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M Birnbaum

Publications and source records attributed to M Birnbaum.

At least 19 recordsLinked to original sources
PubMed2003

Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models.

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To understand better the physiological role of the catalytic AMPK subunit isoforms, we generated two knockout mouse models with the alpha1 (AMPK alpha 1(-/-)) and alpha 2 (AMPK alpha 2(-/-)) catalytic subunit genes deleted. No defect in glucose homoeostasis was observed in AMPK alpha 1(-/-) mice. On the other hand, AMPK alpha 2(-/-) mice presented high plasma glucose levels and low plasma insulin concentrations in the fed period and during the glucose tolerance test. Nevertheless, in isolated AMPK alpha 2(-/-) pancreatic islets, glucose-stimulated insulin secretion was not affected. Surprisingly, AMPK alpha 2(-/-) mice were insulin-resistant and had reduced muscle glycogen synthesis as assessed in vivo by the hyperinsulinaemic euglycaemic clamp procedure. Reduction of insulin sensitivity and glycogen synthesis were not dependent on the lack of AMPK in skeletal muscle, since mice expressing a dominant inhibitory mutant of AMPK in skeletal muscle were not affected and since insulin-stimulated glucose transport in incubated muscles in vitro was normal in AMPK alpha 2(-/-) muscles. Furthermore, AMPK alpha 2(-/-) mice have a higher sympathetic tone, as shown by increased catecholamine urinary excretion. Increased adrenergic tone could explain both decreased insulin secretion and insulin resistance observed in vivo in AMPK alpha 2(-/-) mice. We suggest that the alpha2 catalytic subunit of AMPK plays a major role as a fuel sensor by modulating the activity of the autonomous nervous system in vivo.

AMP-Activated Protein Kinases↗
PubMed2001

Unverricht-Lundborg disease in a five-generation Arab family: instability of dodecamer repeats.

BACKGROUND: Unverricht-Lundborg disease (ULD) is the prototypical form of progressive myoclonus epilepsy, and subjects are usually very photosensitive. ULD is caused by mutations in the cystatin B (CSTB) gene; the most common mutation is expansion of a dodecamer repeat near the promoter. The authors studied a five-generation Arab family with ULD lacking photosensitivity. METHODS: An Arab family from the Galilee region of Israel with progressive myoclonus epilepsy was clinically evaluated. Blood samples were obtained from three living affected and 16 unaffected individuals. Expansion of dodecamer repeat in the CSTB gene was examined. RESULTS: The three living affected individuals showed spontaneous and action myoclonus, ataxia, and mild dementia. EEG in two individuals showed generalized polyspike-wave without photosensitivity. The family structure with large sibships and multiple consanguineous loops allowed the authors to examine the gene over four generations of adults. The three living affected individuals were homozygous for repeat expansions and 11 of the 16 unaffected family members were heterozygous. Instability was demonstrated by the presence of expansions of different sizes occurring on the same haplotype background in this inbred family. Fragment size variations could be unequivocally detected in two sibships. The expansions were in the 49 to 54 dodecamer repeat range. Changes in one generation were small, 1 to 4 repeat units, consisting of either enlargements or contractions. CONCLUSIONS: Instability of the expanded dodecamer repeats in the cystatin B gene is frequent. Almost invariably, a small change is observed in parent-child transmission. The lack of photosensitivity in this family is unexplained.

Adult↗
PubMed2001

Association of APOE epsilon4 allele with survival in amyotrophic lateral sclerosis.

APOE epsilon4 allele is associated with poorer outcome in degenerative neurological diseases. Its role in amyotrophic lateral sclerosis (ALS) is still unclear. The aim of the present study was to further analyze the association of APOE epsilon4 allele with progression and survival of ALS. One hundred consecutive ALS patients (53 males) and 133 controls were genotyped for the APOE epsilon4 allele. The association of this allele with survival to death or tracheostomy was analyzed by Kaplan-Meier survival analysis. The frequency of the APOE epsilon4 allele in ALS patients was slightly higher (15.1%) than in the control group (10.9%). Patients with or without an APOE epsilon4 allele had a similar age of onset and frequency of bulbar onset. There was a significant shortening of the 50% probability of survival (by 32 months) in patients carrying the APOE epsilon4 allele (p=0.03). In conclusion, carrying an APOE epsilon4 allele is a poor prognostic factor in ALS. This is compatible with a role of apolipoprotein on neuronal survival and repair.

Adult↗
PubMed2001

APOE genotype is a major predictor of long-term progression of disability in MS.

BACKGROUND AND OBJECTIVE: The authors recently reported that the APOE epsilon4 allele is associated with significantly greater progression of disability in a 2-year follow-up of patients with MS. In this study, these findings are substantiated and extended in a much larger group of patients followed for up to 40 years. METHODS: Two hundred five patients with clinically definite MS who were genotyped for the APOE epsilon4 carrier state were included. Groups of patients with (n = 41) and without (n = 164) APOE epsilon4 alleles were compared for latency to expanded disability status scale (EDSS) scores of 4.0 and 6.0 by Kaplan-Meier analysis with the log rank test. The results were adjusted for age at onset and sex by Cox regression analysis. RESULTS: The APOE epsilon4 allele frequency in patients with MS (0.10) was similar to that in the general Israeli population. There was a significant effect of APOE genotype on the latency to reach EDSS 4.0 and 6.0 (p = 0.0002 and p = 0.0006 by two-tailed log rank test). Median latencies were shorter by 12 and 11 years in the APOE epsilon4 group for these outcomes. These results were significant after adjustment for age at onset and sex. CONCLUSIONS: The APOE epsilon4 allele is associated with significantly faster progression of disability in MS. This is the first genetic factor to be identified with a major impact on the progression of disability in this disease.

Adult↗
PubMed2001

Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival.

beta-Neuregulin (betaNRG) is a potent Schwann cell survival factor that binds to and activates a heterodimeric ErbB2/ErbB3 receptor complex. We found that NRG receptor signaling rapidly activated phosphoinositide 3-kinase (PI3K) in serum-starved Schwann cells, while PI3K inhibitors markedly exacerbated apoptosis and completely blocked NRG-mediated rescue. NRG also rapidly signaled the phosphorylation of mitogen-activated protein kinase (MAPK) and the serine/threonine kinase Akt. The activation of Akt and MAPK in parallel pathways downstream from PI3K resulted in the phosphorylation of Bad at different serine residues. PI3K inhibitors that blocked NRG-mediated rescue also blocked the phosphorylation of Akt, MAPK, and Bad. However, selective inhibition of MEK-dependent Bad phosphorylation downstream from PI3K had no effect on NRG-mediated survival. Conversely, ectopic expression of wild-type Akt not only enhanced Bad phosphorylation but also enhanced autocrine- and NRG-mediated Schwann cell survival. Taken together, these results demonstrate that NRG receptor signaling through a PI3K/Akt/Bad pathway functions in Schwann cell survival.

Animals↗
PubMed1998

Repressor elements in the coding region of the human histone H4 gene interact with the transcription factor CDP/cut.

The coding region of the human histone H4 gene FO108 undergoes dynamic changes in chromatin structure that correlate with modifications in gene expression. Such structural alterations generally reflect transcription factor interactions with gene regulatory sequences. To test for regulatory elements within the coding region, we performed transient transfection experiments in HeLa cells using constructs with histone H4 sequences fused upstream of a heterologous thymidine kinase promoter and CAT reporter gene. H4 gene sequences from -10 to +210 repressed transcription 4.8-fold. Further deletion and mutational analysis delineated three repressor elements within this region. Using oligonucleotide competition analysis and specific antibody recognition in electrophoretic mobility shift assays, as well as methylation interference and DNase I footprinting analyses, we have identified the CCAAT displacement protein (CDP/cut) as the factor that interacts with these three repressor elements. CDP/cut binding to these repressor sites is proliferation-specific and cell-cycle-regulated, increasing in mid to late S phase. Our results indicate that the proximal 200 nucleotides of the histone H4-coding region contain transcriptional regulatory elements that may contribute to cell-cycle control of histone gene expression by interacting with repressor complexes containing CDP/cut homeodomain transcription factors.

Base Sequence↗
PubMed1998

Traumatic asphyxia following stadium crowd surge: stadium factors affecting outcome.

BACKGROUND: Stadium crowd surges frequently occur following major athletic events. A recent crowd surge injured more than 80 persons by trampling and/or crushing. This incident was reviewed to identify injury patterns consistent with crush-related injury. In addition, the incident was reviewed to determine which stadium policy and design factors may have potentiated this event. METHODS: A recent crowd surge occurred following a college football game. This resulted in 86 people being transported to the University of Wisconsin and other area hospitals. All charts were reviewed to evaluate patient outcomes. The stadium was examined as were security system video tapes to evaluate stadium factors that contributed to this event. Current policies were obtained through the university sports administration. RESULTS: Of 86 patients transported for evaluation of stadium-related injuries, 10 were treated for traumatic asphyxia. Other injuries requiring hospital admission included musculo-skeletal trauma in two patients and one grade II liver injury. Six others were admitted overnight for observation. Several stadium factors were identified that contributed to the event, and appropriate changes in crowd control policies and stadium design were instated to prevent recurrence. CONCLUSIONS: This report details the largest single report of traumatic asphyxia second to the England Hillsborough disaster. Several stadium factors were identified that resulted in crush-related injury. Cooperative review and modification of stadium policies and design may prevent such events in the future.

Adolescent↗
PubMed1996

CDP/cut is the DNA-binding subunit of histone gene transcription factor HiNF-D: a mechanism for gene regulation at the G1/S phase cell cycle transition point independent of transcription factor E2F.

Transcription of the genes for the human histone proteins H4, H3, H2A, H2B, and H1 is activated at the G1/S phase transition of the cell cycle. We have previously shown that the promoter complex HiNF-D, which interacts with cell cycle control elements in multiple histone genes, contains the key cell cycle factors cyclin A, CDC2, and a retinoblastoma (pRB) protein-related protein. However, an intrinsic DNA-binding subunit for HiNF-D was not identified. Many genes that are up-regulated at the G1/S phase boundary are controlled by E2F, a transcription factor that associates with cyclin-, cyclin-dependent kinase-, and pRB-related proteins. Using gel-shift immunoassays, DNase I protection, and oligonucleotide competition analyses, we show that the homeodomain protein CDP/cut, not E2F, is the DNA-binding subunit of the HiNF-D complex. The HiNF-D (CDP/cut) complex with the H4 promoter is immunoreactive with antibodies against CDP/cut and pRB but not p107, whereas the CDP/cut complex with a nonhistone promoter (gp91-phox) reacts only with CDP and p107 antibodies. Thus, CDP/cut complexes at different gene promoters can associate with distinct pRB-related proteins. Transient coexpression assays show that CDP/cut modulates H4 promoter activity via the HiNF-D-binding site. Hence, DNA replication-dependent histone H4 genes are regulated by an E2F-independent mechanism involving a complex of CDP/cut with cyclin A/CDC2/ RB-related proteins.

Base Sequence↗
PubMed1995

Cytokine induction of proliferation and expression of CDC2 and cyclin A in FDC-P1 myeloid hematopoietic progenitor cells: regulation of ubiquitous and cell cycle-dependent histone gene transcription factors.

To evaluate transcriptional mechanisms during cytokine induction of myeloid progenitor cell proliferation, we examined the expression and activity of transcription factors that control cell cycle-dependent histone genes in interleukin-3 (IL-3)-dependent FDC-P1 cells. Histone genes are transcriptionally upregulated in response to a series of cellular regulatory signals that mediate competency for cell cycle progression of the G1/S-phase transition. We therefore focused on factors that are functionally related to activity of the principal cell cycle regulatory element of the histone H4 promoter: CDC2, cyclin A, as well as RB- and IRF-related proteins. Comparisons were made with activities of ubiquitous transcription factors that influence a broad spectrum of promoters independent of proliferation or expression of tissue-specific phenotypic properties. Northern blot analysis indicates that cellular levels of cyclin A and CDC2 mRNAs increase when DNA synthesis and H4 gene expression are initiated, supporting involvement in cell cycle progression. Using gel-shift assays, incorporating factor-specific antibody and oligonucleotide competition controls, we define three sequential period following cytokine stimulation of FDC-P1 cells when selective upregulation of a subset of transcription factors is observed. In the initial period, the levels of SP1 and HiNF-P are moderately elevated; ATF, AP-1, and HiNF-M/IRF-2 are maximal during the second period; while E2F and HiNF-D, which contain cyclin A as a component, predominate during the third period, coinciding with maximal H4 gene expression and DNA synthesis. Differential regulation of H4 gene transcription factors following growth stimulation is consistent with a principal role of histone gene promoter elements in integrating cues from multiple signaling pathways that control cell cycle induction and progression. Regulation of transcription factors controlling histone gene promoter activity within the context of a staged cascade of responsiveness to cyclins and other physiological mediators of proliferation in FDC-P1 cells provides a paradigm for experimentally addressing interdependent cell cycle and cell growth parameters that are operative in hematopoietic stem cells.

Base Sequence↗
PubMed1993

Infection with Moloney murine sarcoma virus inhibits myogenesis and alters the myogenic-associated (2'-5')oligoadenylate synthetase expression and activity.

Infection of rat skeletal muscle cultures on the first or second day in vitro with Moloney murine sarcoma virus (MSV) led to the arrest of myotube formation and to inhibition of both the synthesis of the muscle-specific proteins acetylcholine receptors and creatine kinase and the expression of the myosin light chain-2. Mos-specific RNA transcripts were readily detected at 1 day after infection indicating that viral genes were expressed in infected cells. In parallel, the expression of the cell growth-associated gene--c-myc--in uninfected muscle cultures was drastically reduced with time, while in MSV-infected myoblasts, the amount of c-myc-specific RNA transcripts gradually increased with time after infection. Under these conditions we could demonstrate that the interferon-induced gene (2'-5')oligoadenylate synthetase (2-5A synthetase) was transiently activated in uninfected muscle culture reaching a peak activity on the third day. Infection of myoblasts with murine leukemia virus did not alter the pattern of 2-5 synthetase activity observed in uninfected cells. However, infection with MSV on the second day led to a slight reduction in activity followed by a significant increase on the sixth and seventh day. Similarly, 2-5A synthetase gene expression was down-regulated with time in culture in uninfected myoblasts while re-expressed between the fourth and seventh days in MSV-infected cultures.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Rationing health care. Impact on critical care.

Critical care practitioners are faced with ethical dilemmas every day. The increasing costs of health care coupled with the scarcity of resources, including critical care nurses, have created yet another ethical dilemma--rationing of health care. Rationing of critical care is occurring today and current conditions indicate that these decisions will become an increasing issue in the delivery of critical care services. This article identifies some of the ethical issues associated with the rationing of critical care and examines the foundations of ethical thought upon which such decisions can be based. Understanding the overall cost containment movement as well as the potential problems associated with medical gatekeeping will allow critical care practitioners to better deal with the ethical dilemmas of today as well as help them anticipate those that will arise in the near future.

Cost Control↗
PubMed1990

Activation of the interferon system during myogenesis in vitro.

Differentiation of skeletal muscle involves withdrawal of myoblasts from cell replication, fusion to form multinucleated myotubes, coordinate appearance of a variety of muscle-specific proteins and the disappearance of a set of other proteins responsible for cell growth. The possible activation of the interferon (IFN) system in this process was studied. Thus, the activity of two IFN-induced enzymes known to be part of the system-(2'-5') oligoadenylate synthetase (2-5A synthetase) and double-stranded RNA-activated protein kinase as well as the expression of 2-5A synthetase coding genes were examined during myogenesis. It is demonstrated that the activity of the enzymes is transiently increased in cultured myoblasts, reaching a peak activity on the 3rd day in culture and then declining to a basal level. This peak activity precedes both cell fusion and the appearance of muscle-specific proteins--acetylcholine receptors (AChR) and creatine kinase. The same kinetics of 2-5A synthetase activity was evident in myoblasts from chick, rat or mouse origin. The enzymatic product appears to be primarily the trimer form of 2-5A, rather than a set of oligomers observed in enzymatic reactions performed on IFN-treated cells, including muscle cultures. The kinetics of 2-5A synthetase gene expression revealed that the largest amount of specific RNA transcripts appeared on the 1st day after seeding, followed by a reduction thereafter. In addition, a decrease was also observed in expression of c-myc, a cell-growth-associated protooncogene. However, an increase towards the 2nd day of both AChR and myosin light chain gene expression was evident, indicating selective regulation of gene expression during myogenesis.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Involvement of interferon-system in the regulation of cell growth and differentiation.

In this report we review the current knowledge on the involvement of the interferon (IFN) system in the regulation of cell growth and differentiation. We also summarize our own data which provide evidence for the strong correlation between IFN-mediated growth-arrest of transformed cells and the elevated enzymatic activity of an IFN-induced protein. Similarly, it is demonstrated that elevated levels of IFN-induced proteins accompany the early phases of in-vitro cell differentiation. IFN-treatment of NIH/3T3 mouse fibroblasts transformed by Moloney-murine sarcoma virus (MSV) resulted in a significant reduction in the rates of cell growth, protein synthesis and cloning efficiency. In parallel, 2-5A-synthetase activity was induced ten-fold above the background level. Treatment of these cells for 3 days with 450 international units (IU)/ml of IFN followed by its removal, resulted in a gradual increase in all parameters associated with cell growth while the 2-5A-synthetase activity was reduced to its normal level. However, almost no recovery occurred when cells were treated with 1,800 IU/ml. In parallel, 2-5A-synthetase activity remained highly elevated even at 3 days after the removal of IFN. In these cells, the expression of both c-myc and v-mos was reduced rapidly following IFN treatment. Upon removal of IFN after 24 h of treatment, the expression of both genes was resumed but with a different kinetics, suggesting that different mechanisms are responsible for the reduction in gene expression. In rat skeletal muscle cultures which differentiate to form myotubes, the level of both 2-5A-synthetase and protein kinase activities was transiently elevated, reaching a peak at 3 days followed by a decrease to background levels. This peak activity precedes the appearance of the major muscle differentiating proteins.

2',5'-Oligoadenylate Synthetase↗