Stem cell factor retards differentiation of normal human erythroid progenitor cells while stimulating proliferation

Stem cell factor (SCF), the ligand for the c-kit tyrosine kinase receptor, markedly stimulates the accumulation of erythroid progenitor cells in vitro. We now report that SCF delays erythroid differentiation among the progeny of individual erythroid progenitors while greatly increasing the proliferation of these progeny. These effects appear to be independent of an effect on maintenance of cell viability. Highly purified day-6 erythroid colony-forming cells (ECFC), consisting mainly of colony-forming units-erythroid (CFU-E), were generated from human peripheral blood burst-forming units-erythroid (BFU-E). Addition of SCF to the ECFC in serum-free liquid culture, together with erythropoietin (EP) and insulin-like growth factor 1 (IGF-1), resulted in a marked increase in DNA synthesis, associated with a delayed peak in cellular benzidine positivity and a delayed incorporation of 59Fe into hemoglobin compared with cultures without SCF. In the presence of SCF, the number of ECFC was greatly expanded during this culture period, and total production of benzidine-positive cells plus hemoglobin synthesis were ultimately increased. To determine the effect of SCF on individual ECFC, single-cell cultures were performed in both semisolid and liquid media. These cultures demonstrated that SCF, in the presence of EP and IGF-1, acted on single cells and their descendants to delay erythroid differentiation while substantially stimulating cellular proliferation, without an enhancement of viability of the initial cells. This was also evident when the effect of SCF was determined using clones of ECFC derived from single BFU-E. Our experiments demonstrate that SCF acts on individual day-6 ECFC to retard erythroid differentiation while simultaneously providing enhanced proliferation by a process apparently independent of an effect on cell viability or programmed cell death.     

The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma.

Ninety-two patients from 12 kindreds with hereditary medullary thyroid carcinoma (MTC) were evaluated. We sought to determine if the stimulated plasma calcitonin (CT) level at the time of diagnosis was of prognostic significance. The patients were divided into four groups according to their preoperative stimulated plasma CT levels (1) 250-1,000 pg/ml (n=25); (2) 1,000-5,000 pg/ml (n=36); (3) 5,000-10,000 pg/ml (n=8); (4) greater than 10,000 pg/ml (n=23). Compared between the four groups were several parameters, including incidence of regional lymph node metastases, incidence of residual MTC post-thyroidectomy (as indicated by increased (greater than 300 pg/ml) plasma CT levels after operation), incidence of distant metastases, and incidence of death. Also compared were the incidences of microscopic or gross MTC in thyroidectomy specimens. The incidence of regional lymph node involvement ranged from a minimum of one (4%) of 25 patients in Group 1 to 13 (57%) of 23 patients in Group 4. Similarly, plasma CT levels were elevated in only one (4%) of 25 patients in Group 1 compared to 14 (61%) of 23 patients in Group 4. There was no evidence of distant metastases or death in the patients in Groups 1, 2, or 3. In the 23 patients in group 4, however, four (17.4%) had distant metastases and two (8.7%) died of disease during the period of observation. Of th 25 patients in Group 1, MTC was evident only by microscopic examination in 14 (56%). Eleven (44%) of the patients in Group 1 had macroscopically evident medullary thyroid carcinoma. This is in contrast with patients in Group 4 where all 23 had grossly evident MTC. These data indicate that the stimulated plasma CT level at the time of diagnosis is an excellent prognostic indicator of the extent of a disease in patients with hereditary MTC. Aggressive screening of kindred members at risk is of critical importance for establishing the diagnosis and instituting therapy at a time when the neoplasm is confined to the thyroid gland.     

Reverse LISS plating for intertrochanteric Hip Fractures in elderly patients

Background  

Fractures of the intertrochanteric hip are common and the treatment of unstable fractures generally requires an operative approach. In elderly patients, osteoporosis makes internal fixation problematic and frequently contributes to failed fixation and poor clinical results. We have attempted to apply the Less Invasive Stabilization System (LISS) in reverse position for the repair of intertrochanteric hip fractures in elderly patients with osteoporotic bones. A retrospective review is presented of the cases of 28 elderly patients with stable and unstable fractures of the intertrochanteric hip treated using the reverse LISS.     

The Malawi National Tuberculosis Programme: an equity analysis

Background  

Until 2005, the Malawi National Tuberculosis Control Programme had been implemented as a vertical programme. Working within the Sector Wide Approach (SWAp) provides a new environment and new opportunities for monitoring the equity performance of the programme. This paper synthesizes what is known on equity and TB in Malawi and highlights areas for further action and advocacy.     

Estimating the burden of disease in one Swiss canton: what do disability adjusted life years (DALY) tell us?

BACKGROUND: Examining life expectancy and general mortality rates, the health of the population of Geneva can be described as one of the best in the world. However, in some areas Geneva fares worse than the rest of Switzerland or Europe. To re-appraise the current health priorities of the Genevan population, we analysed the relative importance of specific diseases and injuries calculating DALYs. METHODS: We followed the procedures developed for the Global Burden of Disease (GBD) study to ensure comparability. Some adaptations were made for mortality coding. Disability was estimated based on data for countries classified as Established Market Economies (EME) in the GBD study. RESULTS: Non-communicable diseases accounted for 79% of the disability adjusted life years (DALY), injuries represented 12%, and communicable diseases and other disorders 9%. Ischaemic heart disease was the largest single contributor to DALY, followed by unipolar major depression. Neuropsychiatric disorders and mental health accounted for more than 23% of DALY. CONCLUSIONS: Some of the most important problems identified-depression, osteoarthritis and alcohol abuse-would have been overlooked in an analysis based solely on mortality data. The most striking finding is the importance of mental health problems. The main limitation is the lack of morbidity data for Geneva.     

Tumor-specific down-regulation of the tumor necrosis factor-related apoptosis-inducing ligand decoy receptors DcR1 and DcR2 is associated with dense promoter hypermethylation

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis in a large variety of cancer cells but not in most normal human cells. This feature makes TRAIL, a potential antitumor agent. TRAIL can bind to four different receptors, two pro-apoptotic death receptors (DRs), DR4 and DR5, and two antiapoptotic decoy receptors (DcRs), DcR1 and DcR2. Normal cells express all four of the receptors. The increased TRAIL sensitivity of tumor cells has been postulated to result from the lack of DcR expression. We studied the tumor-specific down-regulation of the TRAIL receptors DcR1 and DcR2, as well as DR4 and DR5, in a group of pediatric tumor cell lines [nine neuroblastoma and three peripheral primitive neuro-ectodermal tumors (PNETs)] and three cell lines from adult tumors. Lack of expression of DcR1 and DcR2 was widespread (13 of the 15 cell lines and 10 of 15, respectively), both in the adult tumor cell lines and in the pediatric tumor lines. DR4 and DR5 were expressed in 8 of 15 and 12 of 15 cell lines, respectively. To understand the tumor-specific down-regulation of the TRAIL receptors, the promoter regions were studied for possible methylation changes of their CpG islands. All normal tissues were completely unmethylated, whereas in the tumor cell lines, we found frequent hypermethylation of the promoter. For DcR1 and DcR2, we found dense hypermethylation in 9 (69%) of 13 and 9 (90%) of 10 of nonexpressing cell lines, respectively. DR4 and DR5 were methylated in 5 (71%) of 7 and 2 (67%) of 3 nonexpressing cell lines, respectively. Treatment with the demethylating agent 5-aza-2'deoxycytidine resulted in partial demethylation and restored mRNA expression. In addition, we performed mutation analysis of the death domains of DR4 and DR5 by sequencing exon 9. Mutations were not present in any of the neuroblastoma or PNET cell lines. A panel of 28 fresh neuroblastoma tumor samples also lacked expression of DcR1 and DcR2 in 85 and 74% of cases, respectively. Hypermethylation was observed in 6 (21%) of 28 for DcR1 and 7 (25%) of 28 for DcR2. DR4 and DR5 were both expressed in 22 of 28 tumors, and no promoter methylation was observed. These data suggest that hypermethylation of the promoters of DcR1 and DcR2 is important in the down-regulation of expression in neuroblastoma and other tumor types.     

Unusual presentation of perirenal lung metastases

Lung cancer is not commonly known to metastasise to the perirenal space, with only five such cases previously published. We present an unusual case of perirenal lung metastases manifesting as diffuse perinephric stranding which to our knowledge has not been described before.     

Noonan's and DiGeorge syndromes with monosomy 22q11

A boy with the dysmorphic features of Noonan's syndrome and pulmonary valve stenosis who had evidence of hypoparathyroidism and abnormal T lymphocyte numbers in the neonatal period is reported. He had a normal karyotype but molecular analysis revealed a submicroscopic deletion within chromosome 22q11, the region deleted in DiGeorge syndrome. Thus this child has both Noonan's syndrome and DiGeorge syndrome; 22q11 is a candidate region for a gene defective in Noonan's syndrome.