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Biomedical subjects

M Rowley

Publications and source records attributed to M Rowley.

At least 19 recordsLinked to original sources
PubMed2005

Severe gestational (incidental) thrombocytopenia: to treat or not to treat.

Thrombocytopenia is common in pregnancy and is diverse in etiology. Immune thrombocytopenic purpura (ITP) may affect both mother and the newborn. Gestational (incidental) thrombocytopenia in an otherwise fit woman, at term is the most frequent type of thrombocytopenia and poses no clinical consequences for mother or infant. We report six women who presented with severe thrombocytopenia during pregnancy. Five were treated in late pregnancy, either with intravenous immunoglobulin (IVIg), or IVIg followed by steroids. There was no response, and four received a platelet transfusion during delivery. The platelet counts in all the infants were normal and the maternal thrombocytopenia resolved spontaneously after delivery in all cases. Our observations suggest that this is a group of patients with a severe form of gestational thrombocytopenia. The severe form of gestational thrombocytopenia appears to be rare, and recognition is important, as it may recur in subsequent pregnancies and does not require any therapeutic intervention.

Adult↗
PubMed2005

Severe hypothermia: challenging normal physiology.

Accidental hypothermia is not a frequent cause of death in Australia. Moreover it is rare to have an admission to hospital with a core temperature below 32 degrees C. Among the cases described in the literature, it is clear that temperature and prognosis are related. Our patient presented with severe accidental hypothermia and even though the admission core temperature was below 26 degrees she was successfully discharged from hospital after active re-warming with three different devices. She had laboratory and ECG findings associated with severe hypothermia.

Aged↗
PubMed2004

Criteria for elective admission to the paediatric intensive care unit following adenotonsillectomy for severe obstructive sleep apnoea.

During the period 1997 to 2002, 42 children were electively admitted to the Paediatric Intensive Care Unit at the John Hunter Children's Hospital following adenotonsillectomy for severe obstructive sleep apnoea. Forty children had a preoperative sleep study, of which 33 were complete polysomnograms. Of the 42 children admitted, 35 required no intervention while seven (17%) required an additional intervention beyond supplemental oxygen. Our criteria for elective admission to Paediatric Intensive Care following adenotonsillectomy for severe obstructive sleep apnoea are presented.

Adenoidectomy↗
PubMed2003

Remission induced by Campath-1H for thymoma-associated agranulocytosis.

Thymoma-associated agranulocytosis is a rare but almost universally fatal condition. Reports to date have described several immunosuppressive therapies including steroids, cyclophosphamide and vincristine as adjuvants to thymectomy, in an effort to improve neutropenia. We report the response to the monoclonal antibody Campath-1H of a patient with a thymoma and associated agranulocytosis with complete absence of bone marrow granulocyte precursors, which had failed to respond to thymectomy. Treatment with Campath-1H resulted in complete responses of promising durability sustained with the addition of cyclosporin and mycophenolate mofetil as maintenance therapy.

Agranulocytosis↗
PubMed2001

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT(2A) receptor antagonists.

The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.

Animals↗
PubMed2000

3-(4-Piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles as bioavailable h5-HT2A antagonists.

A series of 3-(4-piperidinyl)- and 3-(8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indoles have been prepared and evaluated as ligands for the h5-HT2A receptor. 3-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-phenyl-1H-indole is a high-affinity (1.2nM), selective (>800 fold over h5-HT2C and hD2 receptors) antagonist at the h5-HT2A receptor with oral bioavailability in rats.

Administration, Oral↗
PubMed2000

Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan.

Because there is no known genetic abnormality common to all patients with myeloma, it is important to understand how genetic heterogeneity may lead to differences in signal transduction, cell cycle, and response to therapy. Model cell lines have been used to study the effect that mutations in p53 and ras can have on growth properties and responses of myeloma cells. The U266 cell line has a single mutant p53 allele. Stable expression of wild-type (wt) p53 in U266 cells results in a significant suppression of interleukin (IL)-6 gene expression and in the concomitant suppression of cell growth that could be restored by the addition of exogenous IL-6. Expression of wt p53 also leads to cell cycle arrest and protection from doxorubicin (Dox)- and melphalan (Mel)-induced apoptosis. The addition of IL-6 resulted in cell cycle progression and blocked p53-mediated protection from apoptosis. ANBL6 is an IL-6-dependent cell line that is sensitive to dexamethasone (Dex), Dox, and Mel. IL-6 is able to protect ANBL6 cells from Dex- and Mel- but not Dox-induced apoptosis. To study the effect of an activating mutation in ras, the ANBL6 cell line transfected with either a constitutively activated N- or K-ras gene was used. Both N-ras12 and K-ras12 genes were able to protect ANBL6 cells from apoptosis induced by Dex, Dox, and Mel. These data show that changes in ras or p53 can alter the myeloma cell response to IL-6 and demonstrate that the genetic background can alter therapeutic responses.

Apoptosis↗
PubMed2000

Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangement reaction

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S, 4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S, 4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.

Journal Article↗
PubMed2000

N-(indol-3-ylglyoxylyl)piperidines: high affinity agonists of human GABA-A receptors containing the alpha1 subunit.

A new class of N-(indol-3-ylglyoxylyl)piperidines are high affinity agonists at the benzodiazepine binding site of human GABA-A receptor ion-channels, with modest selectivity for receptors containing the alpha1 subunit over alpha2 and alpha3. All three receptor subtypes discriminate substantially between the two enantiomers of the chiral ligand 10.

GABA-A Receptor Agonists↗
PubMed1999

Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl)propyl)indoles gives selective human 5-HT1D receptor ligands with improved pharmacokinetic profiles.

It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.

Administration, Oral↗
PubMed1999

Crucial points at diagnosis. Type 2 diabetes or slow type 1 diabetes.

Two major types of diabetes have been recognized since the late 1930s. However, in recent times there have been major changes in classification and understanding of these types, including improved knowledge of maturity-onset diabetes in the young, with the identification of mutations relating to impaired insulin secretion and the recognition of slow-onset type 1 diabetes in adults now designated as latent autoimmune diabetes in adults (LADA). A major problem area in diabetes classification concerns cases of slowly progressive forms of type 1 and type 2 diabetes, particularly in adults aged 25-50 years. This is a more contemporary problem because cases of type 2 diabetes are presenting at an increasingly younger age. In the landmark U.K. Prospective Diabetes Study of type 2 diabetes, islet cell antibodies (ICAs) and antibodies to glutamic acid decarboxylase (anti-GAD) were measured at diagnosis in 3,672 patients. The overall proportion with ICAs was 6%, and anti-GADs was 10%. These subjects clearly had type 1 diabetes or LADA by both phenotypic and genotypic features. The presence of auto antibodies correlated particularly with a younger age and phenotypic features consistent with type 1 diabetes (e.g., early age at diagnosis, lower BMI, and reduced beta-cell function). Overall, of patients requiring insulin by 6 years, 38% were anti-GAD+ at baseline compared with 5.3% of those not on insulin at 6 years. Antibodies to GAD indicate an underlying autoimmune process and have a high positive predictive value for type 1 diabetes and future insulin dependency in adults.

Adult↗
PubMed1998

Type 1 diabetes in insulin-treated adult-onset diabetic subjects.

The frequency of autoimmune features was compared in adult-onset diabetic subjects either requiring insulin treatment within 12 months of diagnosis or progressing to insulin therapy after a latency of at least 5 years. Adult-onset insulin-treated diabetic subjects were sampled from the population-based Canterbury Diabetes Registry (n = 1580). There were 237 (15%) registrants who met the study criteria of age < 75 years at 1 January 1993, age at diagnosis of diabetes > or = 45 years and duration of diabetes between 5 and 15 years; 101 subjects commenced insulin 5-15 years after diagnosis (group 1) and 80 subjects commenced insulin within 1 year of diagnosis (group 2). C-peptide levels, islet cell antibodies (ICA) and antibodies against glutamic acid decarboxylase (anti-GAD) were determined in all individuals from group 1 (n = 27) and group 2 (n = 23) who agreed to be recruited to the study. The group 1 and group 2 samples did not differ significantly in their demographic characteristics, nor were they different from the two groups from which they were drawn (mean age, 64.2 years; age at diagnosis, 53.5 years; duration of diabetes, 10.7 years; body mass index, 28.6 kg/m2). Overall, 12 of the 50 (24%) study subjects tested positive for anti-GAD; 43% (10) of group 2 subjects were anti-GAD positive compared with only 7.4% (2) of group 1 subjects (P < 0.01). Postprandial C-peptide levels were significantly lower in group 2 subjects compared with group 1 subjects (627 vs 1124 pM, P < 0.05). All subjects were ICA negative. These observations suggest that autoimmune destruction of beta-cells explains early requirement for insulin in adult-onset diabetes.

Age of Onset↗