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S Ludwig

Publications and source records attributed to S Ludwig.

At least 73 records · Page 4Linked to original sources
PubMed1999

A fatal relationship--influenza virus interactions with the host cell.

Influenza A viruses are important worldwide pathogens for humans and different animal species. The infectious agent is the prototype of the orthomyxoviridae which are characterized by a segmented negative strand RNA genome that is replicated in the nucleus of the infected cell. The genome has a combined coding capacity of about 13 kb and contains the genetic information for ten viral proteins. Despite this relatively small coding capacity--large DNA viruses like herpes or poxviruses express about 150-200 gene products--influenza A viruses are able to successfully infect and multiply in a wide range of mammalian and avian species. It is therefore not surprising that influenza A viruses extensively use and manipulate host cell functions. This includes multiple interactions of viral proteins with cellular proteins. In recent years an increasing amount of information about the identity of the cellular factors that are involved in viral transcription and replication, intracellular trafficking of viral components and assembly of the virus particle has accumulated. This article aims to review recent developments in this field with a focus on cellular factors and processes which are activated by the virus to either support viral replication or to counteract host-cell defense mechanisms.

Animals↗
PubMed1998

The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway.

Cell response to a wide variety of extracellular signals is mediated by either mitogenic activation of the Raf/MEK/ERK kinase cascade or stress-induced activation of the mitogen-activated protein kinase (MAPK) family members c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) or p38. We have examined communications between these stress- and mitogen-induced signaling pathways. We show here that the stress cascade activator arsenite activates extracellular signal-regulated kinase (ERK) in addition to p38 albeit with different kinetics. Whereas p38 is an early response kinase, ERK activation occurs with delayed time kinetics at 2-4 h. We observed activation of ERK upon arsenite treatment in many different cell lines. ERK activation is strongly enhanced by overexpression of p38 and mitogen-activated protein kinase kinase 6 (MKK6) but is blocked by dominant negative kinase versions of p38 and MKK6 or the specific p38 inhibitor SB203580. Arsenite-induced ERK activation is mediated by Ras, Raf, and MEK but appears to be independent of de novo protein synthesis. These data provide the first evidence for a p38 dependent activation of the mitogenic kinase cascade in stress-stimulated cells.

Arsenites↗
PubMed1998

1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association.

OBJECTIVE: To revise and expand the 1992 edition of the clinical practice guidelines for the management of diabetes in Canada incorporating recent advances in diagnosis and outpatient management of diabetes mellitus and to identify and assess the evidence supporting these recommendations. OPTIONS: All aspects of ambulatory diabetes care, including organization, responsibilities, classification, diagnosis, management of metabolic disorders, and methods for screening, prevention and treatment of complications in all forms of diabetes were reviewed, revised as required and expressed as a set of recommendations. OUTCOMES: Reclassification of types of diabetes based on pathogenesis; increased sensitivity of diagnostic criteria; recommendations for screening for diabetes; improved delivery of care; recommendations for tighter metabolic control; and optimal methods for screening, prevention and treatment of complications of diabetes. EVIDENCE: All recommendations were developed using a justifiable and reproducible process involving an explicit method for the citation and evaluation of the supporting evidence. VALUES: All recommendations were reviewed by an expert committee that included people with diabetes, family physicians, dietitians, nurses, diabetologists, as well as other subspecialists and methodologists from across Canada. BENEFITS, HARM AND COSTS: More aggressive screening strategies and more sensitive testing and diagnostic procedures will allow earlier detection and management of diabetes. Cost-effectiveness analyses suggest that this will lead to savings in health care costs relating to diabetes care by reducing the incidence of complications of diabetes. Similarly, tighter metabolic control in most people with diabetes, through intensive diabetes management, seeks to reduce the incidence of complications and, hence, their associated social and economic burdens. RECOMMENDATIONS: This document contains numerous detailed recommendations pertaining to all aspects of ambulatory diabetes care, ranging from service delivery to prevention and treatment of diabetes-related complications. The terms "insulin-dependent diabetes mellitus" and "non-insulin-dependent diabetes mellitus" should be replaced by the terms "type 1" and "type 2" diabetes. Testing for diabetes using fasting plasma glucose (FPG) level should be performed every 3 years in those over 45 years of age. More frequent or earlier testing should be considered for people with additional specific risk factors for diabetes. The FPG level at which diabetes is diagnosed should be reduced from 7.8 to 7.0 mmol/L to improve the sensitivity of the main diagnostic criterion and reduce the number of missed diagnoses. Depending on the type of diabetes and the therapy required to achieve euglycemia, people with diabetes should generally strive for close metabolic control to achieve optimal glucose levels. This entails receiving appropriate diabetes education through a diabetes health care team, diligent self-monitoring of blood glucose, attention to lifestyle and adjustments in diet and physical activity, and the appropriate and stepwise use of oral agents and insulin therapies needed to maintain glycemic control. Also highlighted is the need for appropriate surveillance programs for complications and management options. VALIDATION: All recommendations were graded according to the strength of the evidence and consensus of all relevant stakeholders. Collateral efforts of the American Diabetes Association and the World Health Organization and the input of international experts were also considered throughout the revision process.

Canada↗
PubMed1997

Cyclical etidronate: its effect on bone density in patients with acute spinal cord injury.

OBJECTIVE: To compare the effects of a 30-week trial of cyclical etidronate therapy (starting within 6 weeks of spinal cord injury [SCI] and conventional rehabilitation without etidronate treatment on the bone density of the lumbar spine and lower extremities of SCI patients. DESIGN: Prospective, randomized control trial. SETTING: Tertiary care, inpatient rehabilitation center. PATIENTS: Acute SCI, within 6 weeks of injury. Thirteen SCI subjects were recruited; 6 were assigned randomly to receive etidronate and 7 to receive conventional treatment. INTERVENTION: Etidronate, 800 mg orally, once per day for 2 weeks of 15 weeks, repeated once. MAIN OUTCOME MEASURES: Dual X-ray absorptiometry of the spine, hip, distal femur, and proximal tibia measured at baseline, 6 months, and 12 months. RESULTS: A significant interaction between etidronate treatment and ambulatory status over time was observed in the bone density of the patients after SCI (p = .0003). The patients who became ambulatory and received etidronate treatment had a preservation of bone density as compared to all other patients who showed a loss of bone density over time. The loss of bone density occurred in the leg bones, not the spine. Cyclical etidronate treatment was tolerated well without adverse or side effects. CONCLUSION: Cyclical etidronate is a feasible treatment and may prevent osteoporosis associated with SCI in patients who eventually walk.

Acute Disease↗
PubMed1997

Prevalence of recurring BRCA mutations among Ashkenazi Jewish women with breast cancer.

The BRCA1 mutations 185delAG and 5382insC and the BRCA2 mutation 6174delT have been detected in a significant proportion of Ashkenazi Jewish women with early-onset breast cancer. A group of 236 Jewish women with breast cancer was screened for the presence of these alterations. Mutations were detected in 25.0% (59/236). Among women with breast cancer diagnosed at or before the age of 45, the prevalence of these mutations was 29.1% (42/144). Among women diagnosed with breast cancer after age 45, mutations were noted in 18.5% (17/92). Among women with a family history of breast or ovarian cancer, the likelihood of detecting a mutation was 32.1% (53/165). BRCA1 185delAG was the most common mutation overall (40/236, 16.9%). The ratio of BRCA1 185delAG to BRCA2 6174delT was 4.0 in women with early-onset breast cancer and 1.3 in women with breast cancer diagnosed after age 45. Clinical features such as age at diagnosis, family history of breast or ovarian cancer, bilateral breast cancer, and personal history of breast and ovarian cancer increase the likelihood of detecting mutations among Ashkenazi women with breast cancer. The yield of testing is low in the absence of any of these features.

Adult↗
PubMed1997

Factors influencing termination of resuscitative efforts in children: a comparison of pediatric emergency medicine and adult emergency medicine physicians.

OBJECTIVES: To examine factors that influence termination of resuscitative efforts (TORE) and compare pediatric emergency medicine (PEM) and general emergency medicine (GEM) physicians regarding TORE in children. DESIGN: Cross-sectional survey. PARTICIPANTS: All physicians board-certified in PEM as of November 1993 and a random sample of board-certified GEM physicians listed in the 1993 American College of Emergency Physicians directory. INTERVENTIONS: Self-administered questionnaires were mailed to participants who were asked about experience providing pediatric cardiopulmonary resuscitation (CPR) and demographic information. We posed a series of management questions eliciting factors that influence TORE decision-making in single context and case scenario format. Specific emphasis was placed on the influence of time and epinephrine dosing. RESULTS: One hundred and sixty (70%) PEM and 127 (62%) GEM responded. These groups differed significantly in years of experience (PEM 8.2, GEM 11.8), urban practice setting (PEM 84%, GEM 32%) and number of pediatric cardiopulmonary resuscitations per year (PEM 10.6, GEM 4.8), P < 0.001 for all. There were no significant differences between groups regarding features pathognomonic of death. PEM were more likely to consider low blood pH and iatrogenic causes of arrest as factors influencing TORE; GEM were more likely to consider co-morbid conditions (P < 0.05 for all). Medians for time estimates of minimum minutes of pulselessness that influence TORE were: PEM 26 to 30 minutes, GEM 31 to 35 minutes for both prehospital and emergency department settings (P < 0.05 for each). Approximately 20% of all respondents did not place a strict limit on time of pulselessness when determining TORE. No difference was observed between groups regarding maximum doses of epinephrine used prior to TORE. However, fewer GEM (50%) than PEM (75%) utilize "high dose" epinephrine according to current Pediatric Advanced Life Support (PALS) guidelines (P < 0.05). PEM physicians were more than two times more likely to terminate resuscitative efforts if return of spontaneous circulation was not achieved by 25 minutes compared to GEM physicians for both prehospital time of pulselessness [odds ratio 2.1, 95% confidence interval (1.01, 4.5)] and emergency department time of pulselessness [odds ratio 2.2, confidence interval (1.1, 4.6)]. CONCLUSIONS: 1) Several laboratory and clinical factors significantly influence physician's decisions regarding TORE; 2) regardless of setting, time of pulselessness does appear to be an influential factor in determining when to terminate resuscitation in children for most physicians; 3) PEM physicians are more likely to terminate resuscitative efforts than are GEM physicians if return of spontaneous circulation is not achieved by 25 minutes; 4) a significant number of PEM and GEM physicians do not use high dose epinephrine in accordance with current PALS recommendations.

Adolescent↗
PubMed1997

Antigenic and genetic analyses of H1N1 influenza A viruses from European pigs.

H1N1 influenza A viruses isolated from pigs in Europe since 1981 were examined both antigenically and genetically and compared with H1N1 viruses from other sources. H1N1 viruses from pigs and birds could be divided into three groups: avian, classical swine and 'avian-like' swine viruses. Low or no reactivity of 'avian-like' swine viruses in HI tests with monoclonal antibodies raised against classical swine viruses was associated with amino acid substitutions within antigenic sites of the haemagglutinin (HA). Phylogenetic analysis of the HA gene revealed that classical swine viruses from European pigs are most similar to each other and are closely related to North American swine strains, whilst the 'avian-like' swine viruses cluster with avian viruses. 'Avian-like' viruses introduced into pigs in the UK in 1992 apparently originated directly from strains in pigs in continental Europe at that time. The HA genes of the swine viruses examined had undergone limited variation in antigenic sites and also contained fewer potential glycosylation sites compared to human H1N1 viruses. The HA exhibited antigenic drift which was more marked in 'avian-like' swine viruses than in classical swine strains. Genetic analyses of two recent 'avian-like' swine viruses indicated that all the RNA segments are related most closely to those of avian influenza A viruses.

Amino Acid Sequence↗
PubMed1997

Incidence and prevalence of diabetes in children aged 0-14 years in Manitoba, Canada, 1985-1993.

OBJECTIVE: To estimate the incidence and prevalence of type I diabetes among Manitoba children aged 0-14 years from 1985-1993. RESEARCH DESIGN AND METHODS: The Manitoba Diabetes Database (a population-based database of individuals diagnosed with diabetes based on Manitoba's health insurance system) was used to estimate the annual incidence of diabetes for the years 1985-1993 and the point prevalence of diabetes at 31 March 1993 for Manitoba children aged 0-14 years. The Diabetes Education Resource for Children and Adolescents program database was used to correct incidence and prevalence rates for ascertainment using the two-source capture-recapture method. RESULTS: The overall ascertainment rate of the Manitoba Diabetes Database was 95% for incident cases and 93% for prevalent cases. The average annual incidence was 20.4 per 100,000 for children aged 0-14 years. The annual incidence appears to be stable for all age-groups 0-14 years over the past decade. The point prevalence of diabetes among children was 120.4 per 100,000. CONCLUSIONS: The incidence of type I diabetes in children aged 0-14 years in Manitoba is higher than reported previously in other urban regions of Canada, but similar to population-based estimates from Prince Edward Island. The incidence appears stable in Manitoba over the past decade even in the 0-4 year age-group. The Manitoba Diabetes Database appears to be a highly accurate population-based source of data on the epidemiology of diabetes in children.

Adolescent↗
PubMed1996

Previous H1N1 influenza A viruses circulating in the Mongolian population.

Four influenza A viruses of the subtype H1N1, isolated from Mongolian patients in Ulaanbaatar between 1985 and 1991, were analysed by sequencing of various RNA segments. The isolate from 1985 was found to be highly related in all genes sequenced to strains isolated from camels in the same region and at about the same time. These camel isolates were presumably derived from a UV-light inactivated reassortant vaccine (PR8 x USSR/77) prepared in Leningrad in 1978 and used in the Mongolian population at that time [19]. The human isolate from 1988 was also found to be a derivative of a reassortant between PR8 and USSR/77; in contrast to the 1985 isolate, however, it contained an HA closely related to PR8. One of the Mongolian isolates from 1991 (111/91) was in all genes sequenced closely related to PR8, while the other isolate from 1991 (162/91) was closely related to H1N1 strains isolated around 1986 in other parts of the world. About 12% of 235 convalescent sera collected in various parts of Mongolia contained antibodies against PR8, while none of German control sera contained such antibodies. The mutational and evolutionary rates of the Mongolian strains seem to be significantly lower when compared to the rates of human influenza A strains isolated in other parts of the world. This might indicate that these rates depend to a certain extent on the population density. Thus, viruses from remote areas might keep the potential to reappear in the human population after several years to cause a pandemic as it had happened in 1977.

Adolescent↗
PubMed1996

3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways.

Recently we have identified a mitogen-activated protein kinase (MAPK)-activated protein kinase, named 3pK (G. Sithanandam, F. Latif, U. Smola, R. A. Bernal, F.-M. Duh, H. Li, I. Kuzmin, V. Wixler, L. Geil, S. Shresta, P. A. Lloyd, S. Bader, Y. Sekido, K. D. Tartof, V. I. Kashuba, E. R. Zabarovsky, M. Dean, G. Klein, B. Zbar, M. I. Lerman, J. D. Minna, U. R. Rapp, and A. Allikmets, Mol. Cell. Biol. 16:868-876, 1996). In vitro characterization of the kinase revealed that 3pK is activated by ERK. It was further shown that 3pK is phosphorylated in vivo after stimulation of cells with serum. However, the in vivo relevance of this observation in terms of involvement of the Raf/MEK/ERK cascade has not been established. Here we show that 3pK is activated in vivo by the growth inducers serum and tetradecanoyl phorbol acetate in promyelocytic HL60 cells and transiently transfected embryonic kidney 293 cells. Activation of 3pK was Raf dependent and was mediated by the Raf/MEK/ERK kinase cascade. 3pK was also shown to be activated after stress stimulation of cells. In vitro studies with recombinant proteins demonstrate that in addition to ERK, members of other subgroups of the MAPK family, namely, p38RK and Jun-N-terminal kinases/stress-activated protein kinases, were also able to phosphorylate and activate 3pK. Cotransfection experiments as well as the use of a specific inhibitor of p38RK showed that these in vitro upstream activators also function in vivo, identifying 3pK as the first kinase to be activated through all three MAPK cascades. Thus, 3pK is a novel convergence point of different MAPK pathways and could function as an integrative element of signaling in both mitogen and stress responses.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1996

Incidence and prevalence of diabetes in Manitoba, 1986-1991.

OBJECTIVE: To estimate the incidence and prevalence of diabetes among adults in Manitoba, Canada, from 1986 to 1991. RESEARCH DESIGN AND METHODS: A population-based database of individuals diagnosed with diabetes (Manitoba Diabetes Database) was created using data from Manitoba Health's comprehensive insurance system. Using this database, estimates of the annual incidence and prevalence of diabetes among Manitoba adults aged > or = 25 years were made for the years 1986-1991. Age-specific and age-adjusted rates were calculated separately for men and women. RESULTS: The prevalence of diabetes in 1991 was 66.9/1,000 among adults > or = 25 years. Between 1986 and 1991 the age-adjusted prevalence rose steadily among both men and women. In 1991, the incidence of diabetes was 5.6/1,000. After an observed decline prior to 1989, the annual incidence of diabetes appears to be relatively stable. CONCLUSIONS: The prevalence of diabetes is increasing steadily despite relatively stable incidence rates. Population-based data are required for projecting future trends and are an important tool for planning the required health resources.

Adult↗
PubMed1995

European swine virus as a possible source for the next influenza pandemic?

According to phylogenetic data, about 100 years ago an avian influenza virus passed the species barrier (possibly first) to pigs and (possibly from there) to humans. In 1979 an avian influenza A virus (as a whole, without reassortment) again entered the pig population in northern Europe, forming a stable lineage. Here it is shown that the early North European swine viruses exhibit higher than normal evolutionary rates and are highly variable with respect to plaque morphology and neutralizability by monoclonal antibodies. Our results are consistent with the idea that, in order to pass the species barrier, an influenza A virus needs a mutator mutation to provide an additional number of variants, from which the new host might select the best fitting ones. A mutator mutation could be of advantage under such stress conditions and might enable a virus to pass the species barrier as a whole even twice, as it seems to have happened about 100 years ago. This stressful situation should be over for the recent swine lineage, since the viruses seem to be adapted already to the new host in that the most recent isolates--at least in northern Germany--are genetically stable and seem to have lost the putative mutator mutation again.

Animals↗
PubMed1995

Amino acid replacements leading to temperature-sensitive defects of the NS1 protein of influenza A virus.

The nonstructural (NS) genes of two influenza virus temperature-sensitive (ts) reassortants have been sequenced and compared with the corresponding wild type sequences. Ts 412 has a single base substitution (G100-->A) leading to an amino acid replacement (Arg 25-->Lys) in the NS1 protein. Ts 451 also has a single base substitution (U273-->C) leading to an amino acid replacement (Ser 83-->Pro) in the NS1 protein. In ts 412 infected cells at the nonpermissive temperature very little M1 and HA mRNA and proteins are synthesized, suggesting that NS1 is involved in a transcriptional regulation process. The ts mutation in ts 451 could be extragenically suppressed by replacement of the PB1 and/or PA protein genes of the mutant by the allelic genes of PR8. Both observations suggest that NS1 cooperates with the polymerase complex.

Influenza A virus↗
PubMed1995

Ten-year review of pediatric bathtub near-drownings: evaluation for child abuse and neglect.

STUDY OBJECTIVE: To evaluate the risk factors associated with bathtub submersion injury and their relationship to child abuse and neglect. DESIGN: Retrospective chart review. SETTING: An urban children's hospital. PARTICIPANTS: Any child sustaining a bathtub near-drowning over the 10-year period from 1982 to 1992. INTERVENTIONS: None. RESULTS: Twenty-one patients were treated for bathtub near-drownings during the 10-year period, accounting for 24% of all submersion injuries. A significant number (67%) had historic and/or physical findings suspicious for abuse or neglect, including incompatible history for the injury, other physical injuries, previous child abuse reports, psychiatric history of the caretaker, and/or psychosocial concerns noted in the chart. The mortality rate of 42% was significant. No demographic characteristics identified the children at risk. CONCLUSION: Many children who are injured in the bathtub suffer from abuse or neglect. Medical evaluation should include social work consultation and a search for other accompanying injuries.

Child↗