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Biomedical subjects

L Williams

Publications and source records attributed to L Williams.

At least 109 records · Page 6Linked to original sources
PubMed1997

Spinal analgesic activity of orphanin FQ/nociceptin and its fragments.

Previous work reveals that orphanin FQ/nociceptin (OFQ/N) administered supraspinally produces an initial hyperalgesic response followed by analgesia. Spinally, OFQ/N elicits a rapidly appearing, naltrexone-reversible, dose-dependent analgesia in the tailflick assay without any indication of hyperalgesia. Two OFQ/N fragments, OFQ/N (1-7) and OFQ/N (1-11), are active, but far weaker. Blockade of sigma receptors with haloperidol enhances the analgesic potency of spinal OFQ/N, OFQ/N (1-7) and OFQ/N (1-11), but not as dramatically as supraspinal OFQ. Antisense probes targeting the second and third coding exons, but not the first exon, of the cloned mouse OFQ/N receptor (KOR-3) partially block OFQ/N analgesia.

Analgesics↗
PubMed1997

Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists.

A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at alpha 1- and alpha 2-adrenoceptors. This class of agents has been shown to have potent and selective agonist activity at the alpha 2-adrenoceptors. The most potent member of this class, 2-[(5-methyl-1,4-benzodioxan-6yl)amino]imidazole, proved efficacious for the reduction of intraocular pressure upon topical administration and for the reduction of blood pressure upon intravenous administration. During the course of our studies, we developed a new reagent that allowed rapid assembly of the target compounds. This reagent, N-(2,2-diethoxyethyl)carbodiimide, was convenient to prepare and was stable under low-temperature storage conditions.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1997

NMDA and D1 receptors regulate the phosphorylation of CREB and the induction of c-fos in striatal neurons in primary culture.

Numerous in vivo studies have demonstrated that psychostimulant drugs such as amphetamine and cocaine can induce the expression of the immediate early gene c-fos in striatal neurons via the activation of D1 dopamine receptors. NMDA receptor activation is also known to induce c-fos in the striatum. In the present study we have used a primary striatal neuronal culture preparation to examine the mechanisms whereby these stimuli lead to changes in gene expression. Direct application of NMDA to striatal cells in culture caused a rapid increase in the expression of c-fos as well as an increase in the phosphorylation of the transcription factor CRE binding protein (CREB). This was prevented by NMDA receptor antagonists, and required extracellular calcium, but did not involve L-type calcium channels. The induction of c-fos and CREB phosphorylation following NMDA were unaffected by inhibition of protein kinase C; tyrosine kinases or nitric oxide synthase. However, the response to NMDA was blocked by KN62, a selective inhibitor of calcium/calmodulin-dependent protein kinase. Application of the D1 agonist SKF 38393, or direct stimulation of adenylyl cyclase with forskolin, also resulted in the phosphorylation of CREB and the induction of c-fos in striatal neurons. These effects were blocked by the protein kinase A inhibitor H89. These observations are consistent with the hypothesis that calcium/calmodulin-dependent phosphorylation of CREB induced by NMDA, or cAMP-dependent phosphorylation of CREB induced by D1 agonists, underlie the induction of c-fos seen following activation of these receptors in striatal neurons.

Animals↗
PubMed1997

Secondary cytoreductive surgery at second-look laparotomy in advanced ovarian cancer: a Gynecologic Oncology Group Study.

Reports which analyzed the effects of secondary cytoreductive surgery at second-look laparotomy have often included small numbers of patients who have been treated with a variety of first-line chemotherapy regimens and those who may have progressed on first-line therapy. The purpose of this study was to analyze survival following secondary cytoreductive surgery at second-look laparotomy in patients with advanced ovarian cancer. Review of the surgical data of 153 patients allowed classification of tumor size found at second-look laparotomy and tumor size remaining after cytoreduction. Multivariate analysis evaluated multiple risk factors for survival. Of 153 patients, 124 had macroscopic tumor at second-look laparotomy and 29 had microscopic disease only. Fifteen of 69 (22%) patients were found to have tumor > 1 cm in diameter and were cytoreduced to microscopic residual and 18/69 (26%) were left with 1 cm tumor. Twenty-one of 55 (38%) patients with < or = 1 cm tumor were debulked to microscopic residual. The shortest survival relative to patients found to have microscopic disease at second-look laparotomy was observed among patients whose maximum tumor size remained > 1 cm following second-look laparotomy (relative risk = 3.1, P = 0.0004). No difference in survival was seen between patients found to have microscopic disease and those cytoreduced to microscopic disease (P = 0.24). The risk of death was lower among patients debulked to a lower category (< or = 1 cm debulked to microscopic, relative risk = 0.48, P = 0.02; > 1 cm reduced to < or = 1 cm, relative risk = 0.49, P = 0.02; > 1 cm reduced to microscopic, relative risk = 0.44, P = 0.01). Whether this apparent beneficial effect of cytoreductive surgery at second-look laparotomy reflects the biology of the tumor which allows surgical cytoreduction or the effects of cytoreduction can only be addressed in a randomized prospective trial.

Adult↗
PubMed1997

Inv(10)(p11.2q21.2), a variant chromosome.

We present 33 families in which a pericentric inversion of chromosome 10 is segregating. In addition, we summarise the data on 32 families in which an apparently identical inv(10) has been reported in the literature. Ascertainment was through prenatal diagnosis or with a normal phenotype in 21/33 families. In the other 12 families, probands were ascertained through a wide variety of referral reasons but in all but one case (a stillbirth), studies of the family showed that the reason for referral was unrelated to the chromosome abnormality. There has been, to our knowledge, no recorded instance of a recombinant chromosome 10 arising from this inversion and no excess of infertility or spontaneous abortion among carriers of either sex. We propose that inv(10)(p11.2q21.2) can be regarded as a variant analogous to the pericentric inversion of chromosome 2(p11q13). We conclude that prenatal chromosome analysis is not justified for inv(10) carriers. In addition, family investigation of carrier status is not warranted in view of the unnecessary concern this may cause parents and other family members.

Abortion, Spontaneous↗
PubMed1997

Impact of liver transplantation on quality of life: a longitudinal perspective.

The impact of transplantation on quality of life in liver transplant recipients was studied in a longitudinal sample of 41 subjects. Quality of life was measured during the pretransplantation and posttransplantation phases of the transplant process. Quality of life improved significantly over time, except in the family domain. This study suggests that quality of life improves after a liver transplant despite the number and length of rehospitalizations. Satisfaction and importance of family remained high throughout the transplant phases. Of the demographic variables, only age and income correlated significantly with quality of life.

Adult↗
PubMed1997

Participation in teleconference support groups: application to drug-using pregnant patients.

This paper describes our experience using telephone conference calls to conduct support groups for chemically-dependent women. Forty-seven women agreed to participate in regular, weekly support groups that were conducted by two chemical dependency counselors. Counselors attempted to conduct 59 support groups via a telephone conferencing system. Our data indicated that attendance at these sessions was poor. Seventeen sessions had no participants. No group sessions were attended by 4 or more women, and only 3 sessions (7.1%) included 3 participants. Very few clients made regular use of the support groups. Only 4 clients (8.5%) participated in more than 3 group sessions. Our findings suggest that teleconferencing may not be the most effective method for providing support services to chemically-dependent women.

Female↗
PubMed1997

Neosartorya fischeri: an invasive fungal pathogen in an allogeneic bone marrow transplant patient.

Invasive fungal infections are a complication of allogeneic BMT. We report the first case of a Neosartorya fischeri fungal infection in a patient following allogeneic BMT. Neosartorya fischeri is related to Aspergillus fumigatus, but it is a distinct fungal species. Despite granulocytic engraftment and aggressive anti-fungal therapy with amphotericin B, the patient died of overwhelming fungal infection on day 60 post-BMT. Neosartorya fischeri is a pathogen that grows slowly in culture which can delay or confuse identification. This case further supports the need for more effective prophylaxis and treatment of non-Candida fungal infections in the allogeneic BMT population.

Aspergillus fumigatus↗
PubMed1997

Consent to treatment by minors attending accident and emergency departments: guidelines.

The absolute right to refuse medical treatment, even if the reasons are irrational, is confined to competent adults. Children under 16 years can give legal consent to treatment in the absence of consent from those with parental responsibility. Children under 18 years do not, however, have an absolute right to consent, or refuse to consent, to treatment. The views of children assume increasing importance with age and maturity. Accident and emergency medical and nursing staff may face difficult decisions when children, or those with parental responsibility, refuse to consent to medical treatment. This paper presents guidelines designed to guide the decision making process in immediately or potentially life threatening conditions and in non-life-threatening conditions.

Adolescent↗
PubMed1997

Repetitive cycles of cyclophosphamide, thiotepa, and carboplatin intensification with peripheral-blood progenitor cells and filgrastim in advanced breast cancer patients.

PURPOSE: As an alternative to single-cycle cyclophosphamide, thiotepa, and carboplatin (CTCb) intensification, we evaluated the feasibility of administering one-quarter dose CTCb for four cycles with peripheral-blood progenitor-cell (PBPC) and filgrastim (granulocyte colony-stimulating factor [G-CSF]) in advanced-stage breast cancer patients. PATIENTS AND METHODS: From June 1992 to August 1993, 20 stage IIIB (n = 7) and IV (n = 13) breast cancer patients received 78 cycles of induction with doxorubicin 90 mg/m2 by intravenous (IV) bolus with G-CSF 5 microg/kg/d by subcutaneous injection (SC) repeated every 14 to 21 days for four cycles. PBPC were collected by 2-hour single-blood volume leukapheresis on 2 consecutive days at the time of hematologic recovery from each cycle of doxorubicin. Eighteen patients received 61 cycles of intensification with cyclophosphamide 1,500 mg/m2, thiotepa 125 mg/m2, and carboplatin 200 mg/m2 by IV continuous infusion with G-CSF 10 microg/kg/d SC and PBPC support repeated every 21 to 42 days for four cycles. RESULTS: Twelve of 20 patients (60%) completed all four planned cycles of doxorubicin induction followed by four cycles of one-quarter dose CTCb intensification. Statistically significantly decreases in the yield of mononuclear cells (MNC) (median slope per day, -0.032; P = .03), granulocyte-macrophage colony-forming unit (CFU-GM) (median slope per day, -0.57; P = .0008), and burst-forming unit-erythroid (BFU-E) (median slope per day, -1.18; P = .006) were observed over the course of the eight leukaphereses. Of 18 patients who began CTCb, 12 (67%) completed four cycles. Six patients were removed from study during intensification: two for progressive disease (PD), one refused further treatment, and three for dose-limiting hematologic toxicity. A fourth patient fulfilled the criteria for dose-limiting hematologic toxicity after cycle 4. The toxicity of the multiple cycle CTCb intensification regimen consisted of grade IV leukopenia, grade IV thrombocytopenia, and febrile neutropenia in 100%, 100%, and 26% of cycles, respectively. The median duration of each CTCb cycle was 24 days (range, 18 to 63), and the median duration of an absolute neutrophil count (ANC) < or = 500/microL and platelet count < or = 20,000/microL during each cycle was 6 days (range, 2 to 15) and 4 days (range, 0 to 38), respectively. CONCLUSION: It is feasible to administer repetitive cycles of one-quarter dose CTCb intensification with PBPC and G-CSF. Additional studies are required to determine whether multiple cycles of CTCb intensification might offer a therapeutic advantage over a single high-dose cycle.

Adult↗
PubMed1997

Influence of time and storage conditions on plasma HIV viral load measurements.

Quantification of human immunodeficiency virus (HIV) RNA in plasma from HIV-infected patients is now widely used as a clinical indicator of disease prognosis and of response to antiretroviral therapy. However, controversy exists as to whether values obtained under different testing conditions could vary significantly, thus jeopardizing the appropriate interpretation of data. Herein, we demonstrate that results obtained after testing plasma versus whole blood, or immediate versus deferred processing, do not appear to influence viral load measurements significantly. Thirty blood samples from HIV-infected patients were analysed. The second generation branched-DNA assay was used for quantification of plasma viral load. HIV RNA remained stable for at least 24 h at room temperature, either in plasma or in whole blood, in 72.4% of the samples (< 0.2 log difference in viral load values) although lower levels of HIV RNA tend to be seen in samples after being stored as whole blood at room temperature. Only 3.4% of samples showed a decline > 0.5 log when they were left as whole blood at room temperature for 24 h in comparison with testing after immediate plasma separation. Although immediate separation and refrigeration of plasma samples may reduce the chance of significant falls in viral load measurements, this level of processing can be limited in regions where clinical blood samples cannot be processed rapidly. Our data provide confidence in the results obtained when testing specimens, either plasma or whole blood, 24 h after venepuncture and storage at room temperature, mimicking the conditions in the transport of blood samples to reference centres.

Blood Specimen Collection↗
PubMed1997

Religious restrictions and the trauma patient.

This article discusses some of the dilemmas the Certified Registered Nurse Anesthetist (CRNA) faces when the patient refuses potential life-saving blood products or a blood transfusion. Even if the CRNA disagrees with the patient's decision, the patient's right to refuse is taken very seriously in the legal arena. Without a court order, the patient cannot be forced to receive blood or blood products. It would be easier if there were clear guidelines; unfortunately, these do not exist. In the past, courts were more likely to agree with the anesthesia provider and order the transfusion, even if the patient were competent. Today, courts are less likely to do so in these cases. However, there are circumstances in which obtaining a court order for the transfusion is more predictable, such as if the patient is a child in a true emergency situation, or if the patient is pregnant and the fetus is viable.

Adult↗
PubMed1997

Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma.

R24 is a monoclonal antibody that recognizes the disialoganglioside GD3 expressed on the surface of malignant melanoma cells. Once bound, it can mediate destruction of these cells through both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Agents such as interleukin 2 (IL-2), which can augment effector cell function and promote destruction of antibody-coated tumor cells, might produce improved antitumor responses when combined with R24. In this series, we evaluated the combination of R24 and IL-2 in a Phase 1b study in patients with metastatic melanoma. Twenty-eight patients with metastatic melanoma were entered into the protocol at two institutions. Patients received 8 weeks of IL-2 by continuous i.v. infusion at a dose (4.5 x 10(5) Amgen units/m2/day) designed to selectively expand natural killer (NK) cells. In weeks 5 and 6, patients received R24 for a total of four doses. Twenty-four h after each R24 infusion, patients received a 2-h bolus dose of IL-2 to help promote activity of NK effectors against antibody-coated melanoma targets. Additional IL-2 boluses were administered in weeks 7 and 8. Doses were escalated through two bolus doses of R24 (5 or 15 mg/m2) and two bolus doses of IL-2 (2.5 or 5.0 x 10(5) units/m2). Although one patient experienced severe capillary leak syndrome during IL-2, therapy was otherwise well tolerated. At the higher dose level of R24, two of four patients experienced transient but severe abdominal and chest discomfort, necessitating dose reduction. One patient with ocular melanoma and liver metastases had a partial response. Two additional patients had minor responses. A dramatic increase in NK cell number was noted as a result of treatment, as was augmentation of cytolytic activity against cultured NK-sensitive targets. Antibody-dependent cellular cytotoxicity against cultured melanoma cells in the presence of exogenous R24 or in the presence of serum obtained from patients following R24 infusion also increased during treatment. Our experience indicates that R24 and low-dose IL-2 can be safely combined in patients with metastatic melanoma and that this combination can promote destruction of cultured melanoma cells. The clinical activity of this combination against ocular melanoma may merit further investigation.

Adult↗
PubMed1996

A clinical phase I/II study of recombinant human interleukin-1 receptor in glucocorticoid-resistant graft-versus-host disease.

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation. GVHD is accompanied by the release of inflammatory cytokines, including interleukin (IL)-1, and previous work has demonstrated that IL-1 participates in the pathogenesis of GVHD. The recombinant human IL-1 receptor (rhuIL-1R) is the soluble form of the type I IL-1 receptor that can bind to IL-1 and prevent cellular activation. We report a phase I/II trial utilizing the rhuIL-1R in the treatment of allogeneic bone narrow transplant patients not improving with glucocorticoid therapy. RhuIL-R was given at four dose levels for 21 days to 14 patients with progressive or persistent acute GVHD. The study drug had no clinical or persistent hematopoiesis and the treatment was tolerated by patients without toxicity at all dose levels. Eight of 14 patients (57%) had an improvement of GVHD after rhuIL-1R therapy. Improvement in GVHD was noted at each dose level, although a dose-response effect for rhuIL-1R treatment was not observed. This work supports the concept that IL-1 plays a role in the inflammation associated with acute GVHD. A controlled study of the rhuIL-1R for treatment of prophylaxis of GVHD is warranted.

Adult↗
PubMed1996

Synthesis and evaluation of 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline, a potent, peripherally acting alpha 2 adrenoceptor agonist.

We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.

Adrenergic alpha-2 Receptor Agonists↗