Affective symptoms and change in diabetes self-efficacy and glycaemic control.

AIMS: To examine the role of baseline depression, anxiety and stress symptoms on post-intervention diabetes self-efficacy and glycaemic control (HbA(1c)). METHODS: The current study analysed data from patients (n = 85) with treated but uncontrolled Type 2 diabetes who participated in a comparative effectiveness study of two diabetes self-management interventions. Hierarchical linear regression was used to examine the relationships between baseline affective symptoms and post-intervention diabetes self-efficacy and the moderating effects of baseline affective symptoms on the relationship between changes in diabetes self-efficacy and post-intervention HbA(1c). RESULTS: Baseline depression was inversely associated with post-intervention diabetes self-efficacy (P = 0.0001) after adjusting for baseline characteristics including diabetes self-efficacy. In contrast, normal-mild levels of stress were associated with higher post-intervention diabetes self-efficacy (P = 0.04). Anxiety and stress symptoms significantly and independently moderated the relationship between changes in diabetes self-efficacy and post-intervention HbA(1c) (P = 0.02 and P = 0.03, respectively). Further evaluation of these interactions demonstrated that changes in diabetes self-efficacy were associated with lower post-intervention HbA(1c), but only among those with higher baseline affective symptoms. CONCLUSIONS: We found a moderating effect across affective symptoms on the relationship between diabetes self-efficacy changes and post-intervention HbA1c in the context of a self-management intervention. Results suggest that patients with poorly controlled diabetes who have higher levels of depression, anxiety and stress symptoms may derive greater benefits from self-management interventions known to improve diabetes self-efficacy.

KADIAN (morphine sulfate extended-release) capsules for treatment of chronic, moderate-to-severe, nonmalignant pain.

Chronic pain, one of the most common reasons for which patients seek medical attention, is defined as pain that persists beyond the normal healing time, usually about 3 months. Chronic pain can be malignant or nonmalignant in origin, or can appear in the absence of identifiable pathology. Pharmacological treatment options include non-opioid and opioid analgesics, as well as adjuvant medications. Opioids, the most potent analgesics, are typically reserved for the treatment of chronic, moderate-to-severe pain that has not responded to non-opioid therapy. Morphine remains the gold standard among commonly used opioids. Long-acting opioids are formulated to offer continuous delivery of analgesia around the clock. These agents are formulated to maintain therapeutic blood levels of morphine, with minimal fluctuations. KADIAN Capsules, which contain polymer-coated extended-release morphine sulfate pellets, is one such formulation available for the treatment of moderate-to-severe pain for which an analgesic is indicated for more than a few days. This article reviews KADIAN and identifies unique features from early pharmacokinetic and pharmacodynamic studies, recent data on pharmacokinetic interactions with alcohol and results from recent trials in treating nonmalignant pain.

Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.

BACKGROUND AND AIMS: The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer. MATERIALS AND METHODS: Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease. RESULTS: Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity. CONCLUSION: PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.

Antibody-dependent cell-mediated cytotoxicity: a flow cytometry-based assay using fluorophores.

Using flow cytometry (FCM), an assay has been developed for the determination of antibody-dependent cell-mediated cytotoxicity (ADCC). Target cells were labelled with a membrane dye, PKH-26, to allow discrimination when incubated with effector cells and antibody. Post-incubation, cell death within the PKH-26+ target cell population was assessed by the addition of the viability probe TO-PRO-3 iodide (TP3). This ADCC method allows analysis to be conducted on a single cell basis and overcomes the need for radiochemicals. This communication indicates that the assay is accurate and reproducible with the potential to be a useful tool for evaluating the therapeutic potential of antibodies and antibody-based reagents.

Antibody targeting studies in a transgenic murine model of spontaneous colorectal tumors.

Monoclonal antibodies (mAbs) have been used to treat malignancies in humans with varying degrees of success. Progress has been hindered by the lack of suitable animal models, which would ideally consist of immunocompetent animals that are tolerant to tumor-associated antigens. Suitable models would allow the study and optimization of anti-tumor immunotherapy. We describe a murine model for the study of immunotherapy in colorectal cancers. Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein that is expressed on normal human intestinal epithelium and that is overexpressed in intestinal tumors. Mice that are transgenic for the human CEA gene (CEA.Tg) were crossed with multiple intestinal neoplasia (MIN) mice. MIN mice carry a germline APC mutation and are prone to the development of intestinal adenomas. The offspring from the MIN x CEA.Tg cross developed intestinal adenomas that were shown by immunohistochemistry to overexpress CEA. Pharmacokinetic studies by using (125)I-labeled anti-CEA mAb PR1A3 showed rapid localization of antibody to tissues expressing CEA, especially the gastrointestinal tract. Macroscopic and microscopic radioautographic analysis of the gastrointestinal tracts from MIN/CEA.Tg mice indicated that PR1A3 targeted and was retained in tumors at levels higher than in areas of normal gut. These results demonstrate the utility of the MIN/CEA.Tg mouse as a model for the study of anti-CEA immunotherapy and, furthermore, demonstrate the efficiency of tumor localization by PR1A3.

Age-independent and dose-response effects of ethanol on spatial memory in rats.

Results of previous studies have shown that ethanol impairs the acquisition of spatial memory in adolescent rats at doses below those required to impair the acquisition in adults. However, the previous work did not identify doses of ethanol that failed to impair acquisition in adolescents or that impaired acquisition in both adolescent and adult animals. This was our aim in the present study. Male, Long-Evans hooded rats (adolescent and adult) were treated intraperitoneally with 0.0, 0.5, or 2.5 g/kg of ethanol 30 min before daily training on a spatial or nonspatial version of the Morris water maze task. Twenty-four hours after training on the spatial task the animals were given a 1-min probe trial. The low dose of ethanol (0.5 g/kg) failed to impair the performance of animals from either age group on any tasks. It did, however, enhance the initial rate of acquisition on the spatial task. The 2.5-g/kg dose eliminated acquisition of spatial learning in animals of both ages and significantly attenuated performance on a nonspatial task in both age groups. However, the treatment effect in the nonspatial task was eliminated with controlling for baseline performance. These results establish a low dose of ethanol (0.5 g/kg) that does not impair acquisition of spatial memory in adolescent or adult rats. Moreover, the study findings show that 2.5 g/kg of ethanol markedly impairs acquisition of spatial memory in both adolescent and adult animals.

Development of a novel flow cytometric cell-mediated cytotoxicity assay using the fluorophores PKH-26 and TO-PRO-3 iodide.

A flow cytometric (FCM) assay has been developed for the determination of cell-mediated cytotoxicity (CMC). In the assay, the target tumour cell population was labelled with a membrane dye, PKH-26, prior to incubation with splenocyte effector cells. Cell death within the target population was assessed by the addition of the viability probe TO-PRO-3 iodide (TP3) and analysed by flow cytometry. The extent of cytotoxicity was determined by the relative number of live target cells labelled with PKH-26 only and dead, permeabilised cells labelled with both PKH-26 and TP3. This CMC method allows the analysis to be conducted on a single cell basis and overcomes the need for radiochemicals. This communication indicates that the FCM assay is an accurate and reproducible experimental system capable of analysing natural killer (NK) cell and antibody-dependent cell-mediated cytotoxicity. The procedure is comparable to the chromium release assay. We believe that this is one of the first demonstrations of an FCM-based antibody-dependent cell-mediated cytotoxicity (ADCC) assay.

A transgenic mouse model for tumour immunotherapy: induction of an anti-idiotype response to human MUC1.

MUC1 is a membrane bound, polymorphic epithelial mucin expressed at the luminal surface of glandular epithelium. It is highly expressed in an underglycosylated form on carcinomas and metastatic lesions and is, therefore, a potential target for immunotherapy of cancer. The monoclonal antibody HMFG1 binds the linear core protein sequence, PDTR, contained within the immunodominant domain of the tandem repeat of MUC1. The efficacy of murine and humanized HMFG1 (Ab1) used as an anti-idiotypic vaccine was examined in mice transgenic for human MUC1 (MUC1.Tg) challenged with murine epithelial tumour cells transfected with human MUC1. Humoral idiotypic cascade through Ab2 and Ab3 antibodies was observed in MUC1.Tg mice following multiple antibody inoculations in the presence of adjuvant. Impaired tumour growth at day 35 and highest Ab3 levels were found in mice that had received mHMFG1 with RAS adjuvant. However, comparison of Ab3 levels in individual mice with tumour size in all treatment groups did not show a correlation between smaller tumours and increased levels of anti-idiotype antibody. This suggests that the anti-tumour effects of anti-idiotype vaccination are not solely related to the induction of idiotypic antibody cascades and probably involve other mechanisms.

Localized monocyte chemotactic protein-1 production correlates with T cell infiltration of synovium in patients with psoriatic arthritis.

OBJECTIVE: To examine normal and psoriatic skin and synovial tissue from patients with psoriatic arthritis (PsA) for evidence of monocyte chemotactic protein-1 (MCP-1) mediated T cell chemotaxis. METHODS: Peripheral blood (PB), synovial fluid (SF), normal and psoriatic skin, and synovial biopsies were obtained from patients with PsA (n = 19) and compared to samples from normal (n = 5) and disease (n = 5) controls (NC, DC). Immune cell populations in PB and SF samples were assessed by immunofluorescent labeling and flow cytometry, levels of soluble MCP-1 were determined by quantitative ELISA, and immunohistochemistry was used to detect T cell subsets and macrophages and MCP-1 protein in frozen skin and synovial tissue sections. RESULTS: CD8+ but not CD4+ T cells were elevated in SF compared to PB, and the majority of these cells expressed CD45RO. Plasma MCP-1 levels in PsA were elevated relative to NC. MCP-1 levels were significantly higher than paired plasma samples in patients with recent onset (< 6 mo) synovitis (n = 10). A positive correlation was observed between synovial T cell numbers and MCP-1 levels in SF. MCP-1 protein was present in all tissues examined, but most intense expression was observed in synovium. CONCLUSION: Elevated concentrations of MCP-1 concomitant with memory T cell infiltration in PsA SF suggests that MCP-1 mediated chemotaxis is involved in the recruitment of T lymphocytes into the synovial compartment of patients with PsA.

The evolving role of antiepileptic drugs in treating neuropathic pain.

For many years, tricyclic antidepressants (TCAs) were used as initial therapy for the pharmacologic management of neuropathic pain. First-generation antiepileptic drugs (AEDs) are also used for the treatment of pain, and two drugs in this group, carbamazepine and sodium valproate, have received FDA approval for trigeminal neuralgia and migraine headache, respectively. Although TCAs are associated with side effects that limit their usefulness, particularly in the elderly or in patients with multiple medical problems, comparative meta-analyses show their tolerability to be greater than that of the first-generation AEDs. Recently, newer AEDs with more favorable side-effect profiles have been tested in placebo-controlled clinical trials for the treatment of neuropathic pain, including painful diabetic neuropathy and postherpetic neuralgia. The results of these trials, together with advances in understanding the pathophysiology of neuropathic pain, provide the basis for reevaluating some of the commonly accepted paradigms that guide approaches to treatment.

Treatment of chronic pain in failed back surgery patients with spinal cord stimulation: a review of current literature and proposal for future investigation.

Objective. The authors attempted to design and conduct a randomized, prospective study to investigate the efficacy of spinal cord stimulation (SCS) for patients with chronic back and leg pain following at least one previous surgery. While the scientific advantages of the randomized, prospective trial are considerable, the authors encountered numerous practical and ethical difficulties with conducting these trials. These are reviewed and an alternative investigative technique proposed. Materials and Methods. The literature on interventional and minimally invasive treatments for this population group is reviewed, and the strengths and weaknesses of different methodologies for conducting clinical research in an interventional setting are examined. Results. The difficulties inherent in a randomized, prospective study for an intervention vs. a nonintervention group are addressed, and an alternative methodology is proposed-that of a randomized interventional design. In this design, patients are assigned to a given treatment group, with each treatment exclusively available at different centers. Conclusions. By utilizing a randomized interventional study design, problems of comparability of procedures, provider reluctance to participate in randomized clinical trials, provider bias, detection bias, and transfer bias are eliminated. It is suggested that future investigations, particularly those which are interventionally or device-based, conform to this particular model.

Humanisation and characterisation of PR1A3, a monoclonal antibody specific for cell-bound carcinoembryonic antigen.

Carcinoembryonic antigen (CEA) is highly expressed by most tumours of gastrointestinal origin, but its use as a target for tumour therapy is complicated by the high levels of soluble CEA that are found circulating in the blood of cancer patients. A monoclonal antibody PR1A3 has been prepared, which binds preferentially to cell-surface rather than soluble CEA, this cell selectivity should make PR1A3 an ideal candidate for antibody-targeted tumour therapy. PR1A3 has been humanised and shown to retain its cell-surface specificity and affinity. Stable expression of the humanised antibody from chinese hamster ovary (CHO) cells has been achieved after transfection and amplification. Since PR1A3 binds preferentially to cell-associated CEA, a cell-free enzyme-linked immunosorbent assay (ELISA) has been developed to allow characterisation and routine assay of the antibody. This assay was developed using a recombinant chimeric protein constructed by cloning the domain of CEA that is bound by PR1A3 (the B3 domain) into a hybrid gene containing the Fc portion of IgG and three domains of biliary glycoprotein. Stable expression of this hybrid protein has been achieved from CHO cells. In ELISA both humanised and murine PR1A3 bound strongly to this antigen but only at a minimal level to soluble CEA. Two binding sites for the antibody were found on the gastric carcinoma cell line MKN45, one of higher affinity (1 nM) and the other at lower affinity (60 nM). Similar affinities were found for both murine and humanised antibodies. The data presented make it unlikely that the differential binding to cell-surface as distinct from soluble CEA can be accounted for by low affinity of PR1A3 for CEA, and provides further support for the hypothesis that some conformational change takes place on CEA release from cells and that it is this change that blocks PR1A3 binding to its epitope.

Maternal hypoglycemia: is it associated with adverse perinatal outcome?

OBJECTIVE: To determine if maternal hypoglycemia is associated with adverse perinatal outcome, particularly low birth weight. STUDY DESIGN: In this prospective study, all patients after 24 weeks' gestation were screened for gestational diabetes using 50 gm of glucola (oral) followed by a 1-hour plasma glucose measurement and hypoglycemia was defined as < or = 88 mg/dl. RESULTS: In these 426 women the mean (+/- SD) 1-hour plasma glucose value was 99.8 +/- 22.7 mg/dl. Of these, 16 were diagnosed with gestational diabetes and 46 were lost to follow-up leaving 364 patients; 116 with hypoglycemia and 248 with euglycemia. Women with hypoglycemia weighed less at the beginning of pregnancy and at delivery, but total weight gain during pregnancy was similar between both groups. There was no difference between groups in maternal symptomatology, birth weight, or the rate of fetal growth restriction. CONCLUSION: Hypoglycemia on the 1-hour glucola screen is not predictive of fetal growth restriction or other adverse perinatal consequence.

Pathogenic mechanisms in psoriatic arthritis.

Psoriatic arthritis is an inflammatory arthritis which can develop in some psoriasis patients. The absence of a serological test means that diagnosis must be based on consideration of clinical indices. This article summarizes the inflammatory mediators and immunological events which characterize psoriatic arthritis and examines evidence for involvement of an infectious agent in its aetiology.

A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor.

BACKGROUND: We evaluated the efficacy and safety of ketorolac (Toradol). METHODS: In this prospective trial, 88 women in confirmed preterm labor at < or =32 weeks' gestation were randomized to receive magnesium sulfate given as an initial 6 g intravenous bolus followed by continuous infusion therapy (2 to 6 g/hr) or intramuscularly administered ketorolac (60 mg loading dose) followed by 30 mg every 6 hours for a maximum of 24 hours. RESULTS: The study groups were similar with respect to age, parity, cervical status, and gestational age on admission. Ketorolac was more rapid (2.71 hr+/-2.16) in the arrest of preterm labor than was magnesium sulfate (6.22 hr+/-5.65). No patient required discontinuance of either drug due to adverse effects. There was no difference in the incidence of neonatal complications between the two groups. CONCLUSION: In gestations with preterm labor at <32 weeks, ketorolac appears to be an appropriate first-line tocolytic agent.

Ultrasonographic estimate of birth weight at 24 to 34 weeks: a multicenter study.

OBJECTIVE: The study was intended to compare the accuracies of ultrasonographic estimates of birth weights among infants born between 24 and 34 weeks' gestation at 3 tertiary centers. STUDY DESIGN: In this retrospective study subjects were matched for gestational age (1:1); all underwent ultrasonographic examination within 2 weeks of delivery. The estimates of birth weight were obtained according to 26 published regression equations and their accuracies were assessed with the mean standardized absolute error. For each center the equation with the lowest error was selected to generate (1) receiver-operating characteristic curves for an estimate to identify actual weight < 1500 g and (2) prediction limit calculations to determine the estimate that ensures at 70% confidence a birth weight > 1500 g. RESULTS: One hundred seventy-one cases were analyzed at each center. Comparison of the 26 mean standardized errors at each center indicated that (1) the range was rather wide (eg, 89 +/- 87 to 365 +/- 313 g/kg) and (2) 73% (19/26) of the equations had significantly (P < .05) different accuracies. Receiver-operator characteristic curves show that fetal weight estimates of > or = 1600 g at 2 centers and > or = 1700 g at the third center are required to predict actual birth weight < 1500 g. Prediction limit calculation suggests that different fetal weight estimates (> 1600 g at center 1, > 1900 g for the center II, and > 1800 g at center III) are needed to predict actual weight > 1500 g with a 70% accuracy. CONCLUSIONS: Ultrasonographic estimates of weight for preterm infants, as obtained from 26 equations, are characterized by a rather wide range of accuracy; for most of the equations the accuracies of estimates differ markedly among centers.

Hospital readmission for postpartum endometritis.

This study identified risk factors associated with readmission for postpartum endometritis. The study group consisted of 109 mothers (Group I) who were discharged after delivery and readmitted with endometritis. Control groups consisted of women who had endometritis immediately after delivery but who did not require readmission (Group II, n = 109), and women who had no intrapartum or puerperal infection and also were not readmitted (Group III, n = 109). Subjects in Groups II and III were matched to an index study subject for date of delivery and maternal age, race, and parity; and women in Groups I and III were also matched for route of delivery. Groups were compared in terms of demographic characteristics, intrapartum course, and clinical presentation. The data were analyzed with the t-test, chi2, and multiple logistic regression analyses, and a P value < .05 was considered significant. Women in Groups I and III delivered vaginally more often than mothers in Group II. In addition, mothers in Groups I and III had similar postpartum courses, no evidence of infection on discharge after delivery, and a similar period from delivery until postpartum discharge. Although women in Group I were more likely to have spontaneous rupture of membranes, a shorter latent period, and have fewer bilateral tubal ligations than mothers in Group II, multivariate analysis identified route of delivery as the only significant maternal variable associated with postpartum endometritis requiring readmission. Women who were readmitted for endometritis usually delivered vaginally, and the occurrence of late-onset postpartum endometritis was unrelated to the length of stay following delivery.

Ascertainment of 68,XX double aneuploidy by midtrimester biochemical screening: a case report.

A fetus with 68,XX karyotype was ascertained by an elevated midtrimester MSHCG. By antenatal ultrasound, the only unusual finding was in relation to the placenta. Preterm delivery was mandated by the development of severe preeclampsia. Postmortem examination of the stillborn fetus demonstrated no abnormal physical findings other than bilateral syndactyly of fingers and toes.

Prophylactic angiotensin II infusion during spinal anesthesia for elective cesarean delivery.

BACKGROUND: Angiotensin II may prove useful in treating regional anesthesia-induced hypotension in obstetric patients, because it causes less uterine vasoconstriction than do other vasoconstrictor drugs (such as phenylephrine). This study compared (1) maternal blood pressure and heart rate and (2) fetal status at delivery in parturients given either prophylactic angiotensin II or ephedrine infusion during spinal anesthesia for elective cesarean delivery. METHODS: Fifty-four women were randomized to receive either angiotensin II or ephedrine infusion intravenously during spinal anesthesia for elective cesarean section delivery. Simultaneous with subarachnoid injection, infusion of angiotensin II (2.5 microg/ml) or ephedrine (5 mg/ml) was initiated at 10 ng x kg(-1) x min(-1) and 50 microg x kg(-1) x min(-1), respectively. The rate of each infusion was adjusted to maintain maternal systolic blood pressure at 90-100% of baseline. RESULTS: Cumulative vasopressor doses (mean+/-SD) through 10, 20, and 30 min were 150+/-100, 310+/-180, and 500+/-320 ng/kg in the angiotensin group and 480+/-210, 660+/-390, and 790+/-640 microg/kg in the ephedrine group. Maternal heart rate was significantly higher (P < 0.001) during vasopressor infusion in the ephedrine group than in the angiotensin group. Umbilical arterial and venous blood pH and base excess were all significantly higher (P < 0.05) in the angiotensin group than in the ephedrine group. CONCLUSIONS: Angiotensin II infusion maintained maternal systolic blood pressure during spinal anesthesia without increasing maternal heart rate or causing fetal acidosis.