level of the sciatic notch, with the left side serving as control. Half the animals received a subcutaneous implant of TP, the others were sham implanted. Animals were sacrificed at 1, 3, 7 and 10 days post-operative. Lumbar spinal cord tissue was harvested and in situ hybridization was performed using a cytoskeletal cDNA probe complementary to betaII-tubulin. RESULTS: On the injured side, sciatic motoneuron tubulin mRNA levels were increased in alt groups at alt time points. At 3 and 7 days post- op, the TP treated group had significantly higher levels of tubulin mRNA. CONCLUSIONS: These results suggest that testosterone enhances the rate of regeneration by increasing the neuronal cytoskeletal response after axonal injury. Further, these results, coupled with the results from previous experiments in other rodent models, suggest a common mechanism for gonadal steroid action on regenerating motoneurons across species.

Animals↗
PubMed2000

Kinetics of facial motoneuron loss following facial nerve transection in severe combined immunodeficient mice.

We have recently shown that cells of the acquired immune system are crucial components of motoneuron survival after injury (Serpe et al. [1999] J. Neurosci. 19:RC7). The goal of the present study was to determine the kinetics of facial motoneuron (FMN) loss in wild-type, scid, and reconstituted scid mice after a right facial nerve axotomy at the stylomastoid foramen. Scid mice showed a significant decrease in FMN survival at all weekly postoperative (wpo) times. One, two, four, and ten wpo, ipsilateral FMN survival in scid mice was 90% +/- 1.8%, 84% +/- 1.3%, 52% +/- 3.7%, and 45% +/- 2.5%, respectively, of the contralateral, unoperated side. In contrast, FMN loss after axotomy in wild-type and reconstituted scid mice was not observed until 4 wpo (86% +/- 2.5% and 83% +/- 3.5%, respectively) relative to the contralateral, unoperated side. However, the levels of FMN in both wild-type and reconstituted scid mice were significantly higher than those in the nonreconstituted scid at 4 wpo. By 10 wpo, FMN survival in both wild-type and reconstituted scid mice had continued to decline significantly (60% +/- 2.1% and 58% +/- 3.1%, respectively) relative to the contralateral, unoperated side but were still significantly higher than that of the nonreconstituted scid at 10 wpo. Several important controls were also added to this study. Because the scid mutation is present in all cells (although it specifically results in a loss of V(D)J recombination mechanisms, we wanted to rule out the actual DNA mutation as causal in FMN loss). To accomplish this, we used the recombinase-activating gene-2 knockout (RAG-2 KO) mouse model, in which the RAG-2 has been disrupted and prevents maturation of T and B cells. As with the scid model, there was a significant loss of FMN at 4 wpo in the RAG-2 KO that could be reversed with whole splenocyte reconstitution. We also compared FMN numbers in nonaxotomized facial nuclei from both scid and RAG-2 KO mice relative to wild-type controls. No differences in normal numbers of FMN were found in either the mutation or the gene knockout model. The ability of T and B lymphocytes to rescue FMN from cell death after peripheral nerve injury supports the hypothesis that cells of the acquired immune system produce neurotrophic factors or neurocytokines to support neuronal survival until target reconnection occurs.

Animals↗
PubMed2000

Neuroregeneration and voiding behavior patterns after pudendal nerve crush in female rats.

Since the pudendal nerve innervates the external urethral sphincter, pudendal nerve injury and resultant neuroregeneration should affect voiding behavior. In this study, neuroregenerative activity of pudendal nerve was correlated to the changes in urinary behavior in female rats. Eighteen female rats underwent bilateral pudendal nerve crush, and 17 to 21 age-matched rats were used as unoperated controls. Urinary volume and frequency were recorded 6 and 13 days post-operatively (dpo). Initiation of pudendal nerve regeneration was indicated by an upregulation of beta(II) tubulin mRNA in the dorsolateral motoneurons (DLM), as measured at 7 and 14 dpo by in situ hybridization with radio-labeled beta(II) tubulin cDNA. At 6 dpo, mean volume voided by the crush group was significantly decreased compared to the control group during the light cycle (P < 0.05). At 7 dpo, the DLM mRNA level was significantly increased in the nerve crush group compared to the control group (P < 0.05). At 13 dpo, there were no differences in volume or frequency between the two groups, suggesting a return to normal voiding behavior. At 14 dpo, there was no significant difference in DLM mRNA levels between crush and control groups. Initiation of nerve regeneration occurs before normalization of voiding behavior after pudendal nerve crush. This data suggest that treatments to accelerate nerve regeneration would improve functional recovery of neurologically based incontinence.

Animals↗
PubMed2000

Androgen receptor mRNA regulation in adult male and female hamster facial motoneurons: effects of axotomy and exogenous androgens.

Testosterone propionate (TP) administration at the time of facial nerve injury in the adult hamster augments the regenerative properties of the injured facial motoneurons (FMN), with the androgen receptor (AR) playing a key role in mediating the actions of TP on facial nerve regeneration. The purpose of the present study was to determine the effects of axotomy on AR mRNA expression in FMN. This was accomplished using in situ hybridization in conjunction with a (35)S-labeled AR riboprobe. Gonadally intact adult male and gonadectomized (gdx) adult female hamsters were subjected to a right facial nerve axotomy, with the left side serving as internal, unoperated control. Half the animals were subcutaneously implanted with a 10-mm TP Silastic capsule, and the other half were sham-implanted. An additional group of nonaxotomized, gonadally intact males was also included. Postaxotomy survival times were 1, 4, and 7 days. At 1 postoperative day 1, there were no effects of axotomy on AR mRNA levels. By postoperative days 4 and 7, axotomy caused a significant decrease in AR mRNA levels in FMN of gonadally intact males, relative to either the contralateral control FMN of the same animals or FMN from the group of gonadally intact males that were not subjected to facial nerve axotomy. There were no significant differences between AR mRNA levels in contralateral control FMN and FMN from the gonadally intact group of nonaxotomized males. TP administration at the time of axotomy had no effect on AR mRNA levels in either the axotomized or contrala(teral control FMN of gonadally intact males, relative to the nonaxotomized, gonadally intact male group. Corroborating our previous work, AR mRNA levels were reduced in the contralateral control FMN of gdx females, relative to the nonaxotomized, gonadally intact male group, with axotomy having no additional effects. The data are discussed in a mechanistic framework suggesting how TP acts to augment facial nerve regeneration.

Animals↗
PubMed2000

A randomized trial of cerclage versus no cerclage among patients with ultrasonographically detected second-trimester preterm dilatation of the internal os.

OBJECTIVE: The aim of this study was to compare perinatal outcomes of patients with second-trimester ultrasonographic evidence of preterm dilatation of the internal os treated with cerclage versus those of patients not treated with cerclage. STUDY DESIGN: From May 1998 through June 1999 patients with ultrasonographic evidence of preterm dilatation of the internal os between 16 and 24 weeks' gestation were randomly assigned to receive a McDonald cerclage or no cerclage. Before random assignment all patients underwent amniocentesis and urogenital cultures and then received 48 hours of therapy with indomethacin and antibiotics. After treatment each patient was followed up as an outpatient with bed rest and weekly ultrasonographic evaluation. RESULTS: Of the 61 patients 31 were randomly assigned to cerclage and 30 were randomly assigned to no cerclage. There were no differences between groups with respect to maternal demographic characteristics, risk factors for preterm birth, cervical measurements, rescue procedures, readmission, chorioamnionitis, and abruptio placentae. The mean gestational age at delivery (33.5 +/- 6.3 weeks) and the perinatal death rate (12. 9%) in the cerclage group were similar to the mean gestational age at delivery (34.7 +/- 4.7 weeks; P =.4) and the perinatal death rate (10.0%; P =.9) in the no-cerclage group. CONCLUSION: Treatment with McDonald cerclage of preterm dilatation of the cervix detected ultrasonographically during the second trimester did not improve perinatal outcomes.

Cervix Uteri↗
PubMed1999

Androgenic regulation of the central glia response following nerve damage.

Current research on the effects of gonadal steroids on the brain and spinal cord indicates that these agents have profound trophic effects on many aspects of neuronal functioning, including cell survival, growth and metabolism, elaboration of processes, synaptogenesis, and neurotransmission (Jones et al., 1985; Luine, 1985; Nordeen et al., 1985; Matsumoto et al., 1988a,b; Gould et al., 1990). Since many of the aspects of normal neuronal functioning altered by gonadal steroids are affected by injury to the nervous system, we initiated a series of experiments designed to exploit the trophic capabilities of steroids as therapeutic agents in neuronal injury and repair (Kujawa et al., 1989, 1991; Kujawa and Jones, 1990). Three steroid-sensitive model systems were used for these studies: the hamster facial motoneuron, the rat sciatic motoneuron, and the hamster rubrospinal motoneuron. The results of our initial series of experiments suggest that androgens, and possibly estrogens, act either directly or indirectly on the injured motoneuron and enhance elements of the neuronal reparative response that are critical to successful recovery of function. Recently, we discovered that gonadal steroids may also modulate the central glia response to nerve damage. In this review, a summary of our data identifying a therapeutic role for androgens in enhancing the reparative response of motoneurons to injury is presented. This is followed by a discussion of the effects of androgens on the glial response to injury.

Androgens↗
PubMed1999

Differential regulation of cytoskeletal gene expression in hamster facial motoneurons: effects of axotomy and testosterone treatment.

We have previously demonstrated that systemic administration of testosterone increases the rate of axonal regeneration following facial nerve crush in adult male hamsters. In the present study, the molecular mechanisms by which androgens could enhance axonal regeneration were examined at a cellular level. Specifically, the following question was addressed using quantitative in situ hybridization with cDNA probes complementary to betaII, and alpha1 tubulin mRNAs: Does exogenous testosterone augment axotomy-induced changes in tubulin mRNA expression in hamster facial motoneurons (FMN)? Castrated adult male hamsters were subjected to right facial nerve severance, with the left side serving as internal control. One-half of the animals received testosterone replacement in the form of subcutaneously implanted silastic capsules containing crystalline testosterone propionate, and the other half were implanted with blank capsules immediately following the axotomy. Postoperative survival times from 2-14 days were examined. Axotomy alone resulted in a significant increase in the levels of both betaII and alpha1 tubulin mRNAs in facial motor neurons between 2-14 days after injury. Administration of testosterone selectively augmented the axotomy-induced increases in betaII-tubulin, but not alpha1 tubulin, mRNA, levels at 7 and 14 days post axotomy. These results demonstrating an effect of testosterone in altering the neuronal cytoskeletal response to axotomy suggest that testosterone may enhance the regenerative properties of motor neurons via molecular mechanisms that involve selective alterations of the neuronal cytoskeleton.

Animals↗
PubMed1999

Estrogen receptor expression in the facial nucleus of adult hamsters: does axotomy recapitulate development?

Testosterone propionate (TP) augments hamster facial motoneuron regeneration following axonal injury by an androgen-mediated mechanism. Although many of the trophic properties of TP are androgenic, TP can be metabolized to estradiol (E). We have recently shown that E administered in supraphysiological doses can also enhance facial nerve regeneration. The mechanism by which E alters nerve regeneration is unknown. The recent discovery of transient estrogen receptor (ER) expression in the developing rat facial motor nucleus (FMN), coupled with the concept that regeneration may recapitulate development, has led to the hypothesis that facial nerve injury may transiently induce expression of ER in the adult hamster FMN or one of its chief afferents, the principal nucleus of the trigeminal nerve (Nu5). In the present study, this hypothesis was tested using steroid hormone autoradiographic procedures. The right facial nerve was injured in castrated or castrated plus TP adult hamsters. A gonadally intact, nonaxtomized group of hamsters was also included to examine constitutive expression of ER in the FMN or Nu5. The paraventricular nucleus of the hypothalamus (PVN; positive control), FMN, and Nu5, were qualitatively and quantitatively examined for the presence of ER. As expected, ER were present in the PVN-positive control in all groups. ER were neither present nor induced with facial nerve injury or TP administration in either the FMN or Nu5. Alternate mechanisms by which E enhancement of facial nerve regeneration without ER might be explained are discussed.

Animals↗
PubMed1999

Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice.

The immune system functions to protect an organism against microbial infections and may be involved in the reparative response to nerve injury. The goal of this study was to determine whether the immune system plays a role in regulating motoneuron survival after a peripheral nerve injury. After a right facial nerve axotomy, facial motoneuron (FMN) survival in C.B-17 (+/+) wild-type mice was found to be 87 +/- 3.0% of the unaxotomized left side control. In contrast, facial nerve axotomy in C.B-17 (-/-) severe combined immunodeficient (scid) mice, lacking functional T and B lymphocytes, resulted in an average FMN survival of 55 +/- 3.5% relative to the unaxotomized left side control. This represented an approximately 40% decrease in FMN survival compared with wild-type controls. The reconstitution of scid mice with wild-type splenocytes containing T and B lymphocytes restored FMN survival in these mice to the level of the wild-type controls. These results suggest that immune cells associated with acquired immunity play a role in regulating motoneuron survival after a peripheral nerve injury.

Animals↗