Amikacin and ceftazidime as empirical antibiotic therapy in severely neutropenic patients: analysis of prognostic factors

This study aimed to evaluate the efficacy of amikacine and ceftazidime as an empirical antibiotic therapy for neutropenic patients affected by haematological neoplasms and to investigate the presence of prognostic features suggesting a poor outcome with this antibiotic combination at the onset of infection. This could allow the identification of subgroups of patients with a low rate of response to amikacin/ceftazidime therapy; in these patients different initial empirical therapy may be indicated. The study population comprised 166 severely neutropenic (absolute neutrophil count below 500/l) oncohaematological patients with fever or clinical signs of infection. Multivariate analysis confirmed four negative prognostic factors: 3 or more days of hospitalization at the onset of an infectious episode, a diagnosis of acute myeloid leukaemia, a haematological disease status different from complete remission, the presence of pneumonia. Depending on how many factors are present, cases can be stratified into three groups, of significantly different prognosis: favourable (0 or 1 factor) 76% success; intermediate (2 factors) 52% success; unfavourable (3 or 4 factors) 19% success. At the onset of an infectious episode a subgroup of patients with a very low response rate to empirical amikacin/ceftazidime antibiotic therapy is identifiable, for whom a different therapy is indicated. Because of the high rate of proven or probable fungal infections in this group, the immediate administration of a systemic antifungal therapy, in addition to antibacterial agents, could be considered in these high-risk patients. Studies should be specifically addressed to evaluating a stratification of empirical antibiotic therapy according to risk factors present at the onset of infection.     

Signal transduction pathway of the muscarinic receptors mediating gallbladder contraction

In gallbladder smooth muscle, carbachol interacts with M₃ receptors to mediate contraction. To examine components of the intracellular second messenger system that is coupled to these receptors we have tested whether carbachol stimulates the formation of inositol phosphates (IP) to cause contraction. Guinea pig gallbladder muscle strips were prelabeled with [³H]inositol and were incubated with 0.1 mmol/l carbachol, a concentration causing maximal contraction. [³H]inositol monophosphates, [³H]inositol bisphosphates and [³H]inositol trisphosphates and contraction were measured at various times (0–90 s). To examine whether a pertussis toxin-sensitive guanine nucleotide binding protein is coupled to the muscarinic receptors, guinea pigs were pretreated with pertussis toxin (180 g/kg i.v./24 h). The effectiveness of pertussis toxin treatment was determined by measuring [³²P]ADP-ribosylation of a –40/41 kDa protein from gallbladder homogenates. Carbachol caused a significant time-dependent increase in the formation of [³H]inositol monophosphates, [³H]inositol bisphosphates and [³H]inositol trisphosphates. The time course of [³H]inositol trisphosphate turnover caused by carbachol was biphasic, and was detectable at 15 s and maximal at 60 s; at 75 s and 90 s formation of [³H]inositol trisphosphates decreased, whereas the time course of carbachol-induced contraction of the gallbladder smooth muscle strips reached a plateau after 90 s. The effects of carbachol on [³H]inositol trisphosphates and on contraction were abolished by atropine. Pretreatment with pertussis toxin resulted in ADP-ribosylation of a 40/41 kDa protein from gallbladder cell membranes but did not affect the concentration-response or time course of carbachol-induced contraction. These results indicate that carbachol-induced contraction of gallbladder smooth muscle cells is accompanied by the activation of inositol phosphate turnover and does not involve a pertussis toxin-sensitive G-protein.This article is based in part on the doctoral thesis of Burkhard Mackensen at the Faculty of Medicine, University of Hamburg, Germany. Some of the results were presented at the meeting of the American Gastroenterological Association (AGA) in San Francisco 1992 (von Schrenck et al. 1992) Correspondence to: T. von Schrenck at the above address     

Olive oil,other dietary fats,and the risk of breast cancer (Italy)

Data from a multicenter case-control study on breast cancer conducted in Italy have been used to analyze the relationship of olive oil and other dietary fats to breast cancer risk. Cases were 2,564 women hospitalized with histologically confirmed, incident breast cancer. Controls were 2,588 women admitted to the same network of hospitals for acute, non-neoplastic, non-hormone related, on-digestive tract disorders. Cases and controls were interviewed between 1991 and 1994 using a validated food-frequency questionnaire. The data were modelled through multiple logistic regression controlling for demographic and reproductive breast-cancer risk factors, energy intake and, mutually, for types of dietary fat. For olive oil, compared with the lowest quintile, the odds ratios (OR) were 1.05, 0.99, 0.93, and 0.87 for increasing quintiles of intake; in a model postulating linear logit increase, the OR per unit (30g) was 0.89 (95 percent confidence interval [CI]=0.81–0.99, P=0.03). Among other oils or fats considered, the OR for the highest level of intake was 0.72 (CI=0.6–0.9) for a group of specific seed oils (including safflower, maize, peanut, and soya) compared with nonusers. The ORs for the highest cf lowest level of intake were 0.80 for mixed or unspecified seed oils, 0.95 for butter, and 0.96 for margarine. The study, based on a large dataset from various Italian regions, shows an inverse relationship of breast cancer risk with intake of olive oil and other vegetable oils, but not with butter or margarine.     

Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats

Rationale: Conflict procedures used to detect anxiolytic-like activity of drugs often rely on maintaining strict schedules of water or food availability. It is ethically and practically desirable to reduce such states of deprivation in animal testing. Objective: The purpose of the present experiment was to develop and pharmacologically characterize a conflict drinking procedure that did not require the use of water-deprived animals. Methods: Rats were tested during daily sessions with alternating unpunished drinking (no tone: lick=sucrose solution) and signaled punished drinking (tone: lick=sucrose+shock) components, and developed individual steady baselines over a brief training period (approximately 3–4 weeks). The drugs tested i.p. were the positive allosteric modulators of γ-amino butyric acid_A (GABA)_A receptors, diazepam (0.03–30 mg/kg), chlordiazepoxide (0.03–30 mg/kg), lorazepam (0.03–10 mg/kg), zolpidem (0.3–10 mg/kg), pentobarbital (1–30 mg/kg), pregnanolone (1–30 mg/kg), and bretazenil (0.03– 10 mg/kg); the 5-hydroxy tryptamine_1A (HT)_1A-mediated anxiolytics, buspirone (1–10 mg/kg) and ipsapirone (1–17 mg/kg); and the negative controls d-amphetamine (0.3–3 mg/kg), haloperidol (0.01–0.3 mg/kg), morphine (0.3–17 mg/kg), and imipramine (0.3–30 mg/kg). Results: The experimental procedure was sensitive to increases in punished drinking by the GABA_A-positive modulators, consistent with their known or putative anxiolytic activity. Further, the 5-HT_1A-mediated anxiolytics increased punished drinking, although to a lesser extent and over a more narrow dose range than did the GABAergic drugs. In contrast, d-amphetamine, haloperidol, morphine, and imipramine failed to increase punished drinking up to doses that decreased unpunished drinking. Conclusions: The present results indicate that water deprivation is not a necessary condition to engender drinking conflict behavior or to obtain pharmacological effects similar to those obtained with other classical conflict procedures. Received: 23 November 1998 / Final version: 15 March 1999     

What is a normal family? Common assumptions and current evidence

The social and applied human sciences have been built upon the assumption that the normal family consists of a first-marriage conjugal couple cohabiting with biological children. It is taken for granted that the wife should be responsible for child and domestic work, and that the husband should be the family's economic provider and ultimate authority. In the professional literature such traditional family structure is often described as normal in the sense of most common, as well as normal in the sense of well-functioning. Current psychological, sociological, anthropological and historical studies, however, do not support the assumption that the traditional nuclear family is the most natural, common, and/or healthy form of family arrangement. The idealization of the traditional nuclear family has had implications for theory, research, mental health practice, and social policy. Scientists and practitioners have been slow to recognize pathology in traditional nuclear families. Families other than traditional nuclear ones have been rendered invisible or pathologized. It is time for contemporary social and applied human sciences to recognize that the traditional nuclear family is a culturally- and historically-specific construct. It is also time for contemporary social and applied human sciences to develop an account of, and a research agenda about, families that take into consideration their variations across time, place, social class, ethnicity, and culture.     

Non-occupational risk factors for adult soft-tissue sarcoma in northern Italy

The role of socioeconomic and anthropometric indicators, tobacco, alcohol consumption, dietary habits, and medical history in the etiology of soft-tissue sarcoma (STS) was examined in a hospital-based case-control study, conducted in the Friuli-Venezia Giulia region of northeast Italy, between 1985 and 1990. A total of 88 STS cases (53 males and 35 females; median age: 52 years) and of 610 controls (306 males and 304 females; median age: 54 years) were interviewed. There were significant excess risks associated with a history of herpes zoster infection (odds ratio [OR]=2.4,95 percent confidence interval [CI]=1.1–5.3), chicken pox (OR=2.2, CI=1.2–4.3) and mumps in childhood (OR=2.0, CI=1.1–3.9). History of diabetes was also linked to a nonsignificant increase in STS risk (OR=1.8, CI=0.6–5.4), whereas exposure to radiation for diagnostic or therapeutic purposes was not related to the probability of developing STS. None of the investigated socioeconomic and anthropometric indicators seemed to affect STS risk; neither did tobacco smoking, nor consumption of alcohol, coffee, and tea beverages. Conversely, among the dietary habits investigated, a significant positive association emerged with an increasing frequency of consumption of dairy products (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=6.8, P<0.01) and oil (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXafv3ySLgzGmvETj2BSbqefm0B1jxALjhiov2D% aebbfv3ySLgzGueE0jxyaibaiiYdd9qrFfea0dXdf9vqai-hEir8Ve% ea0de9qq-hbrpepeea0db9q8as0-LqLs-Jirpepeea0-as0Fb9pgea% 0lrP0xe9Fve9Fve9qapdbaqaaeGacaGaaiaabeqaamaabaabcaGcba% Gaae4XdmaaCaaaleqabaGaaGOmaaaaaaa!3DA2!\[{\rm{\chi }}^2\]for trend=4.3, P<0.05), while a negative association was seen for intake of whole grain bread and pasta (OR for highest cf lowest tertile=0.4, CI=0.2–0.9).Support for this project was contributed by the Italian Association for Cancer Research, Milan, and the Italian National Research Council (CNR Applied Project Oncology, Contract 87.01544.44).     

Serum esterase inhibition in birds: A nondestructive biomarker to assess organophosphorus and carbamate contamination

With the aim of proposing a nondestructive biomarker for monitoring the toxicological risk to birds of exposure to the organophosphorus insecticide azamethiphos and the carbamate insecticide methomyl, laboratory studies were performed on serum B esterases in Japanese quail (Coturnix coturnix japonica). The birds received two single dose treatments of each compound (azamethiphos and methomyl), i.e., 50 mg/kg and 250 mg/kg respectively. In the first treatment, serum butyrylcholinesterase (BChE) and carboxylesterase (CbE) were drastically inhibited in the azamethiphos-treated group, 24 h after the dose. No inhibition was detected for BChE and CbE activities in the methomyl-treated group, 24 h after the dose. In the second treatment, the birds died or were sacrified 3 h after the dose. Serum BChE and brain acetylcholinesterase (AChE) were strongly inhibited after treatment with both insecticides. Serum CbE, hepatic microsomal CbE and 7-ethoxyresorufin dealkylation activities were also inhibited. A statistically significant correlation between serum BChE and brain AChE was found at lethal and sublethal doses of these xenobiotics. The experimental results indicate that the nondestructive biomarker BChE can give an early qualitative and semi-quantitative warning of the toxic effects of organophosphate and carbamate insecticides in birds.     

Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults.

Folate and methionine metabolism is involved in DNA synthesis and methylation processes. Polymorphisms in the genes of folate metabolism enzymes have been associated with some forms of cancer. In a case-control study, we evaluated whether four common polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G), and methionine synthase reductase (MTRR A66G) genes may have a role in altering susceptibility to adult acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). We analyzed DNA of 120 adult ALL, 200 NHL, and 257 healthy control subjects. Individual carrying the MTHFR 677TT genotype showed a 3.6-fold decreased ALL risk [odds ratio (OR) 0.28, 95% confidence interval (95% CI) 0.12-0.72] than wild-types. Similarly, MS 2756GG individuals showed a 5.0-fold decreased ALL risk (OR 0.20, 95% CI 0.02-1.45) than wild-types. In combined results, subjects with the MTHFR 677CT/TT and MS 2756AG/GG genotypes revealed a 3.6-fold ALL risk reduction (OR 0.28, 95% CI 0.14-0.58) and those with the MTHFR 677TT and MTRR 66AG genotypes revealed a 4.2-fold ALL risk reduction (OR 0.24, 95% CI 0.06-0.81). Finally, those with the MS 2756AG/GG and MTRR 66AG/GG genotypes revealed a 2.2-fold ALL risk reduction (OR 0.45, 95% CI 0.10-0.85). Single analysis for NHL did not show any significant difference for all the polymorphisms investigated, but in the low-grade NHL subgroup, we found a 2.0-fold risk reduction for the MTRR 66GG homozygous genotype (OR 0.50, 95% CI 0.25-0.99), which was higher (OR 0.37, 95% CI 0.14-0.85) when analyzed in combination with MS 2756AA genotype. These data are in accordance with the hypothesis that polymorphisms in the genes for folate and methionine metabolism might play a greater role in the occurrence of ALL than NHL by influencing DNA synthesis and/or DNA methylation.     

Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma.

PURPOSE: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3'-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. EXPERIMENTAL DESIGN: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. RESULTS: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P < 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. CONCLUSIONS: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.