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Biomedical subjects

K Phipps

Publications and source records attributed to K Phipps.

17 recordsLinked to original sources
PubMed2005

Tricalcium-phosphate and hydroxyapatite bone-graft extender for use in impaction grafting revision surgery. An in vitro study on human femora.

Impacted morsellised allografts have been used successfully to address the problem of poor bone stock in revision surgery. However, there are concerns about the transmission of pathogens, the high cost and the shortage of supply of donor bone. Bone-graft extenders, such as tricalcium phosphate (TCP) and hydroxyapatite (HA), have been developed to minimise the use of donor bone. In a human cadaver model we have evaluated the surgical and mechanical feasibility of a TCP/HA bone-graft extender during impaction grafting revision surgery. A TCP/HA allograft mix increased the risk of producing a fissure in the femur during the impaction procedure, but provided a higher initial mechanical stability when compared with bone graft alone. The implications of the use of this type of graft extender in impaction grafting revision surgery are discussed.

Arthroplasty, Replacement, Hip↗
PubMed2000

Growth hormone treatment of children with brain tumors and risk of tumor recurrence.

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

Adolescent↗
PubMed1999

A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

Adult↗
PubMed1997

The significance of allelic deletions and aneuploidy in colorectal carcinoma. Results of a 5-year follow-up study.

BACKGROUND: A prospective study was initiated to analyze the prognostic value of both the deletion of candidate tumor suppressor genes and the DNA content in colorectal carcinoma specimens. METHODS: A prospective study was initiated in 1988, into which 104 patients from the Brooklyn VA Medical Center were accrued through March 1992. DNA restriction endonuclease digests, obtained by the Southern blot technique, were examined for allelic deletions by cDNA probes pnm23-H1 (17q21) YNZ 22.1 (17p13), and p15-65 (18q21). DNA content was measured by image analysis cytometry of Feulgen-stained tumor imprints. Median follow-up was 5.5 years (range, 4-8.5 years). RESULTS: Patients with nm23-H1 allelic deletions were 3 times as likely to develop distant metastases as patients without nm23-H1 deletions (relative risk [RR], 3.89; 95% confidence interval [CI], 1.39, 10.89). This connection was even stronger after adjustment for TNM stage and site of primary tumor (RR, 5.27; 95% CI, 1.67, 16.68). No significant association of 17p or 18q deletions or ploidy with either distant metastases or overall survival was noted. In multivariate analysis, clinicopathologic variables associated with decreased survival included intracellular mucin production, nuclear grade, TNM stage, and nerve invasion. CONCLUSIONS: A combination of clinicopathologic and molecular biologic variables may identify patients at high risk for death from disseminated colorectal carcinoma.

Aged↗
PubMed1997

Intrinsic brainstem tumours in childhood: a report of 35 children followed for a minimum of 5 years.

The presentation, pathology and outcome of 35 children with intrinsic brainstem tumours treated at our institution between 1980 and 1990 have been reviewed. Eight children remain alive. There were 19 girls and 16 boys. Mean age at diagnosis was 5 years. The mean duration of symptoms prior to diagnosis was 5 months. The diagnosis was made by computed tomography (CT) in all children and magnetic resonance imaging (MRI), in addition, for 24 children. Twenty-seven tumours (77%) were diffuse, three (8.6%) were predominantly cystic, three (8.6%) were exophytic and two (5.7%) were focal. Cervicomedullary tumours were not included in this study. Definitive histology was obtained in 13 children (37.1%), eight (22.9%) by biopsy alone and five (14.3%) after surgery to debulk the tumours. Eleven of these cases were astrocytomas and two were primitive neuroectodermal tumours (PNET). Twelve children (34.3%) required shunt placement for hydrocephalus. Twenty-eight children (80%) were irradiated using conventionally fractionated radiotherapy to a total dose between 50 and 55 Gy. Six children (17.1%) also received chemotherapy. The overall mean survival time was 10 months, but five of six children who had their tumours debulked survived free of progressive disease for more than 5 years following their diagnosis. The prognosis for brainstem tumours in children remains poor with only a minority falling into the surgically resectable (good prognosis) group.

Adolescent↗
PubMed1997

Medulloblastoma: is the 5-year survival rate improving? A review of 80 cases from a single institution.

A series of 80 cases of medulloblastomas in children undergoing operation and postoperatively followed between 1980 and 1990 at Great Ormond Street Hospital for Children (GOSH) has been reviewed and compared to an earlier series reported from the same institution by McIntosh. The overall 5-year survival rate for the present series was 50%, although three patients died after surviving 5 years. The operative mortality rate was 5%. Survival analysis revealed that the presence or absence of spinal metastases and the necessity for some form of cerebrospinal fluid diversion within 30 days of the operation independently significantly affected survival in this series. Those patients with no spinal metastasis and total tumor removal had a 5-year survival rate of 73%, making this the most favorable subgroup in the series. Patient age and gender, duration of symptoms, Chang T stages, tumor volume, extent of resection, and postoperative chemotherapy were not significant variables. Although these results are better than those reported in the earlier GOSH series, they are not significantly different from the results of the second 5-year cohort of patients described in that article. Radiotherapy remains the greatest advance in treatment, although it is hoped that further improvement will result from the various chemotherapy protocols now being studied and from increasing knowledge of the biological behavior of these tumors.

Adolescent↗
PubMed1997

Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.

Administration, Oral↗
PubMed1996

Erythroid progenitor proliferation is stimulated by phenoxyacetic and phenylalkyl acids.

Short-chain fatty acids, such as butyrate and propionate, are under investigation as therapeutic stimulants of fetal hemoglobin production in the beta-hemoglobin disorders. Significant limitations to these fatty acids and derivatives as optimal therapeutics are their rapid metabolism in vivo and their induction of cell growth arrest in the G1 phase of the cell cycle. This antiproliferative activity is related to their inhibition of metabolic transport pumps which are essential for cell proliferation. Other small carbon compounds, the phenylalkyl acids, phenoxyacetic acids, and phenylacetic acids, which are structurally resistant to oxidative metabolism, are shown here to induce fetal globin production in human erythroid cultures at concentrations of 0.2 mM, lower than those required for most other fatty acids. Certain of these compounds were found not to inhibit cellular neutral amino acid transport function in erythroid cells, nor to inhibit erythroid colony (Bfu-e) growth. Certain of these compounds even stimulated human Bfu-e proliferation in vitro beyond that induced by optimal concentrations of hematopoietic growth factors. The combination of increased fetal globin chain production by these compounds and their stimulatory effects on erythropoiesis result in an increase in Hb F-expressing erythroid cells in culture several-fold greater than that achieved by the butyrates. These new compounds thus have the potential to provide superior therapy for the beta-hemoglobinopathies and other anemias.

Biological Transport↗
PubMed1996

Ventriculo-peritoneal shunt requirement in children with posterior fossa tumours: an 11-year audit.

The authors reviewed 175 paediatric patients with posterior fossa tumours treated at the Hospital for Sick Children at Great Ormond Street, London, between 1983 and 1993, in an attempt to determine the requirement for shunt procedures in these children. The age of the patient population ranged from 4 months to 14 years 6 months. The factors evaluated included age at diagnosis, tumour type, extent of surgical resection, and the presence of CSF leak and/or infection. Shunt placement was required postoperatively in 18.9% of patients. Age of the patient was felt to be a significant factor in the need for shunt placement. Tumour type and completeness of tumour excision were also felt to be significant factors affecting the need for post-operative shunt insertion.

Adolescent↗
PubMed1996

Differential stimulation of Na+ pump activity by insulin and nitric oxide in rabbit aorta.

The effect of insulin on Na+ pump activity, measured as ouabain-sensitive (OS) 86Rb uptake, was studied in the rabbit aorta. In the absence of insulin, incubation of endothelium-intact rings for 3 h in a medium containing a high concentration of glucose (44 mM) decreased OS 86Rb uptake by 42% compared with that observed at 5.5 mM glucose. Addition of insulin (0.1-10 microU/ml) increased OS86 86Rb uptake at both glycose concentrations and eliminated the differences between the groups. Insulin also increased OS 86Rb uptake in endothelium-intact and -denuded (ED) rings in the presence of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine. Removal of the endothelium before the incubations did not diminish the insulin-induced increase in OS 86Rb uptake, which was concentration dependent. The NO donor sodium nitroprusside increased OS 86Rb uptake in ED rings, and its effect and that of insulin were additive. Phorbol 12,13-dibutyrate, a direct activator of protein kinase C (PKC), also increased OS 86Rb uptake in ED rings; however, its effect and that of insulin were not additive. The PKC inhibitor bisindolylmaleimide totally inhibited insulin-induced, but not sodium nitroprusside-induced, increases in OS 86Rb uptake. The results suggest that insulin activates the Na+ pump in the aorta and reverses the inhibition of the pump caused by hyperglycemia. This effect of insulin can occur at physiological concentrations, is independent of endothelium-derived NO, and is presumably mediated by an increase in PKC activity, In contrast, activation of the Na+ pump by NO appears to be independent of PKC.

Animals↗
PubMed1995

Fluoride and bone health.

This paper reviews some of the studies related to the effect of fluoride on the skeletal system of humans and outlines the knowns and unknowns of fluoride and bone health. Current research indicates that, in large enough doses, fluoride stimulates bone formation by osteoblastic stimulation, increases bone formation earlier and to a larger extent in trabecular bone compared to cortical bone, and increases spinal bone density. There is controversy, however, concerning the efficacy of fluoride as a therapeutic agent in the treatment of osteoporosis. Some clinical studies have found a reduction in vertebral fracture rates while others have not. To date, only ecologic studies have been conducted on the association between water fluoridation and hip fractures. The inability of ecologic studies to control for confounding variables makes their interpretation difficult. Based on the literature presented, it is concluded that there are more unknowns than knowns in terms of fluoride's effect on bone, osteoporosis, and fractures. One of the major unknowns in the relationship between fluoride and bone health is dose and duration. Two studies are underway that attempt to describe the dose-response relationship between waterborne fluoride and osteoporosis. These studies will be completed in the near future and their results, while providing new insight into fluoride's effects on bone, will by no means answer all the questions raised on this issue.

Bone Density↗
PubMed1993

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.

Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".

Aged↗
PubMed1993

Fetal growth and impaired glucose tolerance in men and women.

A follow-up study was carried out to determine whether reduced fetal growth is associated with the development of impaired glucose tolerance in men and women aged 50 years. Standard oral glucose tolerance tests were carried out on 140 men and 126 women born in Preston (Lancashire, UK) between 1935 and 1943, whose size at birth had been measured in detail. Those subjects found to have impaired glucose tolerance or non-insulin-dependent diabetes mellitus had lower birthweight, a smaller head circumference and were thinner at birth. They also had a higher ratio of placental weight to birthweight. The prevalence of impaired glucose tolerance or diabetes fell from 27% in subjects who weighed 2.50 kg (5.5 pounds) or less at birth to 6% in those who weighed more than 3.41 kg (7.5 pounds) (p < 0.002 after adjusting for body mass index). Plasma glucose concentrations taken at 2-h in the glucose tolerance test fell progressively as birthweight increased (p < 0.004), as did 2-h plasma insulin concentrations (p < 0.001). The trends with birthweight were independent of duration of gestation and must therefore be related to reduced rates of fetal growth. These findings confirm the association between impaired glucose tolerance in adult life and low birthweight previously reported in Hertfordshire (UK), and demonstrate it in women as well as men. It is suggested that the association reflects the long-term effects of reduced growth of the endocrine pancreas and other tissues in utero. This may be a consequence of maternal undernutrition.

Birth Weight↗
PubMed1992

Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life.

OBJECTIVE: To determine whether reduced fetal and infant growth are associated with higher plasma fibrinogen and factor VII concentrations in adult life. DESIGN: Follow up study of men born during 1920-30 whose weights at birth and at 1 year had been recorded by health visitors, and men born during 1935-43 whose size at birth had been measured in detail. SETTING: Hertfordshire and Preston, England. SUBJECTS: 591 men born in east Hertfordshire who still lived there and 148 men born in Preston who still lived in or close to the city. MAIN OUTCOME MEASURES: Plasma fibrinogen and factor VII concentrations. RESULTS: Among men in Hertfordshire mean plasma fibrinogen and factor VII concentrations fell with increasing weight at 1 year (from 3.21 g/l in men of less than or equal to 18 lb to 2.93 g/l in men greater than or equal to 27 lb and from 122% of standard to 103%; p less than 0.001, p less than 0.005 respectively). The trends were independent of cigarette smoking, alcohol consumption, body mass index, and social class. Neither plasma fibrinogen nor factor VII concentration was related to birth weight. In men in Preston, however, fibrinogen concentration fell progressively as the ratio of placental weight to birth weight decreased (p = 0.01). CONCLUSIONS: Reduced growth in fetal life and infancy is strongly related to high plasma concentrations of the haemostatic factors fibrinogen and factor VII. This may be a persisting response to impaired liver development during a critical early period.

Aged↗
PubMedDate not supplied

Unit-based clinical nurse specialist: redesigning nursing services.

At the Johns Hopkins Hospital, the Medical Nursing Services redesigned its delivery of direct patient care to include nurse managers, staff nurses, nursing support technicians, and unit-based clinical nurse specialists (CNSs). The CNS role proved efficacious to both nursing staff and nurse managers.

Baltimore↗