Distinct and overlapping direct effects of macrophage inflammatory protein-1 alpha and transforming growth factor beta on hematopoietic progenitor/stem cell growth

Both transforming growth factor beta (TGF beta) and macrophage inflammatory protein 1 alpha (MIP-1 alpha) have been shown to be multifunctional regulators of hematopoiesis that can either inhibit or enhance the growth of hematopoietic progenitor cells (HPC). We report here the spectrum of activities of these two cytokines on different hematopoietic progenitor and stem cell populations, and whether these effects are direct or indirect. MIP-1 alpha enhances interleukin-3 (IL- 3)/and granulocyte-macrophage colony-stimulating factor (GM- CSF)/induced colony formation of normal bone marrow progenitor cells (BMC) and lineage-negative (Lin-) progenitors, but has no effect on G- CSF or CSF-1/induced colony formation. Similarly, TGF beta enhances GM- CSF/induced colony formation of normal BMC and Lin- progenitors. In contrast, TGF beta inhibits IL-3/ and CSF-1/induced colony formation of Lin- progenitors. The effects of MIP-1 alpha and TGF beta on the growth of Lin- progenitors were direct and correlate with colony formation in soft agar. Separation of the Lin- cells into Thy-1 and Thy-1lo subsets showed that the growth of Thy-1lo Lin- cells is directly inhibited by MIP-1 alpha and TGF beta regardless of the cytokine used to stimulate growth (IL-3), GM-CSF, or CSF-1). In contrast, two other stem cell populations (0% to 15% Hoechst 33342/Rhodamine 123 [Ho/Rh123] and Lin- Sca-1+ cells) were markedly inhibited by TGF beta and unaffected by MIP- 1 alpha. Furthermore, MIP-1 alpha has no effect on high proliferative potential colony-forming cells 1 or 2 (HPP-CFC/1 or /2) colony formation in vitro, whereas TGF beta inhibits both HPP-CFC/1 and HPP- CFC/2. Thus, MIP-1 alpha and TGF beta are direct bidirectional regulators of HPC growth, whose effects are dependent on other growth factors present as well as the maturational state of the HPC assayed. The spectrum of their inhibitory and enhancing activities shows overlapping yet distinct effects.     

Phototherapy. Short and long-term complications

Use of phototherapy for hyperbilirubinaemia in 300 consecutively treated infants has shown that minor complications are common. With a knowledge of these complications and measures taken to minimize their effects, phototherapy appears to be safe in the short term. The long-term follow-up study showed that growth, and in particular head circumference, was not affected. There was, however, a higher incidence of squints and abnormal developmental performance in those infants treated with phototherapy. This may not have been due to phototherapy usage per se. However, because of these findings, it is suggested that phototherapy should not be used indiscriminately for hyperbilirubinaemia until the results of further long-term studies are available.     

Clinical characteristics of patients with ischemic ocular nerve palsies and lacunar brain infarcts: a retrospective comparative study

BACKGROUND: Ischemic ocular motor nerve palsies (IOMP) and lacunar brain infarcts share a similar pathological mechanism. The clinical characteristics of patients as well as the protective role of aspirin should therefore be similar in both conditions. METHODS: The medical records of 107 consecutive patients with IOMP and 160 patients with lacunar cerebrovascular accidents (CVA) were reviewed and analyzed with respect to patient characteristics, vascular risk factors, and aspirin intake. The data on patients with and without aspirin were compared within each group as well as between both groups. RESULTS: Hyperlipidemia, smoking, high carotid stenosis (>70%) and the presence of more than one vascular risk factor in an individual patient were found to be more common in patients with lacunar brain infarcts regardless of aspirin intake. Absence of vascular risk factors was encountered more in IOMP patients. The recurrence of lacunar CVA was significantly higher than recurrence of IOMP. A history of Bell's palsy was more common in IOMP patients than in patients with lacunar CVA. Within the IOMP group, the prevalence of vascular risk factors did not differ between the aspirin and non-aspirin group. Ischemic heart disease (IHD), CVA and recurrence were found more often in the aspirin group. Within the CVA group hypertension, IHD, cardiac arrhythmia and recurrence rate were more common in the aspirin group whereas smoking was found to be more common in the non-aspirin group of patients. CONCLUSIONS: Arteriosclerosis is the main cause of lacunar CVA and IOMP. However, IOMP depends less on the presence of vascular risk factors than does lacunar CVA. Furthermore, aspirin - at least at low doses - does not seem to have a protective effect on either of these conditions, but more extensive prospective studies of homogeneous groups of patients are needed to clarify the preventive role of antiplatelet agents in IOMP.     

Prevalence of <Emphasis Type="Italic">von Hippel-Lindau</Emphasis> gene mutations in sporadic renal cell carcinoma: results from the Netherlands cohort study

Background  

Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). We studied the VHL mutation status in a large population-based case group.     

The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome

Most targeted gene mutations are recessive and analyses of gene function often focus on homozygous mutant phenotypes. Here we describe parts of the expression pattern of M-twist in the head of developing wild-type mice and present our analysis of the phenotype of heterozygous twist- null animals at around birth and in adults. A number of twist -null heterozygous mice present skull and limb defects and, in addition, we observed other malformations, such as defects in middle ear formation and the xyphoid process. Our study is of interest to understand bone formation and the role of M-twist during this process, as within the same animal growth of some bones can be accelerated while for others it can be delayed. Moreover, we show here that expressivity of the mouse mutant heterozygous phenotype is dependent on the genetic background. This information might also be helpful for clinicians, since molecular defects affecting one allele of the human H-twist ( TWIST ) gene were identified in patients affected with Saethre-Chotzen syndrome (SCS). Expressivity of this syndrome is variable, although most patients present craniofacial and limb malformations resembling those seen in mutant mice. Thus the mutant mouse twist -null strain might be a useful animal model for SCS. The twist -null mutant mouse model, combined with other mutant mouse strains, might also help in an understanding of the etiology of morphological abnormalities that appear in human patients affected by other syndromes.      

Alterations in the Proportions of Skeletal Muscle Proteins following a Unilateral Lesion to the Substantia Nigra Pars Compacta of Rats

It is well established that mammalian skeletal muscles exhibit a considerable degree of plasticity and one of the main determining factors of this plasticity is the activity pattern and duration of motoneurone discharge. Lesions to the right substantia nigra pars compacta (SNpc) of six adult rats were made to determine whether altered output from the SNpc ultimately leads to a change in the expression of proteins in contralateral skeletal muscles. After 4 months, altered motor performance was identified by the administration of amphetamine. After 7 months, 30–70% of dopaminergic cells in the SNpc had been destroyed. The protein content of muscles was then quantified from densitometric scans of gels, and expressed as a % of the amount of actin (the protein used as a reference in this study). The lesion affected the expression of different protein isoforms in the fast- and slow-twitch muscles. In slow-twitch soleus muscles, the lesion decreased the proportion of α-tropomyosin and increased the proportion of β-tropomyosin. In the fast-twitch extensor digitorum longus muscles, the lesion increased the proportion of the fast isoform of troponin-T_1f, and decreased the proportions of the two isoforms of myosin light chain. This study establishes a connection between the chronic effects of a lesion to the SNpc, with a loss of dopaminergic neurones, impaired motor performance, and altered expression of proteins in skeletal muscle. The implication of these results is that the altered motor function observed in Parkinson’s disease may be associated with alterations to the expression of skeletal muscle proteins. Supported by grants from NH & MRC (DF) and Faculty of Health Sciences, LaTrobe University (PD).     

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.      

Microglia activation in sepsis: a case-control study

Background  

infection induces an acute phase response that is accompanied by non-specific symptoms collectively named sickness behavior. Recent observations suggest that microglial cells play a role in mediating behavioral changes in systemic infections. In animal models for sepsis it has been shown that after inducing lipopolysaccharide, LPS, microglia in the brain were activated. The aim of this study was to investigate whether activation of microglia can be detected in patients who died of sepsis.