Somatic stem cell plasticity: current evidence and emerging concepts.
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Animals↗
Biomedical subjects
K A Jackson
Publications and source records attributed to K A Jackson.
Lactose maldigestion, calcium intake and osteoporosis in African-, Asian-, and Hispanic-Americans.
Dietary calcium is critical for the development of the human skeleton and likely plays an important role in the prevention of osteoporosis. Dairy products provide approximately three-fourths of calcium consumed in the diet and are the most concentrated sources of this essential nutrient. One obstacle that likely interferes with calcium consumption among many ethnic groups is lactose maldigestion. The real or perceived occurrence of intolerance symptoms after dairy food consumption may cause maldigesters to avoid dairy products. Several investigators have observed a relationship between lactose maldigestion, dietary calcium and osteoporosis in Caucasian populations. Research on ethnically diverse populations is necessary to better understand how lactose maldigestion influences the risk for osteoporosis. Low calcium intakes, a greater than previously thought potential for low bone density and extensive lactose maldigestion among Hispanic-American and Asian-American populations may create an elevated risk for osteoporosis. Dietary management strategies for lactose maldigesters to increase calcium consumption include consuming (1) dairy foods with meals, (2) yogurts, (3) calcium-fortified foods, (4) using lactose digestive aids and (5) including dairy foods daily in the diet to enhance colonic metabolism of lactose.
Black or African American↗
Stem cell plasticity in muscle and bone marrow.
Recent discoveries have demonstrated the extraordinary plasticity of tissue-derived stem cells, raising fundamental questions about cell lineage relationships and suggesting the potential for novel cell-based therapies. We have examined this phenomenon in a potential reciprocal relationship between stem cells derived from the skeletal muscle and from the bone marrow. We have discovered that cells derived from the skeletal muscle of adult mice contain a remarkable capacity for hematopoietic differentiation. Cells prepared from muscle by enzymatic digestion and 5 day in vitro culture were harvested and introduced into each of six lethally irradiated recipients together with distinguishable whole bone marrow cells. Six and twelve weeks later, all recipients showed high-level engraftment of muscle-derived cells representing all major adult blood lineages. The mean total contribution of muscle cell progeny to peripheral blood was 56%, indicating that the cultured muscle cells generated approximately 10- to 14-fold more hematopoietic activity than whole bone marrow. Although the identity of the muscle-derived hematopoietic stem cells is still unknown, they may be identical to muscle satellite cells, some of which lack myogenic regulators and could respond to hematopoietic signals. We have also found that stem cells in the bone marrow can contribute to cardiac muscle repair and neovascularization after ischemic injury. We transplanted highly purified bone marrow stem cells into lethally irradiated mice that subsequently were rendered ischemic by coronary artery occlusion and reperfusion. The engrafted stem cells or their progeny differentiated into cardiomyocytes and endothelial cells and contributed to the formation of functional tissue.
Age Factors↗
Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.
Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34(-)/low, c-Kit(+), Sca-1(+)) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and alpha-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.
Animals↗
Single-parent evolution algorithm and the optimization of Si clusters.
We describe a novel method for the structural optimization of molecular systems. Similar to genetic algorithms (GA), our approach involves an evolving population in which new members are formed by cutting and pasting operations on existing members. Unlike previous GA's, however, the population in each generation has a single parent only. This scheme has been used to optimize Si clusters with 13-23 atoms. We have found a number of new isomers that are lower in energy than any previously reported and have properties in much better agreement with experimental data.
Journal Article↗
Molecular cloning and sequencing of the low-affinity IgE receptor (CD23) for horse and cattle.
Expression of the low-affinity IgE receptor (CD23) on the surface of mononuclear cells is a critical event in the development of IgE-mediated immunologic responses. Using PCR and cDNA library screening, a 2.7kb cDNA encoding equine CD23 and a 627bp PCR fragment of cattle CD23 were sequenced and characterized. The equine CD23 sequence encodes a complete and continuous open reading frame of 327 amino acids, while the shorter cattle fragment encodes 209 amino acids corresponding to nucleotides 325-1098 of the equine CD23 transcript. In addition to high identities in their nucleotides and translated amino acids with CD23 sequences published for other species, the translated equine CD23 protein also shares many of the structural features of this molecule described for human and rodents. Interestingly, an additional repetitive element of possible functional significance consisting of 18 amino acids, located between the transmembrane region and the carbohydrate-binding lectin domain of horse CD23, was also identified. Based on these sequences, molecular assays will be developed to measure CD23 mRNA in tissues and expression of recombinant proteins will be essential to the production of species-specific antibody reagents. These assays and reagents will be useful in future studies of allergic and lymphoproliferative diseases in horses and cattle.
Amino Acid Sequence↗
Intraepithelial gamma delta T lymphocytes: sentinel cells at mucosal barriers.
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Animals↗
A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial.
A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (k(a)). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F), V/F, and k(a) were estimated, and model 2, in which V/F and k(a) were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41. 9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.
Adult↗
Hematopoietic potential of stem cells isolated from murine skeletal muscle.
We have discovered that cells derived from the skeletal muscle of adult mice contain a remarkable capacity for hematopoietic differentiation. Cells prepared from muscle by enzymatic digestion and 5-day in vitro culture were harvested, and 18 x 10(3) cells were introduced into each of six lethally irradiated recipients together with 200 x 10(3) distinguishable whole bone marrow cells. After 6 or 12 weeks, all recipients showed high-level engraftment of muscle-derived cells representing all major adult blood lineages. The mean total contribution of muscle cell progeny to peripheral blood was 56 +/- 20% (SD), indicating that the cultured muscle cells generated approximately 10- to 14-fold more hematopoietic activity than whole bone marrow. When bone marrow from one mouse was harvested and transplanted into secondary recipients, all recipients showed high-level multilineage engraftment (mean 40%), establishing the extremely primitive nature of these stem cells. We also show that muscle contains a population of cells with several characteristics of bone marrow-derived hematopoietic stem cells, including high efflux of the fluorescent dye Hoechst 33342 and expression of the stem cell antigens Sca-1 and c-Kit, although the cells lack the hematopoietic marker CD45. We propose that this population accounts for the hematopoietic activity generated by cultured skeletal muscle. These putative stem cells may be identical to muscle satellite cells, some of which lack myogenic regulators and could be expected to respond to hematopoietic signals.
Animals↗
Cutting edge: protective response to pulmonary injury requires gamma delta T lymphocytes.
Gamma delta intraepithelial lymphocytes are thought to coordinate responses to pathogens that penetrate the epithelial barrier. To directly test this, mice were inoculated with Nocardia asteroides. At doses that were nonlethal for control mice, gamma delta-deficient mice became severely ill and died within 14 days. Histologic examination of these lungs demonstrated the presence of severe tissue damage and unimpeded bacterial growth in the gamma delta-deficient mice compared with neutrophilic lesions and clearance of the organism in control mice. Interestingly, ozone exposure that targets a comparable lung region also resulted in diffuse epithelial necrosis associated with a similar lack of neutrophil recruitment in gamma delta-deficient mice. These data demonstrate that gamma delta intraepithelial lymphocytes can protect the host from pathogenic and nonpathogenic insults by targeting the inflammatory response to epithelial necrosis.
Acute Disease↗
Opioid substitution to reduce adverse effects in cancer pain management.
OBJECTIVE: To assess the effect of opioid substitution (substituting one member of the opioid class for another) on the incidence and severity of adverse effects in palliative care patients who experience unacceptable, refractory adverse effects when taking an opioid drug. DESIGN: Prospective audit of clinical records. SETTING: Palliative Care Program, Monash Medical Centre, Melbourne, Victoria (comprising an acute 10-bed palliative care unit and a palliative care consultative service). PATIENTS: All palliative care inpatients and patients referred to the consultative service who underwent opioid substitution between February 1996 and June 1997. OUTCOME MEASURES: Adverse effects and pain control profiles before and after opioid substitution. RESULTS: 55 opioid substitutions were undertaken in 49 patients. 49 substitutions were for adverse effects. The substitution produced partial or complete relief from confusion in 18 of 25 cases, from nausea and vomiting in 13 of 19, and from drowsiness in 8 of 15. Substitution also abolished myoclonus associated with renal failure in one patient. CONCLUSION: We found that the incidence and severity of adverse effects differed between opioids in the same patient. A trial of opioid substitution (usually in consultation with a specialist pain or palliative care unit and with auditing of outcomes) should be considered for patients with intolerable, refractory adverse effects of opioids.
Aged↗
Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel.
Episodic ataxia type 1 is a rare, autosomal dominant neurological disorder caused by missense mutations of the Kv1.1 gene from the Shaker K+ channel subfamily. To study the functional effects of the disease-causing mutations in a robust K+ channel background, we introduced seven different episodic ataxia type 1 substitutions into the corresponding, conserved residues of the Shaker K+ channel. K+ channel currents expressed in Xenopus oocytes were studied by electrophysiology. All episodic ataxia type 1 mutations produced functional K+ channels. In a Shaker N-terminal deletion mutant with fast inactivation removed, current amplitudes were significantly reduced in channels harboring an episodic ataxia type 1 mutation. Six of the seven mutations also showed depolarizing shifts (+9 to +36 mV) in the conductance voltage dependence. One mutation (F307I) shifted the midpoint of the conductance-voltage relationship by 23 mV in the hyperpolarizing direction. Episodic ataxia type 1 mutations were also expressed in ShakerH4 with intact N-terminal inactivation. In this construct, current amplitudes for episodic ataxia type 1 mutants were not significantly different from wild-type channels. All mutations altered the voltage range of steady-state inactivation; most changes were coupled to the changes in activation gating. Some episodic ataxia type 1 mutants also caused significant changes in the kinetics of N-type (F307I, E395D) or C-type (F307I, E395D, V478A) inactivation. These results suggest that episodic ataxia type 1 mutations may change K+ channel function by two mechanisms: (i) reduced channel expression and (ii) altered channel gating.
Animals↗
Protein kinase C inhibits Kv1.1 potassium channel function.
The regulation by protein kinase C (PKC) of recombinant voltage-gated potassium (K) channels in frog oocytes was studied. Phorbol 12-myristate 13-acetate (PMA; 500 nM), an activator of PKC, caused persistent and large (up to 90%) inhibition of mouse, rat, and fly Shaker K currents. K current inhibition by PMA was blocked by inhibitors of PKC, and inhibition was not observed in control experiments with PMA analogs that do not activate PKC. However, site-directed substitution of potential PKC phosphorylation sites in the Kv1.1 protein did not prevent current inhibition by PMA. Kv1.1 current inhibition was also not accompanied by changes in macroscopic activation kinetics or in the conductance-voltage relationship. In Western blots, Kv1.1 membrane protein was not significantly reduced by PKC activation. The injection of oocytes with botulinum toxin C3 exoenzyme blocked the PMA inhibition of Kv1. 1 currents. These data are consistent with the hypothesis that PKC-mediated inhibition of Kv1.1 channel function occurs by a novel mechanism that requires a C3 exoenzyme substrate but does not alter channel activation gating or promote internalization of the channel protein.
Animals↗
Intranet technology in Scottish NHS Trusts.
Intranet technology has the potential to turn everything we've taken for granted in internal communication upside down. This paper looks at the uptake and use of Intranet technology in NHS Trusts in Scotland and discusses some of the uses of an Intranet system.
Attitude to Computers↗
The application of population pharmacokinetics to the drug development process.
Population pharmacokinetics is playing an increasing role in clinical drug development. An overview of the population approach, including software and the advantages and limitations of the approach compared to the traditional approach to pharmacokinetic studies, is given. This paper also documents how the area has evolved over the past 15 years and addresses some of the issues that have arisen over the design and conduct of population studies. Finally, some alternative applications of the population approach are given for areas other than clinical drug development.
Humans↗
Effect of in vivo administration of anesthetics on GABAA receptor function.
In research involving tissue derived from animals, the use of anesthesia before sacrifice is recommended by the American Veterinary Medical Association and is strongly encouraged by university committees on the use of animals in research. In this study, the effects of anesthesia on the modulation of the GABAA receptor complex by ethanol, a benzodiazepine, and a barbiturate were determined. In vivo administration of the anesthetic methoxyflurane and CO2 before sacrifice resulted in a decrease in Cl- flux in mouse brain microsacs. These treatments also resulted in the loss of the ability of the GABAA receptor modulatory agents flunitrazepam and ethanol to enhance the Cl- flux in this assay system.
Anesthesia↗
Increased levels of megakaryocyte progenitors in peripheral blood mobilised by chemotherapy and/or haemopoietic growth factor protocols.
We have quantitated colony-forming unit megakaryocyte, (CFU-Mk), burst-forming unit megakaryocyte, (BFU-Mk), colony-forming unit granulocyte-macrophage (CFU-GM), and CD34+ cells in 98 mobilised PB samples from 53 patients mobilised by one of six protocols, including myelosuppressive chemotherapy alone (n = 22), or in combination with recombinant haemopoietic growth factors (n = 32), and growth factors alone (n = 17) or in combination (n = 27). The frequency of megakaryocyte progenitors (total Mk = CFU-Mk + BFU-Mk) in mobilised PB (mean 356, range 0-3240/10(6)) was similar to that in steady-state BM (mean 429, range 0-3315/10(6) n = 45). The levels of total Mk in mobilised PB (mean 1509, range 0-36 099/ml) showed a mean 75-fold increase compared with steady state PB (mean 20, range 0-86/ml, n = 15). In mobilised PB the levels of CFU-Mk were significantly correlated with levels of BFU-Mk (rs = 0.71, P < 0.0001) and the levels of megakaryocyte progenitors correlated significantly with those of myeloid progenitors (rs = 0.59, P < 0.0001) and CD34+ cells (rs = 0.69, P < 0.0001). The mobilisation of megakaryocyte progenitors into the circulation in response to high-dose chemotherapy and/or haemopoietic growth factors contributes to an understanding of the rapid platelet recovery following PBSC transplantation and suggests that the measurement of megakaryocyte progenitors may be a useful indicator for platelet reconstitutive capacity.
Adult↗
Daubert v. Merrell Dow: missed opportunity.
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Abnormalities, Drug-Induced↗