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Biomedical subjects

Kathleen M Foley

Publications and source records attributed to Kathleen M Foley.

At least 19 recordsLinked to original sources
PubMed2005

Stillbirths with placental hemorrhagic endovasculitis: a morphologic assessment with clinical implications.

CONTEXT: Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration affecting fetal-placental blood vessels of all calibers. Hemorrhagic endovasculitis is found in association with stillbirth and abnormalities of growth and development in livebirths. The role of HEV in the pathogenesis of these conditions is not known. OBJECTIVE: To further understand these events, we compare clinicopathologic features of HEV-affected placentas from stillbirths with those from livebirth pregnancies. Additionally, we assess the relationship of morphologic forms of HEV to clinical events and time of fetal death in utero and evaluate the significance of extensive versus localized HEV lesions in placentas of stillbirths. DESIGN: We reviewed the clinical records and slides from 119 stillbirths with placentas affected by HEV classified above a specified severity level (cases) and 119 matched stillbirths with placentas not affected by HEV (controls). A subset of 21 stillbirth placentas exhibiting focal HEV lesions was similarly evaluated. Slides were graded for HEV, villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and lesions indicative of maternal hypertension. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis). Focal, segmental, and diffuse patterns of villous fibrosis were delineated. Interlesional relationships were established by matching HEV severity indices with severity indices of co-existing lesions. Timing of fetal death was determined by published criteria. Data were analyzed for significance using chi2 and t tests. Results were compared with published analyses of livebirths with placental HEV. RESULTS: Lesions occurring with significant frequency in HEV-affected (case) placentas include villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and meconium staining. Interlesional relationships were evident between HEV and villous fibrosis, villitis of unknown etiology, and chorionic thrombi. Growth restriction was more common in case versus control infants (P = .02). A segmental pattern of villous fibrosis predominated in cases versus controls and within the case group (P < .001). Time to delivery after fetal death was longer in cases than controls. Active-vasodestructive forms of HEV correlate with shorter intervals of intrauterine retention, whereas bland forms correlate with longer intervals (P = .04). Placentas with focal HEV were associated with coexisting chorionic thrombi and villous fibrosis but not with fetal growth restriction. CONCLUSIONS: Patterns of interlesional interplay are similar in HEV-affected placentas of livebirths and stillbirths. This suggests that the pathogenesis of infant morbidity and mortality is similar in both groups. Active-vasodestructive forms of HEV may precede whereas bland forms may follow intrauterine demise. The segmental pattern of villous fibrosis and high incidences of growth restriction, erythroblastosis, and meconium in cases suggests a chronicity of adverse intrauterine events that may precede fetal loss. Stillbirths with focal HEV lesions are probably not at risk.

Adult↗
PubMed2003

The structure of the 1L-myo-inositol-1-phosphate synthase-NAD+-2-deoxy-D-glucitol 6-(E)-vinylhomophosphonate complex demands a revision of the enzyme mechanism.

1l-myo-inositol 1-phosphate (MIP) synthase catalyzes the conversion of d-glucose 6-phosphate to 1l-myo-inositol 1-phosphate, the first and rate-limiting step in the biosynthesis of all inositol-containing compounds. It involves an oxidation, enolization, intramolecular aldol cyclization, and reduction. Here we present the structure of MIP synthase in complex with NAD(+) and a high-affinity inhibitor, 2-deoxy-d-glucitol 6-(E)-vinylhomophosphonate. This structure reveals interactions between the enzyme active site residues and the inhibitor that are significantly different from that proposed for 2-deoxy-d-glucitol 6-phosphate in the previously published structure of MIP synthase-NAD(+)-2-deoxy-d-glucitol 6-phosphate. There are several other conformational changes in NAD(+) and the enzyme active site as well. Based on the new structural data, we propose a new and completely different mechanism for MIP synthase.

Binding Sites↗
PubMed1995

Morphine-6-glucuronide concentrations and opioid-related side effects: a survey in cancer patients.

The active morphine metabolite, morphine-6-glucuronide (M-6-G), may contribute to both the analgesia and the adverse effects observed during morphine (MOR) therapy. To evaluate the relationship between M-6-G and adverse effects, we measured steady-state plasma concentrations of MOR and M-6-G and concurrently noted the presence or absence of moderate to severe cognitive impairment or myoclonus in 109 cancer patients who were receiving either oral (n = 71) or parenteral (n = 38) morphine. MOR and M-6-G plasma concentrations were determined by HPLC with electrochemical detection. The presence of cognitive impairment or myoclonus was analyzed in relation to molar M-6-G/MOR ratio, age, morphine dose, the use of other centrally acting drugs, renal function (blood urea nitrogen (BUN) and serum creatinine), hepatic function (serum bilirubin, serum glutamic oxalacetic transaminase (SGOT), and alkaline phosphotase) and serum lactate dehydrogenase (LDH). The patient population consisted of 60 women and 49 men. The mean age was 51.5 years (range: 10-85 years). The mean morphine dose (total dose-prior 48 h) was 486 mg (range: 40-4800 mg) for the oral group and 931 mg (range: (10-9062 mg) for the parenteral group. The mean molar M-6-G/MOR ratios were 6.1 (SD: 18.2; range: 0.01-153.3) for the oral treatment group and 2.7 (SD: 4.16; range: 0.05-23.8) for the parenteral treatment group. Overall, the M-6-G/MOR ratio demonstrated a moderate but significant correlation with BUN (r = 0.4; P < 0.001) and creatinine (r = 0.45; P < 0.001) levels, but not with the other clinical variables examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mRNA.

The injection of dilute formalin results in a stereotyped nociceptive behavioral response. Administration of dextromethorphan (s.c.) but not saline, 30 min prior to intraplantar formalin injection prevents this nociceptive response in a dose-dependent manner. In addition, intraplantar formalin reliably induces c-fos mRNA in the ipsilateral spinal dorsal horn as assessed with quantitative solution hybridization at 30 min postinjection. No change in c-fos mRNA was detected in the contralateral spinal dorsal horn, nucleus raphe magnus, periaqueductal grey, medial thalamus, or sensorimotor cortex. Pretreatment with dextromethorphan at 60 mg/kg s.c., 30 min prior to formalin resulted in a suppression of c-fos induction, so that c-fos mRNA levels in the ipsilateral spinal dorsal horn of animals receiving dextromethorphan prior to formalin did not differ from controls. These data indicate that dextromethorphan suppresses formalin nociceptive behavior and one of the biochemical consequences of formalin nociception, i.e., induction of c-fos mRNA.

Animals↗
PubMed1991

Plasma morphine and morphine-6-glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-state concentrations and the consequences of renal failure.

Morphine-6-glucuronide (M-6-G) is an active metabolite of morphine that may contribute to drug effects. To understand better the relationship between morphine and M-6-G in cancer patients receiving chronic therapy, we employed high performance liquid chromatography with electrochemical detection to measure: (1) morphine and M-6-G plasma concentrations following discontinuation of dosing in 2 patients, one receiving oral therapy and the other an intravenous infusion; (2) morphine and M-6-G concentrations in random blood samples taken at apparent steady state from 8 patients, 7 with normal renal function and 1 with mild renal insufficiency, who were receiving continuous morphine infusions; and (3) morphine and M-6-G concentrations in random blood samples taken over a period of weeks from 4 patients, 2 with stable and 2 with declining renal function. Results demonstrated a slightly slower decline in plasma M-6-G than morphine concentrations following drug discontinuation, as would be expected for metabolite and parent relationship; roughly similar M-6-G: morphine ratios (mean molar ratio = 1.22) across a broad range of morphine doses in patients with normal renal function; and an increase in this ratio over time in patients with progressive renal dysfunction. These data illustrate the kinetics of M-6-G in cancer patients receiving chronic morphine therapy and confirm the importance of renal function in determining the concentration of the metabolite.

Adult↗
PubMed1991

The impact of a comprehensive evaluation in the management of cancer pain.

To evaluate the importance of a comprehensive evaluation in the management of patients with cancer pain, we surveyed 276 consecutive consultations (226 retrospectively and 50 prospectively) performed by the pain consultant at Memorial Sloan-Kettering Cancer Center. For all consultations, the pain diagnosis, other medical and neurologic diagnoses, investigations and suggested therapeutic interventions were recorded. The pain consultation identified a previously undiagnosed etiology for the pain in 64% of patients in both surveys. Metastatic neoplasm was the most common lesion discovered. In addition, the prospective survey yielded new neurologic diagnoses in 36% of patients and an unsuspected infection in 4%. Eighteen percent of prospectively surveyed patients received radiotherapy, surgery or chemotherapy based on the findings of the pain consultant. These data confirm the importance of a comprehensive neuro-oncologic evaluation in the management of cancer pain. An understanding of oncology, neurology and medicine is critical to assess and treat these patients.

Adolescent↗
PubMed1990

The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions.

In recent years, the observation that the response of patients to opioid drugs may be influenced by properties inherent in the pain or pain syndrome, such as its pathophysiology, has evolved into the belief that certain types of pain, e.g., neuropathic pains, may be unresponsive to these drugs. This concept has important implications for both clinical practice and basic understanding of opioid mechanisms. We critically evaluate opioid responsiveness, particularly as it relates to neuropathic pain, and propose a clinically relevant definition and a paradigm for its investigation. The paradigm is illustrated by analgesic responses to opioid infusion in 28 patients with neuropathic pains and by a detailed presentation of the pharmacokinetic and pharmacodynamic relationships in one of these patients, whose central pain responded promptly to an infusion of hydromorphone. From this analysis, we hypothesize that (1) opioid responsiveness in man can be defined by the degree of analgesia achieved during dose escalation to either intolerable side effects or the occurrence of 'complete' or 'adequate' analgesia; (2) opioid responsiveness is a continuum, rather than a quantal phenomenon; (3) opioid responsiveness is determined by a diverse group of patient characteristics and pain-related factors, as well as drug-selective effects; and (4) a neuropathic mechanism may reduce opioid responsiveness, but does not result in an inherent resistance to these drugs. Given the complexity of factors contributing to opioid responsiveness and the observation that outcome cannot be reliably predicted, opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. Both the clinical use of opioids and paradigms to investigate opioid responsiveness should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects.

Dose-Response Relationship, Drug↗
PubMed1990

Clinical analgesic assay of repeated and single doses of heroin and hydromorphone.

A direct comparison of the analgesic activities of heroin and hydromorphone was carried out in cancer patients with postsurgical pain. Intramuscular doses of 5 and 10 mg of heroin were compared with 1 and 2 mg of hydromorphone in a randomized, double-blind, 4-point parallel group assay. Design innovations in the study provided that about half the patients would receive prior repeated doses of the same drug as the test medication, and half would receive the alternate medication. Both test drugs were found to be potent, relatively short acting analgesics with similar profiles of action. Hydromorphone was about 5 times as potent as heroin on a milligram basis. The comparison of those patients who had repeated doses of the same treatment prior to the test dose and those who had repeated doses of the alternate drug demonstrated no significant effect on the relative potency estimates. Side effect occurrence was similar for both drugs, with sleepiness the most prominent effect. The study supports the view that hydromorphone and heroin produce similar clinical effects, and that either drug may adequately substitute for the other. Covariate analysis indicated that time since last analgesic was positively related to analgesia, and amount of prior opioid had a negative relationship. To a lesser extent, increase in patient age was associated with an increase in analgesic scores. Taking these covariates into account served to increase the sensitivity of the analysis.

Affect↗
PubMed1987

Cocaine and morphine interaction in acute and chronic cancer pain.

An evaluation of the analgesic, mood and side effects of the combination of intramuscular morphine and oral cocaine was conducted in 17 patients with postoperative pain and 19 others with chronic malignant pain for the purpose of assessing the therapeutic merits of so-called 'euphoriant' elixirs in the management of pain in cancer patients. The study was designed as a randomized and double-blind single dose but complete cross-over comparison of the combination of 10 mg intramuscular morphine and 10 mg oral cocaine with morphine alone, cocaine alone, and placebo. While patients clearly discriminated between the analgesic effects of morphine and placebo, there were no differences in the analgesic responses to cocaine and placebo, or in responses to morphine and the combination of morphine and cocaine in either patient group. Side effects were predominantly morphine-like and occurred in 59% of patients after the combination, 43% after morphine, 34% after cocaine and 25% after placebo. Interaction effects between cocaine and morphine were observed in terms of positive changes toward selected aspects of mood (e.g., cheerful, friendly) in postoperative patients but toward negative aspects of mood (e.g., sad, serious) in patients with chronic pain.

Adult↗