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Biomedical subjects

K Holder

Publications and source records attributed to K Holder.

14 recordsLinked to original sources
PubMed2004

A randomised study comparing peripheral blood progenitor mobilisation using intermediate-dose cyclophosphamide plus lenograstim with lenograstim alone.

We conducted a prospective randomised study to compare the efficiency of out-patient progenitor cell mobilisation using either intermediate-dose cyclophosphamide (2 g/m(2)) and lenograstim at 5 micrograms/kg (Cyclo-G-CSF group, n=39) or lenograstim alone at 10 micrograms/kg (G-CSF group, n=40). The end points were to compare the impact of the two regimens on mobilisation efficiency, morbidity, time spent in hospital, the number of apheresis procedures required and engraftment kinetics. Successful mobilisation was achieved in 28/40 (70%) in the G-CSF group vs 22/39 (56.4%) for Cyclo-G-CSF (P=0.21). The median number of CD34+ cells mobilised was 2.3 x 10(6)/kg and 2.2 x 10(6)/kg for G-CSF and cyclo-G-CSF arms following a median of two apheresis procedures. Nausea and vomiting and total time spent in the hospital during mobilisation were significantly greater after Cyclo-G-CSF (P<0.05). Rapid neutrophil and platelet engraftment was achieved in all transplanted patients in both groups. In conclusion, G-CSF at 10 micrograms/kg was as efficient at mobilising progenitor cells as a combination of cyclophosphamide and G-CSF with reduced hospitalisation and side effects and prompt engraftment. When aggressive in-patient cytoreductive regimens are not required to both control disease and generate progenitor cells, the use of G-CSF alone appears preferable to combination with intermediate-dose cyclophosphamide.

Adjuvants, Immunologic↗
PubMed2001

Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity.

BACKGROUND: Little is known about the role of cellular immunity in respiratory virus infections after bone marrow transplantation. METHODS: Forty allograft recipients T-cell depleted with Campath antibodies were evaluated for respiratory virus infections in an active surveillance program with early initiation of antiviral therapy. RESULTS: Eighteen episodes of respiratory virus infection were detected in nine patients (22%) at a median of 95 days, with lower respiratory involvement in 44%. Fourteen episodes were treated with antiviral therapy for 7 to 46 days, with 11% mortality. Respiratory virus infections were more common in patients receiving Campath 100 mg in vivo, but delayed CD4+ recovery was the most significant risk factor. CONCLUSIONS: Respiratory virus infections are common and often recurrent in patients with severe CD4+ T lymphopenia. However, the mortality was low, which may have been due to early institution of antiviral treatment or reduced inflammatory damage to the lungs due to severe lymphopenia.

CD4-Positive T-Lymphocytes↗
PubMed2001

Refugial isolation versus ecological gradients. Testing alternative mechanisms of evolutionary divergence in four rainforest vertebrates.

Hypotheses for divergence and speciation in rainforests generally fall into two categories: those emphasizing the role of geographic isolation and those emphasizing the role of divergent selection along gradients. While a majority of studies have attempted to infer mechanisms based on the pattern of species richness and congruence of geographic boundaries, relatively few have tried to simultaneously test alternative hypotheses for diversification. Here we discuss four examples, taken from our work on diversification of tropical rainforest vertebrates, in which we examine patterns of genetic and morphological variation within and between biogeographic regions to address two alternative hypotheses. By estimating morphological divergence between geographically contiguous and isolated populations under similar and different ecological conditions, we attempt to evaluate the relative roles of geographic isolation and natural selection in population divergence. Results suggest that natural selection, even in the presence of appreciable gene flow, can result in morphological divergence that is greater than that found between populations isolated for millions of years and, in some cases, even greater than that found between congeneric, but distinct, species. The relatively small phenotypic divergence that occurs among long-term geographic isolates in similar habitats suggests that morphological divergence via drift may be negligible and/or that selection is acting to produce similar phenotypes in populations occupying similar habitats. Our results demonstrate that significant phenotypic divergence: (1) is not necessarily coupled with divergence in neutral molecular markers; and (2) can occur without geographic isolation in the presence of gene flow.

Adaptation, Biological↗
PubMed2001

Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study.

Infections with the paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can result in serious morbidity and mortality after haemopoietic stem cell transplant (HSCT). Once pneumonia develops, the outcome of these infections is often poor despite anti-viral therapy. Aerosolised ribavirin has been evaluated as pre-emptive therapy for post-transplant RSV infections with some success. Due to the financial and logistic burden involved with the use of aerosolised ribavirin, we explored the efficacy and toxicity of oral ribavirin for pre-emptive therapy of post-transplant RSV and PIV infections in a dose escalating schedule (15-60 mg/kg/day). Five episodes each of RSV and PIV were treated in seven patients. Five patients were receiving treatment for GVHD and two acquired the infection in the pre-engraftment period. All the episodes of RSV infection improved with oral ribavirin with dose escalation to 30-45 mg/kg in three of them. On the other hand, only two of the five PIV infections improved with oral ribavirin. Of the three non-responders, two infections were acquired in the pre-engraftment period with one death from PIV pneumonia. Reversible anaemia was the only side-effect noted in patients treated for over 2 weeks. Thus, the use of oral ribavirin was well tolerated in the post-transplant period with no untoward toxicities. There was a trend towards better response in RSV infections, which needs to be further explored in controlled studies.

Administration, Oral↗
PubMed2000

Glacial vicariance and historical biogeography of rock ptarmigan (Lagopus mutus) in the Bering region.

In this paper, we address alternative hypotheses for the evolution of subspecies of rock ptarmigan (Lagopus mutus) endemic to the Aleutian Archipelago. To do this we examined patterns of genetic differentiation among populations of rock ptarmigan in the Aleutian Islands and parts of both Alaska and Siberia. Variation in mitochondrial control region sequences of 105 rock ptarmigan from 10 subspecies within the Bering region revealed three major phylogenetic lineages, two of which are endemic to the Aleutian Islands. Accordingly, haplotype and nucleotide diversities of rock ptarmigan within the archipelago are much higher than within mainland Alaska or Siberia. For Aleutian rock ptarmigan, analyses of molecular variance indicated significant genetic structuring and low estimates of gene flow among populations, despite small interisland distances within the archipelago. However, isolation by distance did not describe the pattern of gene flow or differentiation at this scale. Our estimates of divergence times of lineages suggest that Aleutian rock ptarmigan became isolated prior to the most recent Pleistocene glaciation event (late Wisconsin Stade) and that current patterns of genetic variation reflect the postglacial redistribution of divergent lineages and subsequent limited gene flow. In addition, genetic divergence among lineages was concordant with the distribution of plumage types among subspecies. The patterns of genetic variation described here for rock ptarmigan provide evidence for the role of glacial vicariance in contributing to genetic diversity within this and other Bering region species.

Alaska↗
PubMed2000

Comparative avian phylogeography of Cameroon and equatorial Guinea mountains: implications for conservation.

We illustrate the use of Faith's 'Phylogenetic Diversity' measure to compare the phylogeographic structure of two bird species with patterns of avian endemism across six mountains in Cameroon and Equatorial Guinea. The Mountain Greenbul and Cameroon Blue-headed Sunbird showed phylogeographic patterns that together defined three biogeographic regions: Bioko, Mt. Cameroon, and the northern mountains of Cameroon. In contrast, the distributions of endemic species were largely a function of geographical distance, with close mountains sharing more endemic species than distant mountains. Moreover, for both species, populations on Mt. Cameroon were distinctive with respect to the ecologically relevant character bill size. Our results, while preliminary, illustrate the utility of a comparative approach for identifying geographical regions that harbour evolutionarily distinct populations and caution against using only the distributional patterns of endemics to prioritize regions for conservation. Results show that patterns of endemism may not be concordant with patterns of phylogenetic diversity nor morphological variation in a character important in fitness. While incorporation of additional species from unrelated taxa will be necessary to draw definitive conclusions about evolutionarily distinct regions, our preliminary results suggest a conservation approach for the Afromontane region of the Gulf of Guinea that would: (i) emphasize protection of both Bioko and Mt. Cameroon, thereby maximizing preservation of within-species phylogenetic and morphologic diversity; (ii) emphasize protection within the northern mountains to further conserve intraspecific phylogenetic diversity and maximize protection of endemic species.

Animals↗
PubMed1999

Role of Notch pathway in terminal follicle cell differentiation during Drosophila oogenesis.

During Drosophila oogenesis the body axes are determined by signaling between the oocyte and the somatic follicle cells that surround the egg chamber. A key event in the establishment of oocyte anterior-posterior polarity is the differential patterning of the follicle cell epithelium along the anterior-posterior axis. Both the Notch and epithelial growth factor (EGF) receptor pathways are required for this patterning. To understand how these pathways act in the process we have analyzed markers for anterior and posterior follicle cells accompanying constitutive activation of the EGF receptor, loss of Notch function, and ectopic expression of Delta. We find that a constitutively active EGF receptor can induce posterior fate in anterior but not in lateral follicle cells, showing that the EGF receptor pathway can act only on predetermined terminal cells. Furthermore, Notch function is required at both termini for appropriate expression of anterior and posterior markers, while loss of both the EGF receptor and Notch pathways mimic the Notch loss-of-function phenotype. Ectopic expression of the Notch ligand, Delta, disturbs EGF receptor dependent posterior follicle cell differentiation and anterior-posterior polarity of the oocyte. Our data are consistent with a model in which the Notch pathway is required for early follicle cell differentiation at both termini, but is then repressed at the posterior for proper determination of the posterior follicle cells by the EGF receptor pathway.

Animals↗
PubMed1997

Behavioural correlates of monogamy in the noisy miner, Manorina melanocephala

Mating behaviour of female cooperatively breeding noisy miners was examined. Dow & Whitmore (1990, Cooperative Breeding in Birds (Ed. by P. B. Stacey & W. D. Koenig), pp. 559-592, Cambridge: Cambridge University Press) suggested that female noisy miners mate promiscuously to recruit males as helpers to their nests, and that the benefit of doing so might be (1) increased genetic variability of their broods or (2) increased survival of their offspring as a direct result of multi-male care. Multilocus DNA profiling has since shown that 96.5% of nestlings resulted from monogamous matings and that extra-group and multiple paternity within broods were rare (Poldmaa et al. 1995, Behav. Ecol. Sociobiol.37, 137-143). In this study, strong behavioural correlates of monogamy were found. A breeding female associated more often with only one male in her social group, and most of the female's sexual behaviours were directed towards this male. Females were observed copulating repeatedly with the same male, but never with more than one male. Home ranges of breeding females rarely overlapped with each other, but home ranges of breeding males overlapped greatly. Furthermore, a greater percentage of a female's home range was shared with that of her genetic mate than with those of other males. Thus, behavioural evidence is consistent with the genetic evidence that noisy miners mate monogamously in some populations.1997The Association for the Study of Animal Behaviour

Journal Article↗
PubMed1997

Plasma bupivacaine concentrations associated with continuous extradural infusions in babies.

The maximum recommended dose for extradural infusions of bupivacaine in children older than 1 month is 0.5 mg kg-1 h-1 but there are few specific reports of the associated blood concentrations during infusions in babies. Toxic symptoms can occur in children at plasma concentrations of bupivacaine as low as 2 micrograms ml-1. We attempted to measure venous plasma concentrations of total and free bupivacaine in babies aged 3-12 months during extradural infusions given at a rate commonly used in our hospital. We studied eight babies (mean age 33 weeks; mean weight 7.8 kg). After a mean initial dose of 1.2 mg kg-1 (range 1.1-1.3 mg kg-1), bupivacaine was infused at a mean rate of 0.38 (0.36-0.39) mg kg-1 h-1 for a mean of 31 (4-44) h. Blood was obtained at 4, 8, 16, 24, 32 and 40 h after starting the infusion and plasma separated by centrifugation. Total plasma bupivacaine concentration was measured using high pressure liquid chromatography (HPLC). Plasma concentrations of total bupivacaine were mostly less than 2 micrograms ml-1. One baby had a concentration of 2.02 micrograms ml-1 at 32 h and showed clear evidence of accumulation of bupivacaine. Babies can accumulate bupivacaine and achieve plasma concentrations above the threshold for toxic side effects, despite infusion rates below the currently accepted maximum. The samples size in our study was small but we believe an extradural infusion rate of 0.375 mg kg-1 h-1 is probably an absolute maximum for babies younger than 12 months.

Abdomen↗
PubMed1997

A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery.

The efficacy and safety of remifentanil and alfentanil for patients undergoing major abdominal surgery were compared. Premedicated patients received a loading dose of remifentanil (1.0 microgram.kg-1; n = 116) and a continuous infusion of 0.5 microgram.kg-1.min-1, or a loading dose of alfentanil (25 micrograms.kg-1; n = 118) and a continuous infusion of 1.0 microgram.kg-1.min-1. Propofol was administered (10 mg every 10 s) until loss of consciousness. Patients' lungs were ventilated with 66% nitrous oxide and 0.5% (end-tidal) isoflurane in oxygen. The study drug infusion rate was reduced by 50% 5 min after intubation. Alfentanil was discontinued 15 min before the end of surgery, whereas remifentanil was continued in the immediate postoperative period at a reduced dose. Responses to intubation (28%) and skin incision (17%) occurred approximately twice as often in the alfentanil group (15% and 8%; p = 0.014 and p = 0.037, respectively). More patients receiving alfentanil had one or more responses to surgery (72% vs. 57%; p = 0.016). The time to spontaneous respiration, adequate respiration, response to verbal command and time to recovery room discharge were similar. However, owing to decreased variability, the time to extubation was shorter with remifentanil than with alfentanil (p = 0.048). There was a similar overall incidence of adverse events in both groups, 82% and 75% of patients, respectively. Adverse events associated with remifentanil were rapidly controlled by dose reductions. The incidence of intra-operative hypotension and bradycardia was higher in the remifentanil group (p < or = 0.033). An initial remifentanil infusion rate of 0.1 microgram.kg-1.min-1 titrated to individual need provided postoperative pain relief in the presence of adequate respiration in 71% of patients. When using remifentanil in the immediate postoperative setting, rapid administration of bolus doses and infusion rate increases resulted in a relatively high incidence of muscle rigidity, respiratory depression and apnoea. Changing the postoperative regimen to avoid rapid changes in remifentanil blood concentration resulted in more effective analgesia and dramatically reduced the incidence of adverse events during this period. In patients undergoing major abdominal surgery, remifentanil appears to offer superior intra-operative haemodynamic stability during stressful surgical events compared with alfentanil without compromising recovery from anaesthesia. Remifentanil can be administered as a postoperative analgesic agent at a starting dose of 0.1 microgram-.kg-1.min-1; however, it should only be used in the presence of adequate supervision and monitoring of the patient. Administration of bolus doses is not recommended in this setting.

Abdomen↗
PubMed1996

Expression of constitutively active Notch arrests follicle cells at a precursor stage during Drosophila oogenesis and disrupts the anterior-posterior axis of the oocyte.

During early development, there are numerous instances where a bipotent progenitor divides to give rise to two progeny cells with different fates. The Notch gene of Drosophila and its homologues in other metazoans have been implicated in many of these cell fate decisions. It has been argued that the role of Notch in such instances may be to maintain cells in a precursor state susceptible to specific differentiating signals. This has been difficult to prove, however, due to a lack of definitive markers for precursor identity. We here perform molecular and morphological analyses of the roles of Notch in ovarian follicle cells during Drosophila oogenesis. These studies show directly that constitutively active Notch arrests cells at a precursor stage, while the loss of Notch function eliminates this stage. Expression of moderate levels of activated Notch leads to partial transformation of cell fates, as found in other systems, and we show that this milder phenotype correlates with a prolonged, but still transient, precursor stage. We also find that expression of constitutively active Notch in follicle cells at later stages leads to a defect in the anterior-posterior axis of the oocyte.

Animals↗
PubMedDate not supplied

Influence of cardiovascular diseases upon the results of the cardiovascular reflex tests in diabetic and nondiabetic subjects.

Cardiovascular reflex tests are used to assess cardiac autonomic neuropathy in diabetes mellitus. Cardiovascular diseases (CVD) are known to alter baroreflex mechanisms. Diabetic patients are at a high risk for cardiovascular complications. In order to prove whether cardiovascular diseases reduce the diagnostic value of the cardiovascular reflex tests in diabetic autonomic neuropathy unselected groups of 274 nondiabetic and 103 diabetic patients were studied: E/I, 30/15, and Valsalva ratios, sustained handgrip test and blood pressure response to standing. Both groups were subdivided into young (less than or equal to 45 years) and older (greater than 45 years) patients and into subjects with and without CVD. In young nondiabetic patients with CVD, E/I and Valsalva ratios were significantly lower than in those without CVD. In young diabetic patients with CVD, only E/I ratios were significantly reduced compared to those without CVD. The tests reflecting sympathetic nerve function did not differ between patients with and without CVD, neither in the nondiabetic nor in the diabetic subjects. In the older nondiabetic and diabetic patients, cardiovascular reflexes were generally impaired, but did not show any difference between subjects with and without CVD. In young diabetic patients suffering from CVD, the diagnostic value of cardiovascular reflex tests is reduced as far as cardiac autonomic neuropathy is concerned. In older patients, the tests are not suitable for the diagnosis of diabetic autonomic neuropathy. More specific methods are required.

Blood Pressure↗