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Biomedical subjects

K Ward

Publications and source records attributed to K Ward.

At least 19 recordsLinked to original sources
PubMed2007

Use of the recto-sigmoid index to diagnose Hirschsprung's disease.

The recto-sigmoid index on barium enema may aid in the diagnosis of Hirschsprung's disease. However, data on its reliability in different age groups are sparse. The recto-sigmoid index and transitional zone were evaluated blindly in 107 patients with diagnostic rectal suction biopsies. Patients were divided into 3 groups: neonates, infants older than 1 month, and children. The recto-sigmoid index and transitional zone agreed with the histopathologic diagnosis in 79% and 87% of the cases, respectively. Their negative predictive values reached clinical significance in infants and children but not in neonates. Their positive predictive values were not significant in any age group. The recto-sigmoid index identified 4 patients with recto-sigmoid Hirschsprung's disease whose diagnosis was missed by evaluating the transitional zone alone.

Adolescent↗
PubMed2006

Long telomeres in the mature human placenta.

OBJECTIVE: To investigate whether telomere shortening may play a role in senescence of the placenta. STUDY DESIGN: Villous tissue was collected from single, random sites of full-term placentas (39-41 weeks of gestation; n=10) as well as multiple, specific sites of the same placenta (39-41 weeks of gestation; n=5). For the latter group of placentas, samples were taken near the umbilical cord and at the periphery on both the maternal and fetal sides (a total of 4 samples per placenta). Cord blood samples were also obtained from all placental donors. Telomerase activity was assessed by the TRAP assay, and telomere length measured by Southern analysis of mean terminal restriction fragment (TRF) length. RESULTS: We show for the first time that telomeres are longer ( approximately 25% longer; P<0.001) in placenta tissue than in cord blood from the same donor. CONCLUSION: Telomere shortening is unlikely to have a significant role in senescence or terminal maturation of the placenta.

Blotting, Northern↗
PubMed2006

Benfotiamine accelerates the healing of ischaemic diabetic limbs in mice through protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis.

AIMS/HYPOTHESIS: Benfotiamine, a vitamin B1 analogue, reportedly prevents diabetic microangiopathy. The aim of this study was to evaluate whether benfotiamine is of benefit in reparative neovascularisation using a type I diabetes model of hindlimb ischaemia. We also investigated the involvement of protein kinase B (PKB)/Akt in the therapeutic effects of benfotiamine. METHODS: Streptozotocin-induced diabetic mice, given oral benfotiamine or vehicle, were subjected to unilateral limb ischaemia. Reparative neovascularisation was analysed by histology. The expression of Nos3 and Casp3 was evaluated by real-time PCR, and the activation state of PKB/Akt was assessed by western blot analysis and immunohistochemistry. The functional importance of PKB/Akt in benfotiamine-induced effects was investigated using a dominant-negative construct. RESULTS: Diabetic muscles showed reduced transketolase activity, which was corrected by benfotiamine. Importantly, benfotiamine prevented ischaemia-induced toe necrosis, improved hindlimb perfusion and oxygenation, and restored endothelium-dependent vasodilation. Histological studies revealed the improvement of reparative neovascularisation and the inhibition of endothelial and skeletal muscle cell apoptosis. In addition, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of Nos3 and Akt in ischaemic muscles. The benefits of benfotiamine were nullified by dominant-negative PKB/Akt. In vitro, benfotiamine stimulated the proliferation of human EPCs, while inhibiting apoptosis induced by high glucose. In diabetic mice, the number of circulating EPCs was reduced, with the deficit being corrected by benfotiamine. CONCLUSIONS/INTERPRETATION: We have demonstrated, for the first time, that benfotiamine aids the post-ischaemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, benfotiamine combats the diabetes-induced deficit in endothelial progenitor cells.

Animals↗
PubMed2005

Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT.

Over the last 25 years, the numbers of hematopoietic stem cell transplant (SCT) patients have increased rapidly. Infections have been major obstacles for successful transplantation. Thus, infection prevention is very important in transplant recipients. As the results of transplantation have improved, the number of long-term survivors has increased. Vaccination is a potentially important strategy for reducing the risk for vaccine-preventable infections after SCT. The EBMT produced recommendations for vaccination of SCT recipients published in Bone Marrow Transplantation in 1995. This paper updates the previous recommendations based on current knowledge.

Clinical Trials as Topic↗
PubMed2004

Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes.

OBJECTIVE: Antiphospholipid syndrome is characterized by recurrent pregnancy loss, thrombosis, and antiphospholipid antibodies. However, some women with clinical features of antiphospholipid syndrome test negative for antiphospholipid antibodies ("antiphospholipid-like syndrome"). Women with antiphospholipid and antiphospholipid-like syndromes have serum immunoglobulin G that harms murine pregnancy, suggesting that the mechanisms of fetal death may be similar in both groups. The objective of our study was to determine whether patients with antiphospholipid and antiphospholipid-like syndromes share pathophysiology by comparing the histology of gestational tissues from these groups. METHODS: Placenta and abortion specimens were obtained from 44 pregnancies in 26 women with antiphospholipid syndrome and 37 pregnancies in 21 women with antiphospholipid-like syndrome. Of these, 16 pregnancies with antiphospholipid syndrome and 8 with antiphospholipid-like syndrome were treated with a variety of medications intended to improve pregnancy outcome. Placentas from 31 elective pregnancy terminations and 40 pregnancies complicated by idiopathic preterm delivery served as an additional control group. Twenty histologic parameters were systematically assessed by a single investigator who was blinded to the clinical status of the specimens. Histopathologic findings were compared among groups using multivariate logistic regression analysis. RESULTS: Antiphospholipid syndrome pregnancies included 15 spontaneous abortions, 13 fetal deaths, and 16 live births. Pregnancies in the antiphospholipid-like syndrome group resulted in 5 spontaneous abortions, 30 fetal deaths, and one live birth. Gestational tissues from antiphospholipid and antiphospholipid-like syndrome pregnancies were similar for every histologic feature tested. Decidua from women with both antiphospholipid and antiphospholipid-like syndromes had more necrosis, acute and chronic inflammation, and vascular thrombus compared to controls. Placental tissue from antiphospholipid and antiphospholipid-like syndrome pregnancies showed more infarction, intravascular fibrin deposition, syncytial knot formation, and fibrosis than controls. Histologic features were variable within groups. There were no histologic differences in tissues from live births and pregnancy losses, or in treated and untreated pregnancies. CONCLUSIONS: Placental histopathology is similar in antiphospholipid and antiphospholipid-like syndrome pregnancies, suggesting that these disorders may share pathophysiology. Histologic findings in women with APS are non-specific and may not differentiate between women with APS and APS-like syndromes.

Abortion, Spontaneous↗
PubMed2004

Quality of life evaluations of caregivers of ovarian cancer patients during chemotherapy treatment.

OBJECTIVES: (1) To examine the quality of life (QOL) of caregivers of women undergoing chemotherapy for advanced ovarian cancers, and (2) to correlate the QOL measures of caregivers to those of the women undergoing chemotherapy. METHODS: Over a 9-month period, all women undergoing chemotherapy for ovarian cancer at the Saskatoon Cancer Centre, and their caregivers, were offered participation. Two well-validated instruments were used to measure the "quality of life" concept. Women with ovarian cancer completed the Functional Assessment of Cancer Therapy--Ovarian (FACT-O) questionnaire in the clinic prior to each course of chemotherapy. Each caregiver completed a Caregiver Quality of Life Index--Cancer (CQOL-C) questionnaire at home at the start and conclusion of each chemotherapy regimen (cycle 1 and after the last chemotherapy treatment). The demographics of the caregivers were described. A paired t test was used to detect changes to caregivers' QOL scores before and after chemotherapy treatment. Correlation analysis was carried out to examine the relationship between the caregivers' total QOL scores and the various subscale and total scores of the FACT-O questionnaires completed by the women with ovarian cancer. Multivariate regression models were constructed to examine the relative importance of each of the QOL domain measures of the woman with cancer in predicting the effect on her caregiver's QOL. RESULTS: Thirty different patient-caregiver pairs participated in the study, providing 50 separate assessments since not all pairs had completed the post-chemotherapy assessments. There was improvement (P <.05) in the caregiver's QOL scores at the conclusion of the chemotherapy treatment compared to the baseline assessments. The improvement was unrelated to the performance status or response to chemotherapy of the woman undergoing treatment. There was also a correlation (P <.05) between an increase in a caregiver's distress and worsening scores in the "emotional," "functional," and "concerns" QOL domain assessments of the woman undergoing treatment. Stepwise regression analysis showed the "concerns" score, measuring specific ovarian cancer-related symptoms, to be the only predictor of a caregiver's distress (P <.05). CONCLUSIONS: Standard chemotherapy for ovarian cancer does not worsen a caregiver's QOL. There is a direct relationship between the QOL of women with cancer and that of their caregivers. Future research is required to identify how best to integrate the results of QOL assessments in cancer treatment protocols and to examine the long-term effects of ovarian cancer and its treatment on both caregivers and the women for whom they care.

Adult↗
PubMed2004

Outbreaks of infectious diseases in stem cell transplant units: a silent cause of death for patients and transplant programmes.

Following the closure of the National Blood and Bone Marrow Transplant Unit in Dublin, because of an outbreak of vancomycin-resistant enterococcal infection, a survey was carried out by the EBMT to investigate the occurrence of outbreaks of infection in SCT units and the impact on patient morbidity, mortality and the administration of the transplant programme over a 10-year period from 1991 to 2001. A total of 13 centres reported 23 outbreaks of infection involving 231 patients: 10 bacterial, eight viral and five fungal outbreaks were reported and 56 deaths were attributed to infection. All fungal and bacterial deaths and the majority of viral deaths occurred in allograft recipients. In all outbreaks, the infection was reported to be hospital acquired and in all the viral, and half the bacterial infections, cross-infection was a major factor. All viral, four of 10 bacterial and three of five fungal outbreaks occurred in HEPA filtered rooms. A total of 12 SCT units reported a partial or total closure. The introduction of mandatory quality management systems such as JACIE should result in a change in attitude to 'incident reporting' and together with future surveys should reduce the incidence of infectious outbreaks in SCT units.

Aspergillosis↗
PubMed2004

Pilot scheme for performance assessment of HIV-1 genotypic resistance testing in the UK.

HIV-1 drug susceptibility testing by genotypic methods is now widespread in the UK and it is thus important to determine the reproducibility of such investigations. A pilot study was carried out to determine the reproducibility between laboratories of genotypic testing by nucleotide sequencing of patient samples, and to compare the interpretations of the results provided to the clinicians. Samples were distributed between the participating laboratories. Eight laboratories, using three different methods, sequenced four samples. Nucleotide sequence and reports were collated and compared by one laboratory. Where sequencing data were obtained > 99% concordance was observed for nucleotide designations. No discordances in nucleotide sequencing were found in positions associated with drug resistance. However, there were considerable differences between the laboratories in the interpretation of some of the mutations with respect to their effect on drug susceptibility. This study emphasises the variability in the available interpretation systems, and the importance of joint laboratory-clinical discussion in making decisions about treatment options.

Data Interpretation, Statistical↗
PubMed2001

Azepanone-based inhibitors of human and rat cathepsin K.

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.

Administration, Oral↗
PubMed2001

Continuous, categorical, and time to event cocaine use outcome variables: degree of intercorrelation and sensitivity to treatment group differences.

Although a number of cocaine use variables are available for use in treatment outcome studies, there is little information on how strongly these variables are related or their relative sensitivity for detecting treatment group differences. Eight continuous and categorical variables of cocaine use obtained at 6-, 12-, 18-, and 24-month follow-ups, four event history variables, and one summary measure of cocaine use over the 24-month follow-up period were examined. The variables were generally correlated 0.30--0.50 or greater. An exploratory factor analysis in which the repeated measures were averaged across follow-up points yielded two factors, one made up of incidence of use variables (e.g. percent days cocaine use, monetary value of cocaine, abstinence status, time to relapse, urine toxicology) and a second consisting of perceived severity of use variables (e.g. drug and cocaine composites, craving). This factor solution was supported by confirmatory factor analyses conducted at each follow-up point. None of the variables yielded significant differences between the two treatment conditions in the study, standard group and individualized relapse prevention continuing care. However, monetary value of cocaine used and urine toxicology variables yielded the largest effect sizes (eta(2)=0.020 and 0.010, respectively).

Adult↗
PubMed2001

Parainfluenza virus 3 infection after stem cell transplant: relevance to outcome of rapid diagnosis and ribavirin treatment.

All 456 recipients of hemopoietic stem cell transplants (SCT) at the Hammersmith Hospital, London, from January 1990 through September 1996 were reviewed for parainfluenza virus (PIV) infections. Of the 24 (5.3%) PIV type 3 (PIV3)-infected patients, 10 had upper respiratory tract infection and all survived, but 8 of 14 with pneumonia died. A same-day immunofluorescence test diagnosed PIV3 infection in 20 (83%) of the 24 cases, but virus culture diagnosed only 10 (42%) of the 24 cases after a mean delay of 12 days. Eighteen PIV3-infected patients first received ribavirin at a median of 3 days after onset of symptoms, but, nevertheless, 2 patients shed PIV3 for 4 months. Six of 10 patients with pneumonia died despite early ribavirin therapy. The cause of death was not established by autopsy; 3 patients had concurrent infections, but in 3, only PIV3 was detected. The value of immunofluorescence testing for early diagnosis and treatment of PIV3 infection after SCT is demonstrated, but the outcome was not altered.

Adolescent↗
PubMed2001

Progression after release of obstructive nephropathy.

Progressive glomerular and tubulointerstitial fibrosis develop in 1-year-old rats even after relief (R) of unilateral ureteral obstruction (UUO) at 5 days of age. The present study investigated whether a progressive renal injury model of UUO could be achieved after reversal of UUO (RUUO) in adult instead of neonatal rats. The potential for alpha-tocopherol modulation of mRNA for the fibrogenic cytokine, transforming growth factor-beta1 (TGFbeta1), apoptosis (TUNEL assay), and the presence of the stress protein, heat shock protein-70 (HSP-70), was also studied in this post-obstructive model. Male Sprague-Dawley rats weighing 125-150 g were randomly assigned to groups of 4 animals each for durations of 7 or 14 days of alpha-tocopherol supplementation after RUUO. The groups included: (i) sham, regular chow; (ii) RUUO, regular chow; (iii) RUUO, contralateral nephrectomy (NX); and (iv) RUUO, NX plus alpha-tocopherol supplementation. We found a significant increase in the ratio of kidney weight/body weight in the RUUO+NX group at 14 days compared with the sham and RUUO groups. This rise in the RUUO+NX group was significantly reduced after 14 days of alpha-tocopherol administration. The elevated level of kidney TGFbeta1 mRNA in the RUUO+NX group was only partially reduced at 7 days. But at 14 days this became significantly reduced with the continued alpha-tocopherol treatment. The HSP-70 staining and the apoptosis of the kidney showed results parallel to those of TGFbeta mRNA at 14 days. To separate the effects of hypertrophy after unilateral NX from the RUUO studies, we carried out a second experiment in control animals subjected to NX, with and without alpha-tocopherol supplementation. Fourteen days after NX, the apoptosis and TGFbeta1 mRNA showed no significant differences from the control animals. Our data suggest that a model of progressive renal injury in RUUO can be established in adult rats. After contralateral NX, the progressive injury is evidenced by the increase in the ratio of kidney weight/total body weight, the apoptotic counts, as well as fibrogenic cytokine TGFbeta1 mRNA in the post-obstructed kidney. Finally, our data also support the concept that alpha-tocopherol is renal protective, as judged by TGFbeta1 mRNA, apoptosis, and HSP-70 staining, even in the progressive disease process of the post-obstructed model.

Animals↗
PubMed2001

Antagonism of the osteoclast vitronectin receptor with an orally active nonpeptide inhibitor prevents cancellous bone loss in the ovariectomized rat.

An orally active, nonpeptide Arg-Gly-Asp (RGD) mimetic alpha(v)beta3 antagonist, (S)-3-Oxo-8-[2-[6-(methylamino)-pyridin-2-yl]-1-ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (compound 1), has been generated, which prevented net bone loss and inhibited cancellous bone turnover in vivo. The compound binds alpha(v)beta3 and the closely related integrin alpha(v)beta5 with low nanomolar affinity but binds only weakly to the related integrins alpha(IIb)beta3, and alpha5beta1. Compound 1 inhibited alpha(v)beta3-mediated cell adhesion with an IC50 = 3 nM. More importantly, the compound inhibited human osteoclast-mediated bone resorption in vitro with an IC50 = 11 nM. In vivo, compound 1 inhibited bone resorption in a dose-dependent fashion, in the acute thyroparathyroidectomized (TPTX) rat model of bone resorption with a circulating EC50 approximately 20 microM. When dosed orally at 30 mg/kg twice a day (b.i.d.) in the chronic ovariectomy (OVX)-induced rat model of osteopenia, compound 1 also prevented bone loss. At doses ranging from 3 to 30 mg/kg b.i.d., compound 1 partially prevented the OVX-induced increase in urinary deoxypyridinoline. In addition, the compound prevented the OVX-induced reduction in cancellous bone volume (BV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), as assessed by quantitative microcomputerized tomography (microCT) and static histomorphometry. Furthermore, both the 10-mg/kg and 30-mg/kg doses of compound prevented the OVX-induced increase in bone turnover, as measured by percent osteoid perimeter (%O.Pm). Together, these data indicate that the alpha(v)beta3 antagonist compound 1 inhibits OVX-induced bone loss. Mechanistically, compound 1 prevents bone loss in vivo by inhibiting osteoclast-mediated bone resorption, ultimately preventing cancellous bone turnover.

Animals↗
PubMed2001

SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia.

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been linked to the production of inflammatory cytokines/mediators/inflammation and death/apoptosis following cell stress. In these studies, a second-generation p38 MAPK inhibitor, SB 239063 (IC(50) = 44 nM), was found to exhibit improved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis factor production (IC(50) = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 microg/ml (i.e., begun 15 min poststroke and continuing over the initial 6-h p38 activation period) was used. Significant and dose-proportional brain penetration of SB 239063 was demonstrated during these infusion periods. In both moderate and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respectively. No effects of the drug were observed on cerebral perfusion, hemodynamics, or body temperature. Direct neuroprotective effects from oxygen and glucose deprivation were also demonstrated in organotypic cultures of rat brain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotection emphasizes the potential role of MAPK pathways in ischemic stroke and also suggests that p38 inhibition warrants further study, including protection in other models of nervous system injury and neurodegeneration.

Animals↗
PubMed2001

Safety and efficacy of imiquimod 5% cream in the treatment of penile genital warts in uncircumcised men when applied three times weekly or once per day.

This dose-escalation study was performed to evaluate safety and efficacy of imiquimod 5% cream in the treatment of uncircumcised men with penile warts associated with the foreskin. The cream was applied 3 times/week (n=34) or once per day (n=30) over 8+/-2 h. Imiquimod 5% cream was safe in both treatment groups. However, the 3 times/week regimen was better tolerated with a lower incidence of local skin reactions. In both groups, the 2 most frequently reported local skin reactions were erythema and erosion; they were more severe with the once-daily dosing. The most frequently reported application site reactions were burning, pruritus and irritation or pain (once-daily patients only). Total clearance was achieved in 62% of the patients in the 3 times/week group and by 57% in the once-daily group. Thus, imiquimod 5% cream administered 3 times/week was the optimal dosing regimen in the treatment of penile warts in uncircumcised men.

Administration, Topical↗