Biomedical subjects
Publications and source records attributed to D Powell.
Lipodystrophies are rare disorders of adipose tissue metabolism. Two forms are recognised--partial or generalised. Though loss of body fat is a common feature these have been considered mutually exclusive clinical entities making any unifying pathophysiological concept difficult. We report, for the first time, a case of partial lipodystrophy affecting the face which progressed to become generalised.
One hundred thirty-four patients with bulky and barrel-shaped cervix cancers were treated with preoperative radiation to 40-45 Gy, intracavitary therapy using Cs-137 or Cf-252 and extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) 4-6 weeks after radiotherapy. Outcome of therapy was traced for patients with residual tumor (positive) in the hysterectomy specimen and those who had no residual tumor (negative) in the specimens. All specimens were studied by a set protocol to carefully evaluate the TAHBSO specimen for gross or residual tumor. Ninety-two percent of the patients with negative specimens survived 5 years, but this dropped to 71% if the specimen was positive. These findings were observed in both the Cs-137- and Cf-252-treated patients. Patients with negative specimens failed mainly in distant sites, whereas those with positive specimens failed locally and distantly. Patient survival was less in patients with positive specimens. There was no difference in outcomes for adenocarcinoma and squamous cell carcinomas. The specimen histological findings have predictive value in patients treated with preoperative radiation and surgery.
Girls with Turner's Syndrome respond to growth hormone therapy. In combination with anabolic steroids, studies show a synergistic effect that does not cause an undue increase in bone age. As studies progress, patients are growing taller than their predicted final heights. Whether the increase in linear growth velocity will be sufficient to bring the Turner's Syndrome patient in to the normal range (greater than 150cms) and remove short stature as a necessary stigma for these unfortunate patients remains to be seen.
Since 1976 a clinical trial has been conducted to test the feasibility, the potential, and to develop methods for using the neutron-emitting radioactive isotope, californium-252 (Cf-252), for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced (Stages III and IV) cervical cancer patients using different doses and schedules; they were extended to include unfavorable presentations of Stages I and II because of favorable results in the initial trials. The authors began to treat patients with Stage IB bulky or barrel-shaped tumors and the majority were treated with both radiation and hysterectomy. Actuarial survival was determined for Stage IB disease and was 87% at 5 years and 82% at 10 years. For those tested with preoperative radiation it was 92% at 5 and 87% at 10 years. For Stage II, it was 62% 5 years and 61% at 10. Survival 5 years after combined radiation and surgical therapy for Stage II disease was 68%. For Stage III, it was 33% at 5 years and 25% at 10. However, 5-year survival using the early neutron implant was 46% versus approximately 19% for delayed Cf-252 or cesium 137. Different schedules and sequences of neutrons and photons greatly altered outcome. Neutron treatment before external photon therapy was better for all stages of disease. Only about 5% of all patients developed complications after neutron therapy. No hematologic or mesenchymal second tumors were observed. Neutron brachytherapy was found to be very effective for producing rapid response and greatly improved local control of bulky, barrel, or advanced cervical cancers. The clinical trial identified and evolved schedules, doses, doses per session, and developed methods different from standard photon therapy but highly effective for local control and cure of cervical cancers of all stages. Clinical and radiobiologic understanding for the use of neutron therapy was greatly advanced by this trial. Future trials will focus on patients with advanced disease and will require evaluation of adjuvant chemotherapy studies and neutron-enhancing chemicals.
BACKGROUND: Despite the use of vidarabine, herpes simplex virus (HSV) infection in neonates continues to be a disease of high morbidity and mortality. We undertook a controlled trial comparing vidarabine with acyclovir for the treatment of neonatal HSV infection. METHODS: Babies less than one month of age with virologically confirmed HSV infection were randomly and blindly assigned to receive either intravenous vidarabine (30 mg per kilogram of body weight per day; n = 95) or acyclovir (30 mg per kilogram per day; n = 107) for 10 days. Actuarial rates of mortality and morbidity among the survivors after one year were compared overall and according to the extent of the disease at entry into the study (infection confined to the skin, eyes, or mouth; encephalitis; or disseminated disease). RESULTS: After adjustment for differences between groups in the extent of disease, there was no difference between vidarabine and acyclovir in either morbidity (P = 0.83) or mortality (P = 0.27). None of the 85 babies with disease confined to the skin, eyes, or mouth died. Of the 31 babies in this group who were treated with vidarabine and followed for a year, 88 percent (22 of 25) were judged to be developing normally after one year, as compared with 98 percent (45 of 46) of the 54 treated with acyclovir (95 percent confidence interval for the difference, -4 to 24). For the 71 babies with encephalitis, mortality was 14 percent with vidarabine (5 of 36) and with acyclovir (5 of 35); of the survivors, 43 percent (13 of 30) and 29 percent (8 of 28), respectively, were developing normally after one year (95 percent confidence interval for the difference, -11 to 39). For the 46 babies with disseminated disease, mortality was 50 percent (14 of 28) with vidarabine and 61 percent (11 of 18) with acyclovir (95 percent confidence interval for the difference, -20 to 40); of the survivors, 58 percent (7 of 12) and 60 percent (3 of 5), respectively, were judged to be developing normally after one year (95 percent confidence interval for the difference, -40 to 50). Both medications were without serious toxic effects. CONCLUSIONS: In this multicenter, randomized, blinded study there were no differences in outcome between vidarabine and acyclovir in the treatment of neonatal HSV infection. The study lacked statistical power to determine whether there were sizable differences within the subgroups of those with localized HSV, encephalitis, or disseminated disease.
BACKGROUND: In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates. METHODS: Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection. RESULTS AND CONCLUSIONS: There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences.
Twenty-seven patients with operable Stage II cervical cancer with a mean diameter tumor of 8.0 cm were studied in a feasibility study using preoperative 252Cf implants plus whole-pelvis radiation to 45 Gy followed by extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy 4 to 6 weeks later. Hysterectomy specimens were studied by a set protocol. With the protocol used, 13/27 (51%) specimens and abdominal stagings were negative for residual tumor. The survival rate for the patients with negative findings was 93% at 5 years. In 14/27 (49%) patients the specimens were positive for residual tumor. In contrast, the 5-year survival rate for this group was 46% (P less than 0.001). In these patients several interrelated factors were determined to be of importance, i.e., (1) tumor size greater than 8 cm in maximum diameter, (2) positive or negative residual tumor status, and (3) total dose of radiation given. Survival was lower for larger tumors and specimens were more likely to show residual tumor. A lower treatment dose led to more positive specimens, as well as to poorer survival. While the patients with Stage II disease fared very well when negative specimens were found, further prospective studies of the appropriate treatment for those with positive tumor specimens are needed.
CL 306,293, a substituted quinoline carboxylic acid at a daily oral dose between 1.5 and 3.0 mg/kg suppressed the inflammation and joint destruction (radiological criteria) associated with both developing and established adjuvant arthritis. When a weekly oral dosing regimen was used, joint destruction was attenuated when this agent was administered at a dose of 50 to 200 mg/kg. Inflammation associated with a delayed type hypersensitivity reaction in dogs was suppressed at a daily dose of 0.25 mg/kg or a weekly dose of 1 mg/kg. At efficacious doses, CL 306,293 had no effects on cyclooxygenase or lipoxygenase activities nor did it have an effect on carrageenin induced paw edema. In acute tests, the compound was not ulcerogenic. The above observations indicate that the antiinflammatory effects of CL 306,293 are distinct from those observed with nonsteroidal antiinflammatory agents. Mechanistic studies conducted and to be published indicate that CL 306,293 down regulates T cell function and this mechanism may account, at least in part, for the antiinflammatory and antiarthritic properties observed in animal models of inflammation and joint destruction.
This study explores the effect of extracellular Ca2+ concentration ([Ca2+]o), on the intracellular Na+ concentration ([Na+]i), in frog intact hearts using nuclear magnetic resonance spectroscopy, which allows for the measurement of [Na+]i in perfused, beating hearts. Decreases in [Ca2+]o yielded marked increases in [Na+]i. A similar effect was seen during inhibition of the Na+/K+ pump and was fully reversible. This sensitivity of [Na+]i to [Ca2+]o, previously observed using microelectrodes, supports a crucial physiological role for Na+/Ca2+ exchange in frog intact, beating hearts.
Explore the source record for details and available documents.
High levels of substance-P are present in the plasma of patients with carcinoid tumours and some thyrotoxic conditions. The majority of the substance-P in the blood plasma was shown, by immunoassay, to be associated with high molecular-weight material in a complex that could be dissociated by repeated gel-filtration. Smaller amounts of an intermediate molecular-weight (about 65,000 Da) complex were also detected. Chemical crosslinking with glutaraldehyde was used to show that the radioactively-labelled derivative [125I]Tyr-8-substance-P was able to bind to the high-Mr fraction of human plasma and also to human serum albumin. Binding to serum albumin was also demonstrated by equilibrium gel-filtration. Substance-P added to human plasma from a thyrotoxic subject, which contained high endogenous levels of the tachykinin (980 pg/mL), was rapidly degraded during incubation at 37 degrees, whereas the endogenous substance-P was considerably more stable. These results suggest that the binding of substance-P to blood plasma components may play an important role in protecting it against degradation. Furthermore, immunoassay techniques involving prior extraction, which fail to detect the bound substance-P, will give inaccurate measurements of the levels of this peptide in plasma.
Lipid peroxidation products were measured in the plasma of 24 kidney transplant patients and 12 healthy volunteers (controls) by: (1) 2-thiobarbituric acid assay and (2) the intensity of fluorescence products of malonaldehyde cross-linked proteins. Plasma levels of creatinine, ceruloplasmin, transferrin, prealbumin, albumin and total protein were also measured. Elevated lipid peroxidation products and lowered transferrin levels were observed in transplant patients compared to controls. Ceruloplasmin levels were slightly but significantly elevated in recent transplant recipients (less than 6 months, n = 12, Group A) while no difference was observed between older transplant recipients (greater than 6 months, n = 12, Group B) and controls. Serum, creatinine levels were also slightly but significantly elevated in both groups of patients compared to controls. Serum prealbumin, albumin and total protein levels in both groups of transplant recipients were not different from controls or reference range values.
Explore the source record for details and available documents.
During spermatogenesis, DNA in the sperm head becomes more tightly condensed as histones are replaced by protamine-like molecules. In this article, the question is asked whether, during the production of this highly differentiated cell, controls are imposed on the spatial organization of DNA within the nucleus. Heads from bull spermatozoa were isolated by a technique that removed the plasma membrane and acrosomal contents, and the DNA was induced to decondense by addition of 2-mercaptoethanol and trypsin. Under these conditions, decondensation was induced in all regions of the head. To determine whether there was any spatial restraint on packaging of the genome, three DNA probes were used (pl.709-512, containing an interspersed repetitive sequence; pCSIH, containing a copy of the major bovine centromeric statellite sequence; p18 s and p28 s, containing the 18 S and 28 S ribosomal genes) that might be expected to hybridize to different regions. Results showed that the interspersed repetitive probe hybridized to all regions of the head, whereas the ribosomal and centromeric probes hybridized to sequences that were largely confined to the equatorial region of the sperm. We conclude that organization of the genome in the bovine sperm nucleus is not random.
Clinical data of the University of Kentucky trial using californium (252Cf), or caesium (137Cs), are reviewed for dose-response based on the endpoint of tumour eradication estimated from hysterectomy specimens obtained 4-6 weeks after preoperative irradiation. These data are used to assess the relative biological effectiveness (RBE) for 252Cf neutrons compared with 137Cs gamma radiation. Tumours treated were of common stage but were of bulky or barrel shape suitable for "radiosurgical" therapy. Dose-response curves were constructed, and additional data from the literature used to analyse the curve shape. The photon dose-response curve is complex on a logarithmic plot, whereas the 252Cf neutron curve is exponential. This indicates that the RBE can be different depending on the number of implants, schedule and size of dose delivered per session. The RBE values were approximately 8.0 at low doses or for multiple implants but they may rise to approximately 16 at larger doses or for single 252Cf implants.
325 patients referred to an endocrine clinic with short stature were reviewed, 32 (9.8%) were above the third centile for height and maintained normal growth velocities, fourteen (4.3%) have not had assessment completed. Of 279 children in whom the cause of short stature was established, 140 (50%) had constitutional short stature/delayed puberty (CSS/DP). Seventy-three (26%) had idiopathic growth hormone deficiency (GHD), complete in 23, while 66 patients (34%) had short stature due to other causes. Girls presented earlier (mean age 11.9) than boys (mean age 13.3) and GHD patients earlier than CSS/DP patients with bimodal peaks at 12 and 16 years. Male CSS/DP patients reached their mid pubertal point later than normal at 16.06 +/- 1.19 years (p less than .05) while in GHD males the mid pubertal age was 16.6 years (p less than .05). In female patients with short stature no significant pubertal delay was observed. The average growth velocity of complete GHD patients pre treatment was 3.7 cms/year. Velocity rose to 6.2 cms/year on human growth hormone (HGH) extract and rose further to 8.1 cms/year on biosynthetic HGH. In partial GHD patients the average pre-treatment velocity of 4.3 cm/year rose to an average of 6.0 cm/yr on HGH extract and maintained this velocity on biosynthetic HGH.
Explore the source record for details and available documents.
A T cell clone (ACH-2) derived from T cells infected with HIV-1 was found to produce HIV-1 in response to stimulation with a monokine-enriched supernatant prepared by culturing human monocyte/macrophages with bacterial LPS (LPS-MO SN). Monokine induction of ACH-2 cells resulted in augmented virus production reflected by an increase in reverse transcriptase activity and in the synthesis of all major viral proteins. Examination of the cells by indirect immunofluorescence revealed that 10 to 15% of uninduced cells constitutively expressed HIV proteins, whereas 100% showed positive immunofluorescence in response to LPS-MO SN. This induction of virus by LPS-MO SN resulted in approximately a 100-fold increase of infectious virus production over uninduced ACH-2 cells. LPS alone could not induce HIV-1 expression, whereas LPS-MO SN resulted in the greatest virus expression. Cell separation studies confirmed the source of the inducing factor(s) to be cells bearing the mature monocyte/macrophage marker, Leu M3. Biochemical fractionation of the LPS-MO SN suggested that one or more factors, having apparent Mr of approximately 45 kDa, were involved in this induction. Absorption of the LPS-MO SN with immunoaffinity gels specific for human TNF-alpha was shown to completely remove the HIV inducing activity for the ACH-2 cell line.