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Biomedical subjects

M Salminen

Publications and source records attributed to M Salminen.

At least 19 recordsLinked to original sources
PubMed2006

E6/E7 oncogenes increase and tumor suppressors decrease the proportion of self-renewing neural progenitor cells.

Many if not most tissues need a controlled number of stem cells to maintain normal function. Cancer can be seen as a process of disturbed tissue homeostasis, in which too many cells have or acquire too primitive identity. Here we measured how oncogenes and tumour suppressors affect the differentiation capacity, proportion and characteristics of progenitor cells in a model tissue. Neural progenitor cells (NPCs) were exposed to human papilloma virus E6, E7 or E6/E7 oncogenes, which degrade tumour suppressors p53 and pRb family members, respectively. E6/E7-expressing or p53-/- NPCs were able to differentiate, but simultaneously retained high capacity for self-renewal, proliferation, ability to remain multipotent in conditions promoting differentiation and showed delayed cell cycle exit. These functions were mediated through p53 and pRb family, and involved MEK-ERK signalling. Decreased amount of p53 increased self-renewal and proliferation, whereas pRb affected only proliferation. Our results suggest that the oncogenes increase whereas p53 and pRb family tumour suppressors decrease the number and proportion of progenitor cells. These findings provide one explanation how oncogenes and tumour suppressors control tissue homeostasis and highlight their importance in stem cell self- renewal, linked both to cancer and life-long tissue turnover.

Animals↗
PubMed2005

Xenografted fetal dorsal root ganglion, embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve.

Sensorineural hearing loss is a disabling condition. In the post-embryonic and adult mammalian inner ear, the regeneration of auditory hair cells, spiral ganglion neurons or their axons does not occur naturally. This decrease in excitable neurons limits the success of auditory rehabilitation. Allografts and xenografts have shown promise in the treatment of a variety of neurological diseases. Fetal dorsal root ganglion (DRG) neurons can extend functional connections in the rat spinal cord. Embryonic stem cells (ES cells) and adult neural stem cells (ANSC) have the potential to differentiate into neurons. We have implanted embryonic days (E) 13-16 fetal mouse DRGs from transgenic mouse lines that express Enhanced Green Fluorescent Protein (EGFP) or lacZ reporter genes, EGFP-expressing ES cells or lacZ-expressing ANSC into the injured vestibulocochlear nerve of adult rats and guinea pigs. Survival of the implants was assessed 2 to 4 weeks postoperatively. For further evaluation of the differentiation of the implanted ES-cells, we double labeled with the mouse-specific neuronal antibody Thy 1.2. The rats implanted with EGFP- or lacZ-expressing DRGs showed labeled DRGs after sacrifice. In addition, EGFP-positive nerve fibers were seen growing within the proximal nerve. The results from the EGFP ES cells and lacZ ANSC revealed reporter-expressing cells at the site of injection in the vestibulocochlear nerve of the host rats and guinea pigs but also within the brain stem. Thy 1.2 profiles were seen among the EGFP ES cells within the 8th cranial nerve. The findings of this study indicate that the vestibulocochlear nerve of adult rats and guinea pigs will support xenotransplants of embryonic DRG, ES cells and ANSC. This may have future clinical applicability in recreating a neuronal conduit following neuronal injury between the inner ear and the central nervous system (CNS).

Animals↗
PubMed2004

Updated European recommendations for the clinical use of HIV drug resistance testing.

In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.

Anti-HIV Agents↗
PubMed2001

Evidence of two distinct subsubtypes within the HIV-1 subtype A radiation.

Members of HIV-1 group M are responsible for the vast majority of AIDS cases worldwide and have been classified on the basis of their phylogenetic relationships into nine roughly equidistant clades, termed subtypes. Although there are no known phenotypic correlates for these genotypes, the disproportionate spread of certain of these lineages has been taken to indicate that subtype-specific biological differences may exist. The subtype nomenclature thus remains an important molecular epidemiological tool with which to track the course of the group M pandemic. In this study, we have characterized HIV-1 strains described previously as unusual subtype A variants on the basis of partial sequence analysis. Six such strains from Cyprus (CY), South Korea (KR), and the Democratic Republic of Congo (CD) were PCR amplified from infected cell culture or patient PBMC DNA, cloned, and sequences in their entirety (94CY017, 97KR004, 97CDKTB48, and 97CDKP58) or as half genomes (97CDKS10 and 97CDKFE4). Distance and phylogenetic analyses showed that four of these viruses (94CY017, 97CDKTB48, 97CDKFE4, and 97CDKS10) were closely related to each other, but quite divergent from all other HIV-1 strains, except for subtype A viruses, which represented their closest relatives. In phylogenetic trees from gag, pol, env, and nef regions, the four newly characterized HIV-1 strains formed a distinct sister clade to subtype A, which was as closely related to subtype A as subsubtypes F1 and F2 are to each other. According to current nomenclature rules, this defines a subsubtype, which we have tentatively termed A2. The two other viruses, 97KR004 and 97CDKP58, as well as a full-length HIV-1 sequence from the sequence database (ZAM184), were found to represent complex A2/D, A2/G, and A2/C recombinants, respectively. These results indicate that HIV-1 subtype A is composed of two subsubtypes (A1 and A2), both of which appear to have a widespread geographic distribution. The A2 viruses described here represent the first reference reagents for this new group M lineage.

Cyprus↗
PubMed2001

HIV-1 subtypes in Denmark.

The objective of this study was to investigate the presence of non-subtype B HIV-1 in Denmark. The C2-V3-C3 region of the env gene from proviral DNA obtained from patients suspected of being infected with non-subtype B virus was PCR-amplified and directly sequenced. The DNA sequences were aligned with full-length HIV-1 reference strains from each subtype and analysed using the phylogenetic package PHYLIP 3.1. The neighbour-joining method was used with 100 bootstraps. Of the 144 patients included in this study C2-V3-C3 sequences were obtained from 129 patients (90%). The phylogenetic analyses showed that virus from 49 patients (38%) was subtype A, 39 (30%) subtype C, 9 (7%) subtype D, 14 (11%) subtype CRF01_AE, 16 (12%) subtype B, 1 (1%) subtype F and 1 (1%) subtype J. This study demonstrates that almost all subtypes can be detected in Denmark; all non-subtype B infections could be traced to countries with a high prevalence of non-subtype B virus.

DNA, Viral↗
PubMed2000

An AB recombinant and its parental HIV type 1 strains in the area of the former Soviet Union: low requirements for sequence identity in recombination. UNAIDS Virus Isolation Network.

In the former Soviet Union (SU) increasing numbers of HIV-1 infections among injecting drug users (IDU) have been reported, especially in the Ukraine. The main subtype transmitted among the IDUs seems to be subtype A, but limited numbers of subtype B cases have also been reported. In Kaliningrad, Russia, an AB recombinant strain was earlier shown to be responsible for the local outbreak. Here we describe the genetic relationship of HIV-1 strains circulating among IDUs in the former SU. For subtype A and the AB recombinant strains nearly full-length genomes were sequenced, and for one subtype B strain the entire envelope gene was cloned. The relationship between the AB recombinant strain and the subtype A and subtype B strains and the mosaic structure of the recombinant was studied by phylogenetic analysis. Ukrainian A and B strains were shown to be the probable parental viruses of the Kaliningrad AB recombinant strain. In the envelope gene the recombination breakpoint could also be precisely mapped to a region of similarity of only 14 base pairs. This suggests that only short stretches of absolute sequence identity may be needed for efficient RNA recombination between HIV-1 subtypes.

Base Sequence↗
PubMed2000

Molecular epidemiology of coxsackievirus B4 and disclosure of the correct VP1/2A(pro) cleavage site: evidence for high genomic diversity and long-term endemicity of distinct genotypes.

Genetic diversity among 107 coxsackievirus B4 field isolates has been studied. These isolates included clinical and environmental isolates originating from Finland, the Netherlands and France, and also from several other countries, including the USA. Three genomic regions were used for phylogenetic analyses: the VP1/2A junction, the entire VP1 and the VP4/VP2 region. Alignment of the deduced amino acid sequence in the VP1/2A junction revealed extensive sequence variation at the previously proposed cleavage site. MS analysis of proteolytic fragments from VP1 revealed that the exact cleavage site is situated between amino acid residues Thr-849 and Gly-850. At least seven distinct genetic lineages, or genotypes, had been circulating in Europe during the period 1959-1998. Two genotypes were endemic in the Netherlands during most of the investigated period. Genetically closely related strains could be found in different countries, and different genotypes co-circulated at the same time in a given country. Clustering patterns were identical in the three genomic intervals. In the VP4/VP2 region, the intraserotypic variation approached interserotype variation. Sequence comparisons of the entire VP1 gene gave a reliable genetic identification of enterovirus serotype. It is suggested that, for genotype classification of previously serotyped coxsackievirus B4 isolates, comparison of VP1/2A sequences is sufficient, but for more detailed investigation of genetic relationships, and for 'genetic serotyping', the entire VP1 gene should be used. The VP4/VP2 region is less reliable for genetic serotyping and genotyping, although the primers are able to amplify many different serotypes.

Amino Acid Sequence↗
PubMed2000

Simplified strategy for detection of recombinant human immunodeficiency virus type 1 group M isolates by gag/env heteroduplex mobility assay. Study Group on Heterogeneity of HIV Epidemics in African Cities.

We developed a heteroduplex mobility assay in the gag gene (gag HMA) for the identification of group M subtypes A to H. The assay covers the region coding for amino acid 132 of p24 to amino acid 20 of p7 (according to human immunodeficiency virus type 1 [HIV-1] ELI, 460 bp). The gag HMA was compared with sequencing and phylogenetic analysis of an evaluation panel of 79 HIV-1 group M isolates isolated from infected individuals from different geographic regions. Application of gag HMA in combination with env HMA on 252 HIV-1- positive plasma samples from Bénin, Cameroon, Kenya, and Zambia revealed a high prevalence of a variety of intersubtype recombinants in Yaoundé, Cameroon (53.8%); Kisumu, Kenya (26.8%); and Cotonou, Bénin (41%); no recombinants were identified among the samples from Ndola, Zambia. The AG(IbNG) circulating recombinant form, as determined by gag HMA, was found to be the most common intersubtype recombinant in Yaoundé (39.4%) and Cotonou (38.5%). Using a one-tube reverse transcriptase PCR protocol, this gag HMA in combination with env HMA is a useful tool for rapidly monitoring the prevalence of the various genetic subtypes as well as of recombinants of HIV-1. Moreover, this technology can easily be applied in laboratories in developing countries.

Base Sequence↗
PubMed2000

Netrin 1 is required for semicircular canal formation in the mouse inner ear.

The morphogenetic development of the mammalian inner ear is a complex multistep process, the molecular and cellular details of which are only beginning to be unraveled. We show here that mouse netrin 1, known to be involved in axon guidance and cell migration in the central nervous system, also plays a critical morphogenetic role during semicircular canal formation. netrin 1 is expressed at high levels in the otic epithelium, in cells that will come together to form a fusion plate, a prerequisite for the formation of semicircular canals. In netrin 1 mutant mice, fusion plate formation is severely affected resulting in a reduced anterior semicircular canal and the complete lack of the posterior and lateral canals. Our results suggest that netrin 1 facilitates semicircular canal formation through two different mechanisms: (1) it participates in the detachment of the fusion plate epithelia from the basement membrane, and (2) it stimulates proliferation of the periotic mesenchymal cells which then push the epithelial cell walls together to form the fusion plate.

Alleles↗
PubMed1999

Nutrient intakes and cholesterol values of the parents in a prospective randomized child-targeted coronary heart disease risk factor intervention trial--the STRIP project.

OBJECTIVE: To analyze food consumption, nutrient intakes and serum cholesterol concentrations of the parents in a child-targeted CHD intervention trial, during which the age of children increased from 7 months to 5 y. DESIGN AND SUBJECTS: The children were randomized to an intervention group (n = 540) or a control group (n = 522) at six months of age. The intervention families were counseled at 3-6 month intervals to reduce their child's intake of saturated fat and cholesterol. Dietary issues were discussed with the control families only briefly. The parents' food consumption was analyzed by 24 h dietary recall at the child's age of 7 and 13 months and at 2, 3, 4, and 5 y. Nutrient intakes were calculated using the Micro-Nutrica program. RESULTS: The mothers and fathers of the intervention children used less butter, more margarine and more skim milk than those of the control children (P < 0.001 for all measurements). After the onset of counseling, the intervention mothers consumed continuously less fat (1.4 E% less at the child's age of 5 y), less saturated fat (1.5 E% less at the child's age of 5 y) and more polyunsaturated fat (0.5 E% more at the child's age of 5 y) than the control mothers (P = 0.008, P < 0.001 and P < 0.001 for trend, respectively). After the child's age of 13 months the intervention fathers also had a continuously lower fat intake (2.4 E% less at the child's age of 5 y) and consumed less saturated fat (1.5 E% less at the child's age of 5 y) than the control fathers (P < 0.001 for trend for both measurements). The serum cholesterol concentration of the intervention mothers was consistently lower than that of the control mothers during the intervention (at child's age of 5 y 4.86 and 5.09 mmol/L, respectively; P for trend = 0.03), while the values of the intervention and control fathers showed no differences. CONCLUSIONS: Continuous dietary intervention begun in infancy and focused on modification of the child's diet according to the current principles of preventive cardiology, was accompanied by a moderate decrease in the intake of total and saturated fat in the parents, but serum cholesterol concentration diminished consistently only in the mothers of the intervention children.

Adult↗
PubMed1999

Evidence of recombination among enteroviruses.

Human enteroviruses consist of more than 60 serotypes, reflecting a wide range of evolutionary divergence. They have been genetically classified into four clusters on the basis of sequence homology in the coding region of the single-stranded RNA genome. To explore further the genetic relationships between human enteroviruses and to characterize the evolutionary mechanisms responsible for variation, previously sequenced genomes were subjected to detailed comparison. Bootstrap and genetic similarity analyses were used to systematically scan the alignments of complete genomic sequences. Bootstrap analysis provided evidence from an early recombination event at the junction of the 5' noncoding and coding regions of the progenitors of the current clusters. Analysis within the genetic clusters indicated that enterovirus prototype strains include intraspecies recombinants. Recombination breakpoints were detected in all genomic regions except the capsid protein coding region. Our results suggest that recombination is a significant and relatively frequent mechanism in the evolution of enterovirus genomes.

Enterovirus↗
PubMed1999

Muscle fatigue caused by repeated aerial combat maneuvering exercises.

BACKGROUND: Little is known about the development of in-flight muscular fatigue during repeated flights. HYPOTHESIS: This study was conducted to evaluate muscular fatigue in different upper body and neck muscles during repeated aerial combat maneuvering exercises. METHODS: Six pilots volunteered as test subjects. They performed one-to-one dog fight exercise three times (1 pilot, four times) in one day. During the flights, the pilots' electromyographic activity (EMG) was measured from the abdomen, back, neck and lateral neck. The mean muscular strain for each muscle was calculated. Before the first flight and after each flight, the maximal isometric strength of each muscle was measured. RESULTS: The results showed that maximal isometric strength between the first and last measurement decreased in the back, neck (p < 0.05) and lateral neck muscles. While the G-stress remained the same, the muscular strain during exercises increased in every muscle, but was significant only in neck and lateral neck (p < 0.05-0.01). Due to these changes, the fatigue index in the neck and lateral neck muscles was 2.0-2.1, and 1.3-1.4 (1.0 = no fatigue) in the abdomen and back muscles. CONCLUSIONS: Repeated aerial combat maneuvering exercises caused fatigue in every muscle studied. The fatigue was greater in the neck area, which may increase the risk for neck injuries, and may reduce mission effectiveness. The fighter pilots' muscular strength and endurance in the neck area are subjected to very high demands, especially if exercises are repeated several times. The recovery of the neck muscles from fatigue after repetitive exercises should receive special attention.

Abdominal Muscles↗
PubMed1998

Contribution of the CCR5 and MBL genes to susceptibility to HIV type 1 infection in the Finnish population.

Homozygosity for a variant of a chemokine receptor gene (CCR5) has been shown to protect from HIV-1 infection. Variants of the mannose-binding lectin (MBL) gene have been suggested to predispose to HIV-1 infection. These genetic variants and their possible role in susceptibility to HIV-1 infection were studied in sample material from more than 300 Finnish HIV-infected and control individuals. The genotyping was carried out efficiently using a novel, primer extension assay in a miniaturized oligonucleotide array format. Homozygotes for the protective deletion allele of the CCR5 gene were found only in the control group, and the frequency of the allele was high in the Finnish population. Homozygosity for the MBL variant alleles was enriched significantly in the HIV-1-infected group, thus providing further evidence for the harmfulness of MBL variant homozygosity in HIV-1 transmission.

Carrier Proteins↗
PubMed1998

Efficient poly A trap approach allows the capture of genes specifically active in differentiated embryonic stem cells and in mouse embryos.

Special vectors have been constructed that allow the trapping of genes in mouse embryonic stem (ES) cells. These vectors generally contain the neomycin phosphotransferase (neo) gene for selection and the beta-galactosidase (beta-gal) gene as a marker. Promoterless vectors can be used to identify genes that are active in undifferentiated ES cells. To also have access to genes that are inactive in totipotent ES cells, we constructed a polyadenylation (poly A) trap vector in which the expression of a poly A less neo gene is driven by a constitutive promoter, whereas the expression of beta-gal depends on the trapped sequences. We demonstrate here that this vector integrates with a high frequency into transcription units and that it traps genes with very different expression patterns in vitro and in vivo. The vector integrates efficiently into transcription units that are inactive in undifferentiated ES cells and which can be activated through in vitro differentiation. Furthermore, in vivo expression patterns demonstrate that this vector integrates into genes that exhibit a highly specific temporal and spatial expression pattern during embryogenesis.

Animals↗