Chronic preoperative pain and psychological robustness predict acute postoperative pain outcomes after surgery for breast cancer.

BACKGROUND: Few epidemiological studies have prospectively investigated preoperative and surgical risk factors for acute postoperative pain after surgery for breast cancer. We investigated demographic, psychological, pain-related and surgical risk factors in women undergoing resectional surgery for breast cancer. METHODS: Primary outcomes were pain severity, at rest (PAR) and movement-evoked pain (MEP), in the first postoperative week. RESULTS: In 338 women undergoing surgery, those with chronic preoperative pain were three times more likely to report moderate to severe MEP after breast cancer surgery (OR 3.18, 95% CI 1.45-6.99). Increased psychological 'robustness', a composite variable representing positive affect and dispositional optimism, was associated with lower intensity acute postoperative PAR (OR 0.63, 95% CI 0.48-0.82) and MEP (OR 0.71, 95% CI 0.54-0.93). Sentinel lymph node biopsy (SLNB) and intraoperative nerve division were associated with reduced postoperative pain. No relationship was found between preoperative neuropathic pain and acute pain outcomes; altered sensations and numbness postoperatively were more common after axillary sample or clearance compared with SLNB. CONCLUSION: Chronic preoperative pain, axillary surgery and psychological robustness significantly predicted acute pain outcomes after surgery for breast cancer. Preoperative identification and targeted intervention of subgroups at risk could enhance the recovery trajectory in cancer survivors.

A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.

Interferon (IFN) therapy has been associated with the development of Major Depressive Disorder (MDD) when given to patients with hepatitis C (HCV). The incidence, time course, risk factors, and treatment of IFN-induced MDD are poorly understood. The objectives of the present study were to determine the incidence of IFN-induced MDD, as well as to determine the efficacy of open-label antidepressant treatment, in particular selective serotonin reuptake inhibitors (SSRIs) for IFN-induced MDD. Thirty-nine HCV patients on IFN therapy were monitored weekly using the Beck Depression Inventory (BDI). Those who became depressed were treated with citalopram, a SSRI antidepressant. Main outcome measures included the incidence of IFN-induced MDD, as well as response rates to antidepressants in those patients who developed IFN-induced MDD. Our results showed that 13 of 39 patients (33%) developed IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance use between those who became depressed and those who did not. However, there were significantly fewer African American patients in the depressed group. Patients who developed IFN-induced MDD were on IFN therapy for an average of 12.1 weeks prior to the development of MDD. Eleven of 13 patients (85%) were responsive to antidepressant treatment. We conclude that IFN-induced MDD is common in HCV patients. Health care providers should follow IFN-treated HCV patients for the development of MDD, particularly between the 2nd and 5th months of IFN therapy. SSRIs, in particular citalopram, are an effective treatment for IFN-induced depression in HCV patients.

Plasminogen activator inhibitor-1 is an immediate early response gene in regenerating rat liver.

Plasminogen activator inhibitor-1 (PAI-1), a M(r) 50,000 serine protease inhibitor, is the major physiological inhibitor of plasminogen activation. Quiescent rat hepatocytes do not express the PAI-1 gene in vivo; however, PAI-1 is synthesized both by primary cultures of rat hepatocytes and by hepatoma cells in vitro. Furthermore, PAI-1 is expressed by fibroblastic cells in vitro, in response to mitogen stimulation, suggesting a possible connection between hepatocyte PAI-1 expression and cell proliferation. To determine whether PAI-1 is an early growth response gene in hepatocytes in vivo, we analyzed its expression in regenerating rat liver. Male rats underwent partial (70%) hepatectomy (PH) or sham operation (SO), and liver samples were analyzed by Northern blot analysis and in situ hybridization. PAI-1 mRNA was not present at time 0 h, nor at any other time in SO rats but was induced rapidly in regenerating livers, peaking at 2 h and declining to negligible levels by 8 h posthepatectomy. This induction was not inhibited by cycloheximide. In situ hybridization analysis localized PAI-1 transcripts to hepatocytes. Immunohistochemical analysis demonstrated PAI-1-specific staining in hepatocytes in the livers of both PH and SO rats, but the temporal and spatial distribution profiles differed between PH and SO rats. Our studies demonstrate that PAI-1 is an immediate early response gene, transiently expressed in regenerating liver, expression of which may be important in hepatocyte growth and proliferation in vivo.

Cytokine-induced gene expression of interleukin-8 in human transitional cell carcinomas and renal cell carcinomas.

Chemotactic cytokines play a critical role in recruiting leukocytes to sites of tissue injury. Interleukin-8 (IL-8) is a chemotactic cytokine secreted by a variety of cells (eg, monocytes, endothelial cells, fibroblasts) during the inflammatory response. In this report, the authors demonstrate that human transitional cell carcinomas and renal cell carcinomas have the capacity to elaborate IL-8 in response to the inflammatory mediators IL-1 beta and tumor necrosis factor (TNF)-alpha. All cell lines expressed high levels of IL-8 mRNA on stimulation with either IL-1 beta or TNF-alpha, but not lipopolysaccharide; one expressed the gene constitutively. The authors selected one transitional cell carcinoma cell line (UM-UC-9) and one renal cell carcinoma cell line (UM-RC-5) for further study. Both displayed a time- and dose-dependent increase in steady-state levels of IL-8 mRNA in response to IL-1 beta and TNF-alpha. Specific mRNA was detectable by 1 hour after stimulation. Secretion of antigenic IL-8 measured by enzyme-linked immunosorbent assay into culture supernatants reflected the kinetics of mRNA expression. Because heat-inactivated TNF-alpha failed to induce synthesis of IL-8 mRNA, and cycloheximide augmented TNF-alpha-induced synthesis, IL-8 expression appears to be a stimulus-specific primary induction phenomenon. As with other inflammatory mediators whose mRNA contains a 3' AU-rich sequence (eg, IL-2, TNF-alpha), the half-life of IL-8 mRNA was short, less than 1 hour. Our data suggest that secretion of IL-8 by malignant cells may partly account for the inflammatory infiltrates associated with some malignant neoplasms.

Axillary and rectal temperature measurements in infants.

Rectal and axillary temperatures were measured during the daytime in 281 infants seen randomly at home and 656 at hospital under 6 months old, using mercury-in-glass thermometers. The normal temperature range derived from the babies at home was 36.7-37.9 degrees C for rectal temperature and 35.6-37.2 degrees C for axillary temperature. Rectal temperature was higher than axillary in 98% of the measurements. The mean (SD) difference between rectal and axillary temperatures was 0.7 (0.5) degrees C, with a range of 3 degrees C. When used in hospital to detect high temperature, axillary temperature had a sensitivity of 73% compared with rectal temperature. This is too insensitive for accurate detection of an infant's high temperature. Rectal temperature measurement is safer than previously suggested: perforation has occurred in less than one in two million measurements. If an infant's temperature needs to be taken, rectal temperature should be used.

Symptoms and signs in infants younger than 6 months of age correlated with the severity of their illness.

Symptoms and signs were recorded for 1007 infants younger than 6 months of age seen at home (298) or hospital (709) and correlated with four grades of illness severity. Most symptoms, present in the preceding 3 days, were associated with all grades of illness. Only four symptoms were not reported in well infants: a fluid intake less than a third of normal, convulsions, frank blood in the stools, and bile-stained vomiting. By comparison, many signs were seen only in ill infants. Those associated only with moderate or serous illness were marked retraction of the lower ribs, high-pitched or moaning cry, expiratory grunt, loss of alertness, central cyanosis, and severe hypotonia. Although these will not identify all seriously ill infants, parents and professionals should be taught to recognize these important symptoms and signs of serious illness.

Kupffer cell-derived cytokines induce the synthesis of a leukocyte chemotactic peptide, interleukin-8, in human hepatoma and primary hepatocyte cultures.

Communication circuits operating between activated monocytes/macrophages and adjacent hepatocytes in the liver effect important alterations in hepatocyte function. We demonstrate here that primary human hepatocytes and hepatoma cells are able to function as effector cells in the recruitment of inflammatory cells in hepatic disease and inflammatory states by synthesizing a neutrophil/lymphocyte chemotactic factor, interleukin-8. We have further investigated the possibility that endogenous factors elaborated by activated peripheral blood monocytes and Kupffer cells in the liver are mediators of hepatocyte-derived interleukin-8 expression. Twenty-four-hour conditioned medium from lipopolysaccharide-stimulated peripheral blood monocytes and nonparenchymal human liver cells enriched for Kupffer cells induced a time-dependent increase in interleukin-8 messenger RNA levels in SK-hepatoma cells over a 24-hr period, similar to that seen for tumor necrosis factor-alpha or interleukin-1 beta induction of interleukin-8 in primary hepatocytes. Exogenously added lipopolysaccharide or recombinant interleukin-6 had no effect. Cell-associated interleukin-8 antigen was present in SK-hepatoma and primary hepatocytes that had been incubated with macrophage-conditioned medium, tumor necrosis factor or interleukin-1 beta. Similarly, neutrophil chemotactic activity was secreted by SK-hepatoma cells, a significant proportion of which could be blocked with interleukin-8--specific antiserum. Preincubation of macrophage-conditioned medium with neutralizing antibodies to tumor necrosis factor-alpha or interleukin-1 beta reduced its interleukin-8 messenger RNA-inducing capacity. Exposure of SK-hepatoma to conditioned medium followed by removal of the stimulus resulted in a rapid down-regulation of interleukin-8 messenger RNA to 50% of the maximum level within the first hour. These data suggest that products derived from activated Kupffer cells can modulate hepatoma cells and primary hepatocyte interleukin-8 gene expression. In addition, macrophage/monocyte-derived tumor necrosis factor-alpha and interleukin-1 beta have major roles in the positive regulatory component of this modulation.

Baby Check: a scoring system to grade the severity of acute systemic illness in babies under 6 months old.

A scoring system has been developed to grade the severity of acute systemic illness in babies under 6 months of age. Data were collected on 28 symptoms and 47 signs from 1007 babies with a spectrum of illness ranging from well to seriously ill. Ordinal regression analysis identified 19 symptoms and signs which in combination graded the severity of the illness most accurately. The coefficients were converted to scores. The higher the score the more serious the illness. When applied to a theoretical cohort of 10,000 babies at home, a score less than 8 has a specificity of 98%, and a score of 13 or more a sensitivity of 92%. The positive predictive value for serious illness increases from zero at a score of zero to approaching 100% at scores over 30. The scoring system has been developed into score cards for parents and professionals.

Field trials of the Baby Check score card: mothers scoring their babies at home.

The Baby Check score card has been developed to help parents and health professionals grade the severity of acute illness in babies. This paper reports the results of two field trials in which mothers used Baby Check at home, 104 mothers scoring their babies daily for a week and 56 using it for six months. They all found Baby Check easy to use, between 68% and 81% found it useful, and 96% would recommended it to others. Over 70% of those using it daily used it very competently. Those using it infrequently did less well, suggesting that familiarity with the assessment is important. The scores obtained show that Baby Check's use would not increase the number of mothers seeking medical advice. With introduction and practice most mothers should be able to use Baby Check effectively. It should help them assess their babies' illnesses and make appropriate decisions about seeking medical advice.

Field trials of the Baby Check score card in general practice.

Sixteen general practitioners (GPs) used the Baby Check score card to assess illness severity in 86 babies under 6 months old. Their reactions to Baby Check were positive: in 79 (92%) it gave an accurate assessment of the baby's illness and 16 (100%) said they would trust it. Fifteen (94%) found it useful, and most of those who did not said the baby was not ill or had an obvious diagnosis. Thirteen (81%) said they would use it and wanted their health visitors and midwives to use it and 15 (94%) wanted the mothers in their practice to use it. The majority (64%) of babies scored 0-7; 31% scored 8 to 19; and only 5% scored over 20. Well babies had low scores, while the two sickest babies, needing urgent hospital treatment, scored 29 and 33. The use of Baby Check by GPs would help them assess babies thoroughly and quantify illness severity objectively.

Field trials of the Baby Check score card in hospital.

The Baby Check score card was used by junior paediatric doctors to assess 262 babies under 6 months old presenting to hospital. The duty registrar and two consultants independently graded the severity of each baby's illness without knowledge of the Baby Check score. The registrars assessed the babies at presentation while the consultants reviewed the notes. The consultants and registrars agreed about the need for hospital admission only about 75% of the time. The score's sensitivity and predictive values were similar to those of the registrars' grading. The score's specificity was 87%. Babies with serious diagnosis scored high, while minor illnesses scored low. The predictive value for requiring hospital admission increased with the score, rising to 100% for scores of 20 or more. The appropriate use of Baby Check should improve the detection of serious illness. It could also reduce the number of babies admitted with minor illness, without putting them at increased risk.

Respiratory rate and severity of illness in babies under 6 months old.

This paper defines the normal range of respiratory rate in babies under 6 months of age. It was counted by two observers in 1007 babies of whom 709 were seen when presenting to hospital for assessment of an acute illness, and 298 on a random basis at home. Whether they were asleep, content, or crying was recorded and the severity of their illness graded. The diagnosis was also recorded. The mean (SD) for the respiratory rate in babies seen awake was 61 (18) breaths/minute at hospital and 61 (14) breaths/minute at home. The respiratory rate when awake did not correlate with the severity of a baby's illness or the presence of serious lower respiratory tract infections. Sleeping babies had a significantly lower mean rate than awake babies at 42 (12) breaths/minute. Crying babies had a significantly lower mean rate than awake and content babies: 51 (14) breaths/minute compared with 61 (18) breaths/minute.

Field trials of Baby Check: a scoring system to quantify illness in babies under 6 months.

Baby Check, a scoring system for quantifying illness in young babies, was developed from a study of 1007 well and ill babies in Cambridge and Melbourne. This paper describes the setting up of field trials to test the performance of the scoring system when used by mothers, GPs and hospital doctors. Preliminary results suggest that the scoring system is attractive, easy to use, useful and of high specificity. Its sensitivity to serious illness is also thought to be high but this will become clearer when the main hospital field trial has been completed.

Cytokine-induced gene expression of a neutrophil chemotactic factor/IL-8 in human hepatocytes.

The liver participates in inflammation via the elaboration of acute phase proteins from hepatocytes in response to IL-1, TNF-alpha, and IL-6/INF-beta 2/hepatocyte-stimulating factor. In addition, some inflammatory states of the liver are characterized by leukocyte infiltrates. Here we demonstrate that human hepatocyte lines are capable of expressing mRNA and biologic activity for a neutrophil chemotactic factor (NCF)/IL-8 in response to the inflammatory mediators IL-1 alpha, IL-1 beta, and TNF. Two human hepatoma cell lines (SK-Hep and Hep-G2) displayed a time- and dose-dependent increase in steady state levels of NCF/IL-8 mRNA and secretion of chemotactic activity in response to TNF and IL-1. Neutralizing antibody to NCF/IL-8 inhibited hepatocyte-derived chemotactic activity by 88%. In contrast to IL-1 and TNF, hepatocytes did not respond to LPS or IL-6 within the time and dose parameters used above. Although the expression of NCF/IL-8 mRNA (1.8 kb) was first detectable between 1 and 2 h poststimulation, significant chemotactic bioactivity was not observed until about 4 h. Heat-inactivated (100 degrees C, 30 min) cytokine failed to induced NCF/IL-8 mRNA synthesis, and cotreatment of cells with cytokine and cycloheximide super-induced NCF/IL-8 mRNA while inhibiting production of bioactivity. Thus, NCF/IL-8 expression is a primary induction phenomenon. Our data demonstrate the stimulus specific induction of NCF/IL-8 in hepatocytes and suggest that cytokine cell-to-cell communication circuits may be important in neutrophil-mediated inflammatory processes in the liver.

Symptoms in 298 infants under 6 months old, seen at home.

Symptoms were assessed in 298 infants under 6 months old seen at home. Their mothers were asked if they were concerned about their babies and then questioned about the presence, duration, and severity of 28 predefined symptoms. Forty seven mothers expressed concern about their babies (16%), whereas on direct questioning 241 (81%) reported symptoms present within the last 24 hours. One hundred and twenty three (41%) reported three or more. Many of the symptoms occurred in more than 15 babies (5%). The commonest were cold peripheries (117, 39%), noisy breathing (88, 30%), and rash (68, 23%). These had often been present for many days. Only 257/819 reported symptoms (31%) were of recent onset (less than 4 days) with 168 (21%) graded by the mother as moderate or severe. A few highly specific symptoms that were associated with serious conditions were rare. Symptoms cannot be interpreted without detailed questioning taking their severity and duration into account, and most occur too often to be used as indicators for referral.