Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: real-life data from The Netherlands.

BACKGROUND: The RECOURSE trial showed clinical efficacy for trifluridine/tipiracil for refractory metastatic colorectal cancer patients. We assessed the feasibility and effectiveness of trifluridine/tipiracil in daily clinical practice in The Netherlands. METHODS: Medical records of patients from 17 centers treated in the trifluridine/tipiracil compassionate use program were reviewed and checked for RECOURSE eligibility criteria. Baseline characteristics, safety, and survival times were compared, and prespecified baseline characteristics were tested in multivariate analyses for prognostic significance on overall survival (OS). RESULTS: A total of 136 patients with a median age of 62 years were analyzed. Forty-three patients (32%) did not meet the RECOURSE eligibility criteria for not having received all prior standard treatments (n = 35, 26%) and/or ECOG performance status (PS) 2 (n = 12, 9%). The most common grade ≥3 toxicities were neutropenia (n = 44, 32%), leukopenia (n = 8, 6%), anemia (n = 7, 5%), and fatigue (n = 7, 5%). Median progression-free survival (PFS) and median OS were 2.1 (95% CI, 1.8-2.3) and 5.4 months (95% CI, 4.0-6.9), respectively. Patients with ECOG PS 2 had a worse median OS (3.2 months) compared to patients with ECOG PS 0-1 (5.9 months). ECOG PS, KRAS-mutation status, white blood cell count, serum lactate dehydrogenase, and alkaline phosphatase were prognostic factors for OS. CONCLUSIONS: Our data show that treatment with trifluridine/tipiracil in daily clinical practice is feasible and safe. Differences in patient characteristics between our population and the RECOURSE study population should be taken into account in the interpretation of survival data. Our results argue against the use of trifluridine/tipiracil in patients with ECOG PS 2. FUNDING: Johannes J.M. Kwakman received an unrestricted research grant from Servier.

Whole-genome sequencing analysis reveals the spread of a vanB-carrying transposon among different vancomycin-resistant Enterococcus faecium clinical isolates in a non-endemic setting.

BACKGROUND: Vancomycin-resistant enterococci (VRE), particularly Enterococcus faecium (VREfm), can cause serious nosocomial infections, and have been responsible for healthcare-associated outbreaks. Spreading of VREfm can occur both clonally and by the dissemination of mobile genetic elements. AIM: To report prospective analysis of whole-genome sequencing (WGS) data, including both core-genome multi-locus sequence typing (cgMLST) and transposon analysis, during a vanB VREfm outbreak. METHODS: Screening for vanB-positive VREfm isolates was performed by real-time polymerase chain reaction (PCR) on an overnight enriched broth and, if positive, subculture was performed. vanB-positive VREfm isolates underwent WGS. Generated data were used for molecular typing that was performed by cgMLST using SeqSphere. For transposon characterization, sequence data were mapped against the reference sequence of transposon Tn1549 using CLC Genomics Workbench, or de-novo assemblies were used for BLASTN comparisons. RESULTS: In total, 1358 real-time PCRs were performed. Two hundred and fifty-one specimens from 207 patients tested positive on PCR for vanB, of which 13 specimens obtained from six patients were identified as vanB VREfm positive on culture. These six patients harboured seven unique isolates belonging to four cluster types: CT118 (N=2), CT2483 (N=3), CT2500 (N=1) and CT2501 (N=1). Transposon analysis revealed the presence of an identical vanB-carrying transposon in the isolates cultured from all six patients that could be linked based on epidemiological data. CONCLUSION: A vanB VREfm outbreak occurred in the study hospital, including six patients with isolates belonging to four cluster types. In-depth transposon analysis revealed that dissemination of transposon Tn1549 rather than clonal spread was the cause of the outbreak.

Ethnicity and dangerousness criteria for court ordered admission to a psychiatric hospital.

BACKGROUND: Black and minority ethnic (BME) populations are disproportionately detained in psychiatric hospitals. AIM: To examine the dangerousness criteria for compulsory court ordered admission to a psychiatric hospital in White and BME persons. METHOD: We examined the psychiatric examinations for court ordered compulsory admissions in 506 White and 299 BME persons from October 2004 until January 2008 in Rotterdam, the Netherlands. The White and BME groups are compared using Chi-square tests and in case of significant differences with logistic regression models adjusted for age, gender, mental disorders and socio-economic background. RESULTS: In BME persons, violence towards others and neglect of relatives were more often reasons to request court order admission as compared with Whites (39.8 vs. 25.3%, P < 0.001, respectively, 6.4 vs. 2.4%, P = 0.01). This remained true after adjustment for age, gender, mental disorders and socio-economic background [OR 1.56 (95% CI 1.12-2.18), P = 0.01, respectively; OR 3.08 (95% CI 1.31-7.26), P = 0.01]. The other reasons for a request of court order admission had a similar prevalence in both groups (suicide or self-harm, social decline, severe self-neglect, arousal of aggression of others, danger to the mental health of others, and the general safety of persons and goods). CONCLUSION: Violence towards others and neglect of relatives are more often a reason to request court ordered admission in BME than in White persons. BME patients are more often perceived as potentially dangerous to others.

Involuntary admission may support treatment outcome and motivation in patients receiving assertive community treatment.

OBJECTIVE: Patients with severe mental illness who are treated in assertive community treatment (ACT) teams are sometimes involuntarily admitted when they are dangerous to themselves or others, and are not motivated for treatment. However, the consequences of involuntary admission in terms of psychosocial outcome and treatment motivation are largely unknown. We hypothesized that involuntary admission would improve psychosocial outcome and not adversely affect their treatment motivation. METHODS: In the context of routine 6-monthly outcome monitoring in the period January 2003-March 2008, we used the Health of the Nation Outcome Scales (HoNOS) and a motivation-for-treatment scale to assess 260 severely mentally ill patients at risk for involuntary admission. Mixed models with repeated measures were used for data analyses. RESULTS: During the observation period, 77 patients (30%) were involuntarily admitted. Relative to patients who were not involuntarily admitted, these patients improved significantly in HoNOS total scores (F = 17,815, df = 1, p < 0.001) and in motivation for treatment (F = 28.139, df = 1, p < 0.001). Patients who were not involuntarily admitted had better HoNOS and motivation scores at baseline, but did not improve. CONCLUSIONS: Involuntary admission in the context of ACT was associated with improvements in psychosocial outcome and motivation for treatment. There are no indications that involuntary admission leads to deterioration in psychosocial outcome or worsening of motivation for treatment.

[Independent psychiatrists rarely dispute an application for compulsory admission]. / Bijna altijd toekennen en weinig twijfel: overwegingen van onafhankelijke psychiaters tijdens de beoordeling rechterlijke machtiging.

BACKGROUND: In recent years in the Netherlands there has been a marked increase in the number of compulsory admissions, particularly those that require court authorisation. Little is known about the decision-making process that precedes the issuing of a court authorisation for compulsory admission. AIM: To obtain more insight into the factors that an independent psychiatrist has to consider when assessing whether he or she should sign a medical certificate that will advise on compulsory admission. METHOD: Data on clinical and demographic patient characteristics were gathered for 862 commitment applications. Motives for rejection of the application or doubt about the necessity of commitment were collected. results In the case of 9% of the applications, the psychiatrist hesitated about the need for compulsory admission but nevertheless signed the necessary medical certificate. In the case of 3% of the applications, the psychiatrist turned down the application for compulsory admission. The psychiatrist found to reject or query an application less often if a patient presented a direct physical threat to himself or others. The principal reason for rejecting an application for compulsory admission was the possibility that an alternative type of treatment was available. CONCLUSION: In principle the independent psychiatrist nearly always signs a medical certificate if the clinician treating the patient had requested a court authorisation. Factors that might help to reduce the number of court authorisations are better and earlier use of intensive care services, improved management or the deployment of legal restraints to prevent danger.

[Psychiatric past history and health care after compulsory admission. Care use as an indicator of the quality of care for patients in compulsory care in Rotterdam]. / Psychiatrische voorgeschiedenis en nazorg bij dwangopneming. Zorggebruik als indicator van de kwaliteit van zorg bij inbewaringstellingen in Rotterdam.

BACKGROUND: In evaluations of the Act on Special Admissions to Psychiatric Hospitals in The Netherlands (Dutch acronym BOPZ) hardly any attention has been given to the use of mental health care services before and after a compulsory admission. AIM: To investigate whether patterns of care before and after compulsory admissions can be considered as indicators of the quality of care provided by the mental health services. METHOD: For 623 patients with first-time acute compulsory admissions in Rotterdam, the use of the care services was monitored over a period of 12 months before and after admission. The outcomes were compared for 3 different patient groups: 'old acquaintances', 'newcomers' and 'passers-by'. In order to identify differences before an after the introduction of the BOPZ Act of 1994, we compared the use made of care facilities by patients admitted between 1992 and 1993 and between 1996 and 1997. RESULTS: More than one third of the patients admitted to acute compulsory care leaves the psychiatric hospital within three weeks. The average length of stay is more than two months and in more than half of the cases the first contact with mental health services occurs within one week after discharge. Within one year after the compulsory admission more than one third of patients is re-admitted and after one year more than fifty percent of patients are still receiving mental health care. Intensive care is targeted particularly at the patient group referred to as 'old acquaintances'. Following the introduction of the BOPZ Act the percentage of suicide-threats and cases of self-neglect increased. The number ofcompulsory re-admissions increased as well. CONCLUSION: The research results provide an encouraging picture of the quality of care provided before and after compulsory admissions. However, the cases which fail to receive mental health care before emergency compulsory admission and miss out on outpatient follow-up emphasise the needfor alternative measures such as an earlier conditional compulsory admission (voorwaardelijke machtiging) and more intensive outpatient treatment.

Increased metallothionein in the liver and kidney of patients with amyotrophic lateral sclerosis.

To evaluate the putative role of metals and trace elements in the pathogenesis of classic amyotrophic lateral sclerosis, we studied the metallothionein levels in liver and kidney samples obtained at autopsy from 24 patients with amyotrophic lateral sclerosis and 18 controls. To assay metallothioneins and copper, cadmium, and zinc bound to metallothioneins, we used high-performance liquid chromatography directly coupled to flame atomic absorption spectrometry. Total cadmium, zinc, and copper concentrations were determined separately with the use of graphite furnace atomic absorption spectrometry with Zeeman background correction. The median liver metallothionein level was 60.3 mg/kg (range, 9 to 318 mg/kg) in the patients with amyotrophic lateral sclerosis and 12.6 mg/kg (range, 0 to 104.5 mg/kg) in the controls. In the kidney, median metallothionein levels were 126.9 mg/kg (range, 44 to 387 mg/kg) in the patients with amyotrophic lateral sclerosis and 64 mg/kg (range, 13.1 to 187 mg/kg) in the controls. Total zinc, cadmium, and copper concentrations, as measured by atomic absorption spectrometry, were not significantly different in patients vs controls. Our finding of elevated metallothionein levels in organs from patients with amyotrophic lateral sclerosis may indicate an increased exposure to metals.

Pharmacokinetics of sulphamethoxazole in man: effects of urinary pH and urine flow on metabolism and renal excretion of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole.

A high performance liquid chromatography method for the determination of sulphamethoxazole and its metabolite N4-acetylsulphamethoxazole is described. The renal excretion rate and cumulative renal excretion of sulphamethoxazole is markedly influenced by urinary pH. With constant urinary pH, the renal excretion rate and the renal clearance of sulphamethoxazole is dependent on the urine flow. The renal clearance of the metabolite N4-acetylsulphamethoxazole is not influenced by urinary pH or urine flow. No clear acetylator phenotype could be detected in the group of volunteers studied. The extent of acetylation depends on the amount of sulphamethoxazole available for acetylation, thus indirectly on the urine pH and flow.

Steady-state kinetics of the quinolone derivatives ofloxacin, enoxacin, ciprofloxacin and pefloxacin during maintenance treatment with theophylline.

Some of the new quinolone derivatives may be of value in the treatment of respiratory tract infections. It has been demonstrated that enoxacin, pefloxacin and ciprofloxacin, but not ofloxacin, decreased the metabolic clearance of the bronchodilator theophylline. This resulted in elevated plasma theophylline concentrations and, in some of the patients, theophylline toxicity. When the pharmacokinetic parameters of enoxacin, pefloxacin, ciprofloxacin and ofloxacin obtained in the present study were compared with those obtained from other studies in healthy volunteers not given concomitant theophylline, there was no evidence of theophylline influencing the clearance of the investigated quinolones.

Cytosolic glutathione S-transferases in Drosophila melanogaster.

Post-microsomal supernatants from Drosophila melanogaster and rat liver homogenates were investigated with respect to their glutathione S-transferase (GST) activity. It appeared that the Drosophila transferase did not conjugate the epoxides styrene-7,8-oxide and 1,2 epoxy-3(p-nitrophenoxy)-propane. Attempts to isolate the Drosophila GST isozymes by means of the well-documented method for the purification of the rat liver transferases failed, because the Drosophila transferases did not bind to CM-cellulose. Purification by subsequent ion exchange on DEAE-cellulose, molecular sieving on Sephadex G-100 and hydroxylapatite chromatography, revealed three active fractions from Drosophila cytosol and five active fractions from rat liver cytosol, using 1-chloro-2,4-dinitrobenzene as the electrophilic substrate. None of the Drosophila active fractions catalyzed the conjugation of glutathione with the epoxides mentioned. It is concluded that there are important differences between the GST systems of both species, resulting in differences in the metabolic fate of chemicals that are substrates for glutathione conjugation. This has to be taken into account in the evaluation of genotoxicity testing in Drosophila of potentially harmful compounds.

Microsomal and cytosolic epoxide hydrolase in Drosophila melanogaster.

Subcellular fractions from Drosophila melanogaster and rat liver were investigated on their epoxide hydrolase activity. Both microsomes and the post-microsomal supernatant of Drosophila appeared to contain epoxide hydrolase activity using styrene-7,8-oxide as the substrate. Based on body weight, these activities were in the same order of magnitude. Rat liver cytosol was able to catalyze the hydrolysis of styrene oxide only if the glutathione S-transferase activity was blocked.

Five-day 4'-(9-acridinylamino)methanesulphon-m-anisidide and intermediate-dose cytosine arabinoside in high-risk relapsing or refractory acute myeloid leukemia.

Twenty-two patients with acute myeloid leukemia (AML), having a median age of 48.3 years (range 26-70; 10 male, 12 female), were treated with 4'-(9-acridinylamino) methanesulphon-m-anisidide (m-AMSA) 100 mg/m2 and cytosine arabinoside (AraC) 2 x 1000 mg/m2i.v. on days 1-5. There were 2M1,8 M2, 9 M4, 2M4 Eo, and 1 M5a. Of these, 12 achieved a complete remission, 3 a partial remission and 6 did not respond. The median remission duration was 9.0 months and the median overall survival 8.1 months. Side-effects of induction consisted mainly of haematological toxicity and infections with a median duration of WHO-grade-4 granulopenia and thrombopenia of 20 and 28 days respectively. Organ toxicity was mild with mucositis and cutaneous and liver toxicity being experienced by only a few patients. There was one treatment-related death. Five-day m-AMSA and intermediate-dose AraC is an easy-to-handle condensed treatment schedule with tolerable toxicity. Its effectiveness in relapsed and refractory AML is comparable to combinations of high-dose AraC with m-AMSA, anthracyclines or etoposide.

Delayed effect of the vasopressin metabolite VP4-8 on the social memory of sexually naive male rats.

RATIONALE: Endogenous vasopressin is involved in the social memory of the male rat and administration of exogenous vasopressin improves social memory. These findings are mainly based on studies using sexually experienced males that were tested in the social recognition test. OBJECTIVE: The present study was aimed to establish whether the modulation of social memory by vasopressin fragments depends on the sexual experience of the male rat. For this purpose, the social discrimination test was used, since this test is more suitable than the social recognition test for measuring social memory in sexually naive males. METHODS: Male rats were tested in the social discrimination test and treated subcutaneously with the vasopressin metabolite [pGlu4,Cyt6]vasopressin-(4-8) (VP4-8). VP4-8 shares with vasopressin the effects on memory processes but lacks the peripheral effects of vasopressin. RESULTS: VP4-8 (1 microgram/kg) acutely improved the social memory of sexually experienced male rats, confirming previous reports. However, in sexually naive males VP4-8 failed to improve social memory in doses ranging from 0.1 microgram/kg to 1 microgram/kg. Instead, 1 microgram/kg VP4-8 or 6 micrograms/kg desglycinamide-vasopressin were found to exert a delayed effect in sexually naive rats. This delayed effect resulted in an improved social memory 2 days after administration. CONCLUSIONS: Vasopressin sensitisation is discussed as a possible underlying mechanism of the observed delayed effect of vasopressin fragments. It is concluded that in male rats sexual experience can influence the modulation of social memory by vasopressin.

Spatial, contextual and working memory are not affected by the absence of mossy fiber long-term potentiation and depression.

The mossy fibers of the hippocampus display NMDA-receptor independent long-term plasticity. A number of studies addressed the role of mossy fiber long-term plasticity in memory, but have provided contrasting results. Here, we have exploited a genetic model, the rab3A null-mutant, which is characterized by the absence of both mossy fiber long-term potentiation and long-term depression. This mutant was backcrossed to 129S3/SvImJ and C57Bl/6J to obtain standardized genetic backgrounds. Spatial working memory, assessed in the eight-arm radial maze, was unchanged in rab3A null-mutants. Moreover, one-trial cued and contextual fear conditioning was normal. Long-term spatial memory was tested in the Morris water maze. Two different versions of this task were used, an 'easy' version and a 'difficult' one. On both versions, no differences in search time and quadrant preferences were observed. Thus, despite the elimination of mossy fiber long-term plasticity, these tests revealed no impairments in mnemonic capabilities. We conclude that spatial, contextual and working memory do not depend on mossy fiber plasticity.

An outbreak of Serratia marcescens traced to a contaminated bronchoscope.

An outbreak of colonization and infection with Serratia marcescens in a surgical Intensive Care Unit is described. A case-control study pointed to a bronchoscope as the source of the epidemic strain, and cultures of washing effluent of the incriminated bronchoscope yielded S. marcescens. Discontinuation of the use of the instrument and the implementation of recommendations for future use of bronchoscopes ended the outbreak.

Five-year surveillance of patients with communicable diseases nursed in isolation.

During a five year surveillance program of patients with communicable diseases nursed in isolation, we gathered information on 2880 patients who were nursed in isolation for 28 145 days, from January 1994 to December 1998. The mean number of patients nursed in isolation was 575.4 (range, 427-709) per year. On average 2.4% of patients admitted yearly to the University Medical Center (UMC) were nursed in isolation. The mean number of days nursed in isolation was 9.8 days per patient.1996 was a peak year in isolations due to outbreaks of gentamicin-resistant enterobacteriaceae (GRB) and methicillin resistant Staphylococcus aureus (MRSA). The main reasons for requiring isolation were: GRB, MRSA (proven and suspected cases), Clostridium difficile, viral infections and Mycobacterium tuberculosis. Registration of quantitative data on nursing patients in isolation, as presented in this paper, makes it possible to gain insight into the type and number of isolation indications, the required isolation room capacity on different wards, the workload of healthcare workers resulting from isolation and the trends in incidence of communicable diseases.

Antipyretic effect of central arginine8-vasopressin treatment: V1 receptors specifically involved?

Intracerebroventricular (i.c.v.) administration of the neurohypophyseal neuropeptide arginine8-vasopressin (AVP) results in a dose-dependent attenuation of endotoxin-induced fever (EIF) in rats. Specific antagonists of the neuropeptided(CH2)5[Tyr(Me)2]AVP for V1 receptors, d(CH2)5[dlle2lle4]AVP for the V2 receptors and Des-Gly,NH2d(CH2)5[Tyr)Me2)Thr4Orn8]vasotocin, an antagonist of the oxytocin receptors (AOXT), failed to modify EIF when administered i.c.v. Relatively high doses (100 ng) of all three peptide antagonists effectively blocked the antipyretic effect of AVP. Administered in smaller doses (10 or 30 ng), however, a more specific interaction was observed, i.e. the V1 antagonist being the only effective compound in preventing the effect of AVP. Although the data indicate that peptide-antagonist interactions should be interpreted carefully, the present experiments confirm previous observations on the involvement of V1-type receptors in the antipyretic action of AVP and suggest additional interactions with V2 vasopressinergic and oxytocinergic receptors.

Roles of the basolateral amygdala and hippocampus in social recognition in rats.

Lesions of the amygdala or hippocampus have a large impact on social behavior of rats. In this study we investigated whether a social recognition test was also affected by those lesions. An NMDA-induced lesion of the basolateral amygdala did not impair the ability to distinguish a familiar from an unfamiliar juvenile rat. It was argued that the cortico-medial amygdala may be more important for social recognition than the basolateral amygdala. Fimbria-transected rats could no longer distinguish a familiar from an unfamiliar juvenile. Moreover, during all encounters they spent less time investigating the juvenile. The precise nature of this deficit, especially the reason for the overall reduced social investigation time, could not be specified with the classical procedure of the social recognition test.

Dioxins, dioxin-like PCBs and non-dioxin-like PCBs in foodstuffs: occurrence and dietary intake in The Netherlands.

Data on occurrence of dioxins (polychlorinated dibenzo-p-dioxins [PCDDs] and dibenzofurans [PCDFs]), dioxin-like PCBs (polychlorinated non-ortho and mono-ortho biphenyls) and non-dioxin-like PCBs (as represented by the so-called indicator-PCBs: congeners 28, 52, 101, 118, 138, 153 and 180) in food products consumed in The Netherlands that were collected in measurement programs carried out during 1998 and 1999, and combined with food consumption data to assess the dietary intake of these persistent food contaminants. The estimated median life-long-averaged intake of the sum of dioxins and dioxin-like PCBs in the population is 1.2 pg WHO-TEQ (toxic equivalents) per kg body weight (bw) per day, while the estimated median life-long-averaged intake of indicator-PCBs is 5.6 ng per kg bw per day. The contribution of different food groups to the total intake of both dioxins + dioxin-like PCBs and non-dioxin-like PCBs is fairly uniformly distributed over the foods consumed: meat products (23% and 27%, respectively), dairy products (27% and 17%, respectively), fish (16% and 26%, respectively), eggs (4% and 5%, respectively), vegetable products (13% and 7%, respectively), and industrial oils and fats (17% and 18%, respectively). Compared with earlier intake estimations the present estimation shows a continued reduction in the intake of dioxins as well as PCBs. This reduction is related to the decrease in the concentration of these substances in the majority of foodstuffs. Nevertheless, a small part of the population still has a rather high life-long averaged intake: 8% of the population is exposed to intake levels above the tolerable weekly intake for dioxins and dioxin-like PCBs of 14 pg WHO-TEQ per kg bw per week, as recently derived by the Scientific Committee on Food of the European Commission. For the non-dioxin-like PCBs an internationally accepted maximum intake level is still lacking. However, to provide risk managers with a health-based guideline to prevent health effects of exposure to non-dioxin-like PCBs, the (international) derivation of a tolerable daily intake is recommended. Monitoring the dietary intake of PCBs is just as important as monitoring the intake of dioxins and dioxin-like PCBs, and attempts to decrease the exposure to both compound classes need continuous attention.