PubMed Health⌕ Search

Biomedical subjects

C Jacobson

Publications and source records attributed to C Jacobson.

At least 19 recordsLinked to original sources
PubMed2001

The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane.

The dystrophin-associated protein (DAP) complex spans the sarcolemmal membrane linking the cytoskeleton to the basement membrane surrounding each myofiber. Defects in the DAP complex have been linked previously to a variety of muscular dystrophies. Other evidence points to a role for the DAP complex in formation of nerve-muscle synapses. We show that myotubes differentiated from dystroglycan-/- embryonic stem cells are responsive to agrin, but produce acetylcholine receptor (AChR) clusters which are two to three times larger in area, about half as dense, and significantly less stable than those on dystroglycan+/+ myotubes. AChRs at neuromuscular junctions are similarly affected in dystroglycan-deficient chimeric mice and there is a coordinate increase in nerve terminal size at these junctions. In culture and in vivo the absence of dystroglycan disrupts the localization to AChR clusters of laminin, perlecan, and acetylcholinesterase (AChE), but not rapsyn or agrin. Treatment of myotubes in culture with laminin induces AChR clusters on dystroglycan+/+, but not -/- myotubes. These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan. In addition, they suggest that dystroglycan functions in the organization and stabilization of AChR clusters, which appear to be mediated through its binding of laminin.

Agrin↗
PubMed2001

A novel anaesthetic regimen for surgical procedures in guineapigs.

A combination of tiletamine/zolazepam, xylazine and butorphanol provides deep surgical, long-duration anaesthesia in guineapigs with a smooth induction and recovery period. The described dosages mainly affect the respiratory functions and blood gas parameters, with a minor-to-moderate effect on the cardiovascular system.

Adrenergic alpha-Agonists↗
PubMed2000

Optimum bedside cardiac monitoring.

Correct electrode placement is critical to obtaining accurate information from any monitoring lead. The choice of lead should be based on the goals of monitoring for a specific patient population and on the individual patient's clinical situation. When using a 5-wire monitoring cable, arm electrodes should be placed on the shoulders; leg electrodes, on the lower thorax or hip area; and the chest electrode, in the desired V lead position. When using a 3-wire system, lead placement depends on which lead is desired for monitoring. If arrhythmia diagnosis is the goal of monitoring, lead V1 is the best lead; lead V6 is the next best lead. If ST segment monitoring for ischemia or reocclusion following percutaneous coronary interventions is the goal, the best lead depends on the coronary artery involved. Multiple lead monitoring is superior to single lead monitoring. If two leads are available, V1 and lead III or aVF (or a limb lead with maximal ST segment displacement) are good choices. If three leads are available, leads V1, III, and aVF are the best choices. Continuous 12-lead monitoring is available and offers several advantages.

Benchmarking↗
PubMed2000

Adverse effects on growth rates in rats caused by buprenorphine administration.

As a routine postoperative treatment, a single dose of buprenorphine was given to rats at a dose of 0.05 mg/kg subcutaneously. However, some rats developed abnormal secretions around the nose and mouth and some animals died 3-5 days after surgery and analgesic treatment. At autopsy a yellow fibrous mass was found in the stomach and intestines. Observations of animals given buprenorphine revealed an abnormal ingestion of bedding material. This caused a disturbance to normal digestion, with gastric distension, weight loss or decreased growth rate, constipation and occasionally death. In this study rats were monitored for 6 days following surgery and analgesic treatment. A comparison of growth rates was made between rats given saline and buprenorphine or nalbuphine and between animals kept on bedding or grid floors for the first 24h after treatment. Of the animals held on bedding, the buprenorphine-treated animals did not lose weight as the other animals did, but had on the other hand a decreased growth rate during the measuring period of 6 days after surgery. When denied access to bedding for the first 24 h after surgery, rats given saline or nalbuphine had a reduced weight gain over the first 24 h, similar to the groups held on bedding. Rats held on grid floors and given buprenorphine continued to gain weight for the first 24 h. From day 3, there was no significant difference between the groups, which all gained weight.

Analgesics, Opioid↗
PubMed1999

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia.

BACKGROUND: Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE: We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS: Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS: Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION: In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

5-alpha Reductase Inhibitors↗
PubMed1998

alpha-Dystroglycan functions in acetylcholine receptor aggregation but is not a coreceptor for agrin-MuSK signaling.

alpha-dystroglycan (alpha-DG) is an agrin-binding protein that has been implicated in acetylcholine receptor (AChR) clustering, but it is unclear whether it acts as a coreceptor involved in initial agrin signaling or as a component involved in later events. To investigate its role, we have generated antisense derivatives of the C2 mouse muscle cell line, which have reduced alpha-DG expression. When compared with wild-type cells, the alpha-DG-deficient myotubes have a dramatic reduction in the number of spontaneous and agrin-induced AChR clusters. Several findings suggest that this decrease in AChR clustering is likely not because of a defect in agrin signaling through the MuSK receptor tyrosine kinase. Compared with wild-type cells, the alpha-DG-deficient cell lines showed only a transient reduction in the level of agrin-induced MuSK tyrosine phosphorylation and no reduction in AChR beta-subunit tyrosine phosphorylation. Additionally, agrin-induced phosphorylation of MuSK in wild-type myotubes was not decreased using agrin fragments that lack the domain primarily responsible for binding to alpha-DG. Finally, neural agrin-induced phosphorylation of MuSK was unaffected by treatments such as excess muscle agrin or anti-alpha-DG antibodies, both of which block agrin-alpha-DG binding. Together, these results suggest that alpha-DG is not required for agrin-MuSK signaling but rather that it may play a role elsewhere in the clustering pathway, such as in the downstream consolidation or maintenance of AChR clusters.

Agrin↗
PubMed1998

Laminin and alpha-dystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway.

Specific isoforms of laminin (LN) are concentrated at neuromuscular junctions (NMJs) where they may participate in synaptic organization or function. In myotubes from C2 cells, LN is concentrated within the majority of spontaneous acetylcholine receptor (AChR) aggregates. Neural agrin substantially increases this colocalization, suggesting that agrin can recruit LN into AChR aggregates. Addition of LN to C2 myotubes induces a more than twofold increase in the number of AChR aggregates. These aggregates have a larger size and are more dense than are those induced by agrin, suggesting that LN is involved in the growth and/or stabilization of AChR aggregates. Consistent with this hypothesis, an antiserum to LN reduces the size of individual AChR aggregates but increases their number. In C2 myotubes, extracellular matrix receptors containing the integrin beta1 subunit are poorly colocalized with AChR aggregates, suggesting that integrins may not be involved in LN-induced aggregation. In contrast, almost all AChR aggregates are associated with dystroglycan immunoreactivity, and monoclonal antibody (mAb) IIH6 against alpha-dystroglycan (alpha-DG), a LN and agrin receptor, causes a concentration-dependent inhibition of LN-induced aggregation. Moreover, S27 cells, which lack a functional alpha-DG, and two C2-derived cell lines expressing antisense DG mRNA fail to aggregate AChRs in response to LN. Finally, LN-induced AChR aggregation does not involve the phosphorylation of the muscle-specific tyrosine kinase receptor (MuSK) or the AChR beta subunit. We hypothesize that the interaction of LN with alpha-DG contributes to the growth and/or stabilization of AChR microaggregates into macroaggregates at the developing NMJ via a MuSK-independent mechanism.

Agrin↗
PubMed1997

Laminin-induced clustering of dystroglycan on embryonic muscle cells: comparison with agrin-induced clustering.

The effect of laminin on the distribution of dystroglycan (DG) and other surface proteins was examined by fluorescent staining in cultures of muscle cells derived from Xenopus embryos. Western blotting confirmed that previously characterized antibodies are reactive in Xenopus. In control cultures, alphaDG, betaDG, and laminin binding sites were distributed as microclusters (<1 microm2 in area) over the entire dorsal surface of the muscle cells. Treatment with laminin induced the formation of macroclusters (1-20 microm2), accompanied by a corresponding decline in the density of the microclusters. With 6 nM laminin, clustering was apparent within 150 min and near maximal within 1 d. Laminin was effective at 30 pM, the lowest concentration tested. The laminin fragment E3, which competes with laminin for binding to alphaDG, inhibited laminin-induced clustering but did not itself cluster DG, thereby indicating that other portions of the laminin molecule in addition to its alphaDG binding domain are required for its clustering activity. Laminin-induced clusters also contained dystrophin, but unlike agrin-induced clusters, they did not contain acetylcholine receptors, utrophin, or phosphotyrosine, and their formation was not inhibited by a tyrosine kinase inhibitor. The results reinforce the notion that unclustered DG is mobile on the surface of embryonic muscle cells and suggest that this mobile DG can be trapped by at least two different sets of molecular interactions. Laminin self binding may be the basis for the laminin-induced clustering.

Agrin↗
PubMed1997

A novel herpesvirus amplicon system for in vivo gene delivery.

For gene therapy approaches to succeed, improved vector systems are needed that combine a large carrying capacity with high transduction efficiency in vivo. Towards this goal, we have developed a novel herpes simplex virus (HSV) amplicon vector, pHE, which contains an HSV-1 replication origin (ori S) and packaging sequence that permit vector replication and packaging into HSV-1 capsids. The vector also contains the Epstein-Barr virus (EBV) unique latent replication origin (ori P) sequence and a modified EBNA-1 gene to allow the vector to be maintained as an episome in transfected E5 helper cells. This system allows for efficient packaging of high-titer vector since the E5 cells are first selected for the presence of the pHE vector before helper virus infection. The infectious pHE vector has efficient transgene expression in a variety of human cell lines in vitro. Stereotactic injection of pHE vector supernatant into the rat brain resulted in high, localized reporter gene expression. Finally, the pHE vector could carry a stable 21 kb DNA payload into HSV virions. This pHE vector system should have a broad range of gene transfer applications.

Animals↗
PubMed1996

The estrogen receptor locus is associated with a major gene influencing litter size in pigs.

Identification of individual major genes affecting quantitative traits in livestock species has been limited to date. By using a candidate gene approach and a divergent breed cross involving the Chinese Meishan pig, we have shown that a specific allele of the estrogen receptor (ER) locus is associated with increased litter size. Female pigs from synthetic lines with a 50% Meishan background that were homozygous for this beneficial allele produced 2.3 more pigs in first parities and 1.5 more pigs averaged over all parities than females from the same synthetic lines and homozygous for the undesirable allele. This beneficial ER allele was also found in pigs with Large White breed ancestory. Analysis of females with Large White breed background showed an advantage for females homozygous for the beneficial allele as compared to females homozygous for the other allele of more than 1 total pig born. Analyses of growth performance test records detected no significant unfavorable associations of the beneficial allele with growth and developmental traits. Mapping of the ER gene demonstrated that the closest known genes or markers were 3 centimorgans from ER. To our knowledge, one of these, superoxide dismutase gene (SOD2), was mapped for the first time in the pig. Analysis of ER and these linked markers indicated that ER is the best predictor of litter size differences. Introgression of the beneficial allele into commercial pig breeding lines, in which the allele was not present, and marker-assisted selection for the beneficial allele in lines with Meishan and Large White background have begun.

Animals↗
PubMed1996

Dystroglycan in the cerebellum is a laminin alpha 2-chain binding protein at the glial-vascular interface and is expressed in Purkinje cells.

Dystroglycan is a core component of the dystrophin receptor complex in skeletal muscle which links the extracellular matrix to the muscle cytoskeleton. Dystrophin, dystrophin-related protein (DRP, utrophin) and dystroglycan are present not only in muscles but also in the brain. Dystrophin is expressed in certain neuronal populations while DRP is associated with perivascular astrocytes. To gain insights into the function and molecular interactions of dystroglycan in the brain, we examined the localization of alpha- and beta-dystroglycan at the cellular and subcellular levels in the rat cerebellum. In blood vessels, we find alpha-dystroglycan associated with the laminin alpha 2-chain-rich parenchymal vascular basement membrane and beta-dystroglycan associated with the endfeet of perivascular astrocytes. We also show that alpha-dystroglycan purified from the brain binds alpha 2-chain-containing laminin-2. These observations suggest a dystroglycan-mediated linkage between DRP in perivascular astrocytic endfeet and laminin-2 in the parenchymal basement membrane similar to that described in skeletal muscle. This linkage of the astrocytic endfeet to the vascular basement membrane is likely to be important for blood vessel formation and stabilization and for maintaining the integrity of the blood-brain barrier. In addition to blood vessel labelling, we show that alpha-dystroglycan in the rat cerebellum is associated with the surface of Purkinje cell bodies, dendrites and dendritic spines. Dystrophin has previously been localized to the inner surface of the plasma membrane of Purkinje cells and is enriched at postsynaptic sites. Thus, the present results also support the hypothesis that dystrophin interacts with dystroglycan in cerebellar Purkinje neurons.

Animals↗
PubMed1995

Platelet refractoriness and alloimmunization in pediatric oncology and bone marrow transplant patients.

BACKGROUND: The purposes of this study were to determine the overall incidence of platelet refractoriness and alloimmunization among multiply transfused children on a medical oncology and bone marrow transplant service and to evaluate the effect of routine white cell reduction in blood components on that incidence. STUDY DESIGN AND METHODS: The platelet transfusion records of 128 consecutive children admitted to the hospital and requiring blood component support for the treatment of disease were evaluated retrospectively. Mean corrected count increments (CCIs) for each patient were calculated for all random-donor platelet transfusions given within 7 days of the routine weekly testings of the patient's serum for lymphocytotoxic antibodies (LCTAbs). Mean CCIs for HLA-matched platelet transfusions were calculated separately for the patients receiving them. RESULTS: Thirty-one patients (24%) had or developed persistently positive LCTAbs (patient's serum reacted with > or = 3/10 panel lymphocytes); 22 (71%) of these patients had a mean CCI < 7.5 to random-donor platelet transfusions. In contrast, of the 97 patients with negative or transiently positive LCTAbs, only 25 (26%) had a mean CCI < 7.5. The overall incidence of platelet refractoriness (CCI < 7.5) was 37 percent. Patients with acute myelogenous leukemia had a significantly (p < 0.01) reduced incidence (17%) of low CCIs, with or without positive LCTAbs, as compared to patients with other malignant or nonmalignant disorders (41%). No difference in the incidence of LCTAbs or low CCIs was seen in patients undergoing allogeneic or autologous bone marrow transplant or receiving drug therapy only. Among the 24 patients who received HLA-matched platelets, only those with positive LCTAbs showed a significant improvement in CCIs over that achieved with random-donor platelet transfusions. Routine white cell reduction in red cell and platelet components with third-generation white cell filters was performed prior to transfusion in 73 of the patients. There was no significant difference between the incidence of LCTAbs and/or low CCIs in this group and that in the 55 children receiving unfiltered transfusions. CONCLUSION: Alloimmunization and platelet refractoriness occur in pediatric oncology and bone marrow transplant patients, but the incidence--particularly in children with acute myelogenous leukemia--appears to be low. The detection of LCTAbs predicts a poor response to random-donor platelet transfusion, but most such patients show improved CCIs with HLA-matched platelets. Routine use of white cell-reduction filters has thus far failed to eliminate alloimmunization in children requiring prolonged blood component support.

Adolescent↗
PubMed1995

Distribution of alpha-dystroglycan during embryonic nerve-muscle synaptogenesis.

The distribution of alpha-dystroglycan (alpha DG) relative to acetylcholine receptors (AChRs) and neural agrin was examined by immunofluorescent staining with mAb IIH6 in cultures of nerve and muscle cells derived from Xenopus embryos. In Western blots probed with mAb IIH6, alpha DG was evident in membrane extracts of Xenopus muscle but not brain. alpha DG immunofluorescence was present at virtually all synaptic clusters of AChRs and neural agrin. Even microclusters of AChRs and agrin at synapses no older than 1-2 h (the earliest examined) had alpha DG associated with them. alpha DG was also colocalized at the submicrometer level with AChRs at nonsynaptic clusters that have little or no agrin. The number of large (> 4 microns) nonsynaptic clusters of alpha DG, like the number of large nonsynaptic clusters of AChRs, was much lower on innervated than on noninnervated cells. When mAb IIH6 was included in the culture medium, the large nonsynaptic clusters appeared fragmented and less compact, but the accumulation of agrin and AChRs along nerve-muscle contacts was not prevented. It is concluded that during nerve-muscle synaptogenesis, alpha DG undergoes the same nerve-induced changes in distribution as AChRs. We propose a diffusion trap model in which the alpha DG-transmembrane complex participates in the anchoring and recruitment of AChRs and alpha DG during the formation of synaptic as well as nonsynaptic AChR clusters.

Agrin↗
PubMed1995

Infections caused by Staphylococcus aureus in a Veterans' Affairs nursing home care unit: a 5-year experience.

OBJECTIVES: To describe the frequency and patterns of infection caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S aureus (MRSA) infections in a single nursing home population and to determine the effect of MRSA's entry into the facility on subsequent experience with both MSSA and MRSA infections. DESIGN: Observational and descriptive. Surveillance data on nursing home-acquired infections were reviewed to identify all patients with MSSA and MRSA infections occurring during the 5-year period from 1987 to 1991. The medical records of these patients were reviewed retrospectively to collect additional information about the patients and their infections. SETTING AND PATIENTS: A 120-bed Veterans' Affairs nursing home care unit (NHCU) whose residents predominantly were elderly men with severe underlying diseases and functional impairments. RESULTS: During the 5-year study period, 40 MSSA and 28 MRSA infections were acquired by NHCU residents. Twelve to 19 S aureus infections occurred each year. S aureus accounted for 13% to 17% of all NHCU-acquired infections during the years of study, occurring with a frequency of 0.29 to 0.47 infections per 1,000 resident-care days. MRSA infections, first detected in 1988, accounted for an increasing percentage of S aureus infections in subsequent years, but this increase had little effect on the facility's overall infection rates, the composite S aureus infection rates, or the types of infections observed. MSSA and MRSA infections acquired in the NHCU were comparable. Both affected patients with severe underlying diseases and functional impairments. Pneumonia, urinary tract infections, skin and soft tissue infections, and conjunctivitis were the types of infections observed most frequently, accounting for 28%, 25%, 22%, and 15% of all S aureus infections, respectively. Four bacteremic infections occurred in the MSSA group, and five in the MRSA group (P = .47). Four of the MSSA and three of the MRSA infections resulted in death (P = 1.0). Nine of the MSSA and 12 of the MRSA infections resulted in the patient's transfer to the associated acute care hospital for additional care (P = .13). CONCLUSIONS: In the NHCU setting, MSSA and MRSA infections were similar in terms of the types of residents affected, the sites involved, and the frequency of adverse outcomes. The entry of MRSA into the facility appeared to have no effect on the subsequent experience with NHCU-acquired infections caused by S aureus.

Aged↗