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Biomedical subjects

G W Stewart

Publications and source records attributed to G W Stewart.

At least 19 recordsLinked to original sources
PubMed2001

Familial pseudohyperkalaemia Chiswick: a novel congenital thermotropic variant of K and Na transport across the human red cell membrane.

Two families with inherited abnormalities in Na and K transport across the red cell membrane are described. Both presented with 'pseudohyperkalaemia' as a result of loss of K from the red cells on storage at room temperature. Routine haematology was essentially normal, except for macrocytosis in one family. Studies of the temperature dependence of the passive leak to K showed a novel shoulder pattern with a minimum at 25 degrees C, a maximum at 10 degrees C, followed by a further fall. As in other cases of red cell-based pseudohyperkalaemia, the abnormal temperature dependence of this 'leak' flux could be held to account for the loss of K from the cells at room temperature. These cases represent a novel variant of the temperature dependence of the passive leak of K and Na across the red cell membrane, and can be classified as a mild, non-haemolytic form of the group known as the hereditary stomatocytosis and allied disorders'.

Anemia, Hemolytic, Congenital↗
PubMed2001

Two further British families with the 'cryohydrocytosis' form of hereditary stomatocytosis.

We describe two families with the 'cryohydrocytosis' form of stomatocytosis. Both show a mild stomatocytic anaemia with Hb levels of 12-16 g/dl and reticulocyte counts of 4.3-24%, with very marked autohaemolysis at refrigerator temperatures and pseudohyperkalaemia as a result of loss of K from red cells on storage at room temperature. The ouabain + bumetanide-insensitive 'passive leak' K influx showed a 'U'-shaped temperature dependence, with a minimum at 23 degrees C. In one family, there was consistent variation in haematological severity within the pedigree. In the other, the parents of the proposita were normal, but all three of her children were affected, consistent with a new mutation of a dominant condition. Cold storage of the red cells led to a very marked increase in osmotic fragility and macrospherocytosis, explaining why a diagnosis of 'hereditary spherocytosis' can easily be reached in these pedigrees.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed2001

Pseudohyperkalaemia and pseudomacrocytosis caused by inherited red-cell disorders of the 'hereditary stomatocytosis' group.

Unusual dominantly inherited conditions of the red cell, collected under the generic title 'hereditary stomatocytosis and allied disorders', exist, in which the red cell 'leaks' the univalent cations sodium (Na+) and potassium (K+). In some kindreds with these disorders, bizarre temperature effects can occur that have profound effects on the way in which the cells behave when removed from the body and cooled to either room or refrigerator temperatures. In some types, the cells lose K+ at room temperature, giving rise to pseudohyperkalaemia; in others, this occurs in concert with swelling of the red cell and pseudomacrocytosis. In some of these conditions, a red-cell abnormality is clearly demonstrated by the presence of haemolytic anaemia; however, routine haematology can be virtually normal in the milder versions. All are inherited as dominants, although new mutations can be seen.

Anemia↗
PubMed2000

Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24.

Dehydrated hereditary stomatocytosis (DHS) is a rare genetic disorder of red cell permeability to cations, leading to a well-compensated hemolytic anemia. DHS was shown previously to be associated in some families with a particular form of perinatal edema, which resolves in the weeks following birth and, in addition, with pseudohyperkalemia in one kindred. The latter condition was hitherto regarded as the separate entity, "familial pseudohyperkalemia." DHS and familial pseudohyperkalemia are thought to stem from the same gene, mapping to 16q23-q24. This study screened 8 French and 2 American families with DHS. DHS appeared to be part of a pleiotropic syndrome in some families: DHS + perinatal edema, DHS + pseudohyperkalemia, or DHS + perinatal edema + pseudohyperkalemia. If adequately attended to, the perinatal edema resolved spontaneously after birth. Logistic regression showed that increased mean corpuscular volume and mean corpuscular hemoglobin concentration were the parameters best related to DHS. In patients in whom cation fluxes were investigated, the temperature dependence of the monovalent cation leak exhibited comparable curves. Specific recombination events consistently suggested that the responsible gene lies between markers D16S402 and D16S3037 (16q23-q24). The 95% confidence limits (Z(max) >/= 3.02) spanned almost the complete 9-cM interval between these 2 markers.

Adolescent↗
PubMed2000

Effect of dimethyl adipimidate on K+ transport and shape change in red blood cells from sickle cell patients.

Dimethyl adipimidate (DMA) reduces K+ loss from, and dehydration of, red cells containing haemoglobin S (HbS cells). Three membrane transporters may contribute to these processes: the deoxygenation-induced cation-selective channel (Psickle), the Ca2+-activated K+ channel (or Gardos channel) and the K+-CI- cotransporter (KCC). We show that DMA inhibited all three pathways in deoxygenated HbS cells. The Gardos channel could be activated following Ca2+ loading. Considerable KCC activity was present in oxygenated HbS cells, showing a selective action of DMA on the transporter in deoxygenated cells. Inhibition of sickling correlated strongly with that of Psickle and moderately with that of KCC activity. We conclude that DMA does not inhibit the K+ pathways directly, but acts mainly by preventing HbS polymerisation and sickling. These findings are relevant to the development of novel chemotherapeutic agents for amelioration of sickle cell disease.

Anemia, Sickle Cell↗
PubMed2000

Evolutionary exploitation of design options by the first animals with hard skeletons.

The set of viable design elements available for animals to use in building skeletons has been fully exploited. Analysis of animal skeletons in relation to the multivariate, theoretical "Skeleton Space" has shown that a large proportion of these options are used in each phylum. Here, we show that structural elements deployed in the skeletons of Burgess Shale animals (Middle Cambrian) incorporate 146 of 182 character pairs defined in this morphospace. Within 15 million years of the appearance of crown groups of phyla with substantial hard parts, at least 80 percent of skeletal design elements recognized among living and extinct marine metazoans were exploited.

Animals↗
PubMed1999

Familial pseudohyperkalemia maps to the same locus as dehydrated hereditary stomatocytosis (hereditary xerocytosis).

Familial pseudohyperkalemia is a "leaky red blood cell" condition in which the cells show a temperature-dependent loss of potassium (K) from red blood cells when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced lifespan in vivo but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis (hereditary xerocytosis). Physiological studies have shown that the passive leak to K has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells. We performed genetic mapping on the original family and found that the condition in this kindred maps to the same locus (16q23-ter) that we have previously identified for an Irish family with dehydrated hereditary stomatocytosis, which does not show the same temperature effects.

Anemia, Hemolytic, Congenital↗
PubMed1999

A variant of hereditary stomatocytosis with marked pseudohyperkalaemia.

A family with an unusual form of hereditary stomatocytosis is described. The affected members showed a mild, dominantly-inherited, haemolytic anaemia with intracellular Na and K levels of 41-48 and 44-53 mmol/(l cells) respectively. This anaemia was associated with marked 'pseudohyperkalaemia': that is, loss of K from red cells on storage at room temperature. At 37 degrees C, 'leak' tracer flux rates (assessed as the ouabain + bumetanide-resistant K fluxes) showed a roughly 5-fold acceleration compared to normal, and an abnormal temperature dependence with a shallow slope between 37 and 20 degrees C (mean Q10 (ratio of reaction rates at temperature T and T - 10) over this interval, 1.6; normal 2.2). The pseudohyperkalaemia could be attributed to the disparity between pump and leak at 20 degrees C. This is an identical mechanism to that previously shown for the haemato logically trivial condition, 'familial pseudohyperkalaemia. No protein or lipid abnormality was found in the membrane of these cells.

Anemia, Hemolytic, Congenital↗
PubMed1999

Two British families with variants of the 'cryohydrocytosis' form of hereditary stomatocytosis.

We describe two British families with similar, dominantly-inherited, temperature-related variants of hereditary stomatocytosis, consistent with the original description of 'cryohydrocytosis'. The cells show a 5-6-fold increase in passive permeability at 37 degrees C with abnormal intracellular Na and K levels at 15-20 and 60-65 mmol/(l cells) respectively. Marked temperature effects were evident: lysis of red cells on storage in the cold was blatant and when whole heparinized blood was stored at room temperature, K accumulated in the plasma, producing 'pseudohyperkalaemia'. Studies of the temperature dependence of passive permeability showed that the minimum in the passive permeability, which is seen in normal cells at 8-10 degrees C, was shifted up to 23 degrees C in these abnormal cells, such that the permeability at 0 degrees C exceeded that at 37 degrees C. The abnormal temperature dependence in these genetically abnormal red cells strongly resembles that seen in normal cells when suspended in media in which either Na or Cl has been replaced by an organic cation or anion: it could be said these cells had a genetic mutation that somehow rendered the cell resistant to the stabilizing action of NaCl at low temperatures.

Anemia, Hemolytic, Congenital↗
PubMed1999

Temperature effects on cation transport in hereditary stomatocytosis and allied disorders.

The conditions known as 'hereditary stomatocytosis and allied syndromes' comprise a group of dominantly inherited human haemolytic anaemias characterized by a plasma membrane 'leak' to the univalent cations Na and K, an example of a small but growing group of diseases where pathology can be directly attributed to abnormal membrane transport. A number of case reports in the different variants have alluded to temperature-related phenomena, including loss of K on storage at room temperature (giving 'pseudohyperkalaemia') and lysis of cells when stored in the cold ('cryohydrocytosis'). This review collects together published studies of these temperature effects, which show very major differences in the 'leak' K transport. Two main variations on normal emerge: a 'shallow slope' type, in which the flux shows an abnormally low dependence on temperature in the range 37-20 degrees C, and 'high minimum', in which the minimum in this flux, which occurs in normal cells at 8 degrees C, is shifted up to 23 degrees C. These temperature studies provide a powerful method for phenotypic characterization.

Anemia, Hemolytic, Congenital↗
PubMed1999

The hereditary stomatocytoses and allied disorders: congenital disorders of erythrocyte membrane permeability to Na and K.

The hereditary stomatocytoses and allied disorders are a set of dominantly inherited haemolytic anaemias in which the plasma membrane of the red cell 'leaks' sodium and potassium. There are about 10 different forms of these conditions, ranging from a moderately severe haemolytic anaemia to minor conditions in which the haematology is essentially normal, but where the patients present with pseudohyperkalaemia, due to leakage of K from the red cells on cooling to room temperature. Frequently misdiagnosed as atypical hereditary spherocytosis, these conditions can show marked thrombotic complications after splenectomy, which should be avoided. Laboratory studies of these conditions have drawn attention to a 32 kDa membrane protein, stomatin, which seems to act as a regulator of Na and K transport in human and animal tissues generally, but mutations in this gene do not cause these diseases. Genetic mapping in some kindreds, but not all, points to a mutation locus on chromosome 16.

Anemia, Hemolytic, Congenital↗
PubMed1998

Utilization of an 86 bp exon generates a novel adducin isoform (beta 4) lacking the MARCKS homology domain.

A novel isoform of beta-adducin has been amplified and characterized from a human bone marrow cDNA library (GenBank #U43959). This isoform arises from the insertion of an 86 bp alternatively spliced and previously unrecognized exon (now termed exon 15) within codon 581 of the human red blood cell beta-adducin sequence. This results in an insertion of 28 novel amino acids. The remainder of the red cell beta-adducin mRNA is then translated in a different reading frame, adding an additional 35 novel amino acids prior to the stop codon. This new isoform, thus, replaces beta 1-adducin sequence after residue 580 with a total of 63 new amino acids. Sequences from genomic clones of the human beta-adducin gene show that this alternate exon is flanked by splice consensus sequences and is appropriately located in the genomic map between exons encoding up-stream and down-stream sequences, thus defining a new exon. The COOH-terminus of this new isoform, which we designate beta 4, lacks a 22 amino acid lysine-rich sequence common to both the human red cell alpha- and beta-adducin subunits and homologous to a highly conserved region in MARCKS, a filamentous actin-cross linking protein regulated by protein kinase C and calcium/calmodulin. beta 4-adducin preserves a previously identified calmodulin binding domain. PCR analysis indicates that this new beta-adducin isoform is expressed in fetal brain and liver, bone marrow, and NT-2 (neuroepithelial) cells, but is not detected in several other tissues. We anticipate that this new beta 4 isoform of beta-adducin will display unique and tissue-specific functional properties.

Alternative Splicing↗
PubMed1997

Stomatin.

Stomatin is a 31-kDa integral membrane protein, named after the rare human haemolytic anaemia hereditary stomatocytosis. In some cases of this anaemia, in which the red cells leak sodium and potassium ions, this protein is absent from the membrane, immediately suggesting that it has a role in the regulation of ion transport. The protein has a single hydrophobic domain, presumed to be membrane-associated, is phosphorylated, and is widely distributed in animal tissues. Mutations of a homologue in sensory nerve cells of the nematode Caenorhabditis elegans disrupt a neuronal transduction mechanism, in which mechanosensory information is relayed to an ion channel, whose opening initiates an action potential. It could be that this protein is a molecular link in a genetic stretch-sensitive system. Abnormalities of red cell ion transport are well known in human hypertension, but the molecular basis has never been elucidated: this protein and its functional associates, operating in a stretch- or pressure-sensitive complex, might be important.

Animals↗
PubMed1997

High school football-related cervical spinal cord injuries in Louisiana: the athlete's perspective.

Louisiana has one of the highest rates in the nation of cervical spinal cord injuries to high school football players. When the national rate of these injuries is applied to the number of high school participants in Louisiana, we would expect there to be only one catastrophic neck injury every 14 years. Louisiana, however, has averaged 2.3 spinal cord injuries per year for the past seven football seasons. Players who use the top of their helmets to tackle, block, or strike opponents are at greatest risk for these injuries. This study was undertaken to describe the safe tackling knowledge, attitudes, and practices of Louisiana high school football players. We surveyed 596 players from 16 Louisiana high schools. When asked if it was within the rules to tackle anyone by using the top of their helmet, 29% incorrectly answered "yes". Similarly, when asked if they had ever tackled anyone using the top of their helmet, 33% reported that they had. Twenty-eight percent said that they had been taught to use this unsafe method. Of these, 83% said that their coach taught them this dangerous and illegal method. Using the helmet as a battering ram must be discouraged. Education for officials, coaches, and players is needed to improve recognition of improper tackling. Proper training in tackling and blocking is an important means of minimizing the possibility of catastrophic injury.

Adolescent↗