Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy.

BACKGROUND: Oxaliplatin, combined with capecitabine (CAPOX) or infused 5-fluorouracil (FOLFOX), is standard of care in the adjuvant treatment of colorectal cancer (CRC). Prospective data on prevalence of oxaliplatin induced acute and long-term neuropathy in a real-life patient population and its effects on quality of life (QOL) and survival is limited, and scarce in CAPOX versus FOLFOX treated, especially in a subarctic climate. METHODS: One hundred forty-four adjuvant CRC patients (all 72 CAPOX cases and 72 matched FOLFOX controls) were analyzed regarding oxaliplatin induced sensory neuropathy, which was graded according to NCI-CTCAEv3.0. Ninety-two long-term survivors responded to the QOL (EORTC QLQ-C30) and Chemotherapy-Induced Peripheral Neuropathy (EORTC CIPN20) questionnaires and were interviewed regarding long-term neuropathy. RESULTS: Acute neurotoxicity was present in 94% (136/144) during adjuvant therapy and there was a significant association between acute neurotoxicity and long-term neuropathy (p < .001). Long-term neuropathy was present in 69% (grade 1/2/3/4 in 36/24/8/1%) at median 4.2 years. Neuropathy grades 2-4 did not influence global health status, but it was associated with decreased physical functioning (p = .031), decreased role functioning (p = .040), and more diarrhea (p = .021) in QLQ-C30 items. There were no differences in acute neurotoxicity, long-term neuropathy, or in QOL between CAPOX and FOLFOX treated. Neuropathy showed no pattern of variation according to starting and stopping month or treatment during winter. CONCLUSIONS: Neuropathy following oxaliplatin containing adjuvant chemotherapy is present in two-thirds, years after cessation, and impairs some QOL scales. There is no difference in severity of acute or long-term neuropathy between CAPOX and FOLFOX treated and QOL is similar. No seasonal variation in neuropathy was noted.

Bringing habitat information into statistical tests of local adaptation in quantitative traits: a case study of nine-spined sticklebacks.

Detection of footprints of historical natural selection on quantitative traits in cross-sectional data sets is challenging, especially when the number of populations to be compared is small and the populations are subject to strong random genetic drift. We extend a recent Bayesian multivariate approach to differentiate between selective and neutral causes of population differentiation by the inclusion of habitat information. The extended framework allows one to test for signals of selection in two ways: by comparing the patterns of population differentiation in quantitative traits and in neutral loci, and by comparing the similarity of habitats and phenotypes. We illustrate the framework using data on variation of eight morphological and behavioral traits among four populations of nine-spined sticklebacks (Pungitius pungitius). In spite of the strong signal of genetic drift in the study system (average FST = 0.35 in neutral markers), strong footprints of adaptive population differentiation were uncovered both in morphological and behavioral traits. The results give quantitative support for earlier qualitative assessments, which have attributed the observed differentiation to adaptive divergence in response to differing ecological conditions in pond and marine habitats.

DRIFTSEL: an R package for detecting signals of natural selection in quantitative traits.

Approaches and tools to differentiate between natural selection and genetic drift as causes of population differentiation are of frequent demand in evolutionary biology. Based on the approach of Ovaskainen et al. (2011), we have developed an R package (DRIFTSEL) that can be used to differentiate between stabilizing selection, diversifying selection and random genetic drift as causes of population differentiation in quantitative traits when neutral marker and quantitative genetic data are available. Apart from illustrating the use of this method and the interpretation of results using simulated data, we apply the package on data from three-spined sticklebacks (Gasterosteus aculeatus) to highlight its virtues. DRIFTSEL can also be used to perform usual quantitative genetic analyses in common-garden study designs.

Modelling the impact of varicella vaccination on varicella and zoster.

It has been suggested that the incidence of herpes zoster may increase due to lack of natural boosting under large-scale vaccination with the varicella vaccine. To study the possibility and magnitude of such negative consequences of mass vaccination, we built a mathematical model of varicella and zoster epidemiology in the Finnish population. The model was based on serological data on varicella infection, case-notification data on zoster, and new knowledge about close contacts relevant to transmission of infection. According to the analysis, a childhood programme against varicella will increase the incidence of zoster by one to more than two thirds in the next 50 years. This will be due to increase in case numbers in the 35 years age groups. However, high vaccine coverage and a two-dose programme will be very effective in stopping varicella transmission in the population.

Effect of ingesting sour milk fermented using Lactobacillus helveticus bacteria producing tripeptides on blood pressure in subjects with mild hypertension.

Angiotensin-converting enzyme (ACE) is important in the regulation of blood pressure (BP). Two tripeptides that inhibit ACE, isoleucyl-prolyl-proline (Ile-Pro-Pro) and valyl-prolyl-proline (Val-Pro-Pro), have been isolated from certain sour milks. The aim of the study reported was to evaluate the effect on BP in subjects with mild hypertension of a new sour milk containing tripeptides. The initial number of subjects was 60 (36 men, 24 women). Among the criteria for inclusion in the study were systolic BP (SBP) between 140 and 180 mmHg and/or diastolic BP (DPB) between 90 and 110 mmHg, without antihypertensive drug therapy. There were two study periods with a washout period between. All subjects were given 1.5 dl per day of a placebo (regular sour milk) or of the active product, a milk that had been fermented with Lactobacillus helveticus bacteria and contained 2.4-2.7 mg of Ile-Pro-Pro and 2.4-2.7 mg of Val-Pro-Pro per 1.5 dl. In the first phase, SBP fell 16 mmHg from baseline in the active group, 2 mmHg more than in the placebo group (P=0.0668) and no difference in DBP (P=0.92). There was a statistically significant downward trend both in SBP and DBP (P=0.0001). During the second phase, SBP fell 11 mmHg in the active group (P=0.008). The reduction in SBP was significantly larger in active than placebo group (P=0.012). In the crossover analysis combining both phases, SBP fell on average 2.6+/-15.9 mmHg more on the active product compared with the placebo product, but this difference was not statistically significant (P=0.3111). The difference in DBP, 1.0+/-8.3 mmHg between the two test products was not significant either (P=0.4431). In conclusion, the ingestion of sour milk fermented by L. helveticus bacteria and that containing ACE inhibitory tripeptides seems to lower BP modestly.

Erythromycin and 2'-acetyl erythromycin concentrations in plasma and pelvic tissues after repeated doses of erythromycin acistrate.

The concentrations of erythromycin (E) and 2'-acetyl erythromycin (2'-AE) in female pelvic organs, i.e. endometrium, myometrium, ovary and Fallopian tube, as well as in plasma, were determined after oral dosing of erythromycin acistrate (EA, CAS 96128-89-1), a erythromycin prodrug. Ten patients undergoing selective gynecological operation were given three doses of EA (400 mg) at 8-h intervals immediately before the operation. Tissue samples were taken 75-205 min after the intake of the last dose. Blood samples were collected immediately prior to and up to 8 h after the intake of the last dose. High total antibiotic (erythromycin + 2'-acetyl erythromycin) concentration in plasma were measured throughout the dose interval after the last dose. The concentrations of E in plasma were over the MICs for most of the erythromycin-sensitive bacteria (0.5 micrograms/ml) in 7 out of 10 patients (mean 0.66 micrograms/ml) at the end of the third dose interval. The drug concentrations in tissues were lower than in plasma (due to short treatment time of totally 24 h). The mean percentage of penetration (tissue/plasma ratios) for erythromycin ranged from 63 to 95% in various pelvic tissues. However, rather extensive interindividual variation was observed. The degree of hydrolysis of 2'-acetyl erythromycin to erythromycin was 29-39% in plasma and 42-73% in tissue samples. There were negligible amounts of inactive anhydro forms in plasma after EA and their concentrations in tissue samples were low, as well.

Systolic time intervals in canine experimental acute hemorrhagic pancreatitis.

The effect of experimental acute hemorrhagic pancreatitis on hemodynamics and systolic time intervals were studied simultaneously by catheterization in dogs. Following the initial hemodynamic measurements pancreatitis was induced by a mixture of trypsin and sodium taurocholate infused into the pancreatic duct (PG, n = 7). After 60 min of surveillance the hemodynamic measurements were repeated and the results were compared to those obtained from the sham-operated group (CG, n = 7) paced at a similar contraction frequency to the PG after the follow-up time. Left ventricular ejection time (LVET) and the ratio of PEP/LVET (PEP, preejection period) increased more in the PG than in the CG (P less than 0.05 and P less than 0.001, respectively). This was related to a lower left ventricular end-diastolic volume and pressure in the PG in comparison to the CG (P less than 0.05). PEP remained unaltered in both groups during the interventions. No significant differences between the groups were observed in the responses of the maximum value of the left ventricular systolic pressure rise (dP/dtmax). The ejection fraction decreased more in the PG than in the CG (P less than 0.05), which was related to the decreased end-diastolic volume in the PG (P less than 0.001). Mean aortic pressure decreased significantly in the PG (P less than 0.01). The results indicate that experimental acute hemorrhagic pancreatitis leads to altered loading conditions of the heart and causes marked alterations in the systolic phases of the contraction cycle. This model of experimental pancreatitis does not depress the myocardial contractility on the basis of these results.

Impaired venous return causes circulatory failure in experimental pancreatitic shock in dogs.

The haemodynamic effects in the early phase of canine acute experimental pancreatitis (AP) were studied using a cardiac catheterization technique. AP was induced in anaesthetized dogs with an infusion of trypsin-sodium-taurocholate into the pancreatic duct. The initial haemodynamic measurements were performed after the preparation of the animal and 5 min after the induction of AP. Thereafter, pressure and volume parameters were measured at 10 min intervals. AP induced significant increases in heart rate, dP/dtmax and mean arterial pressure, but a decrease in Vmax 5 min after the induction of AP. After the initial phase, the heart rate remained significantly increased, while constant and significant decreases of stroke volume, cardiac output, end-diastolic volume and end-diastolic pressure developed. The parameters of the contractility of the left ventricle were not affected to the same extent. It is suggested that the circulatory failure observed in AP, characterised by a prompt reduction of cardiac output, was primarily due to a heavy reduction in preload. This supports the theory that cardiac output is primarily affected by impaired venous return with consequently decreased preload rather than by a loss of ventricular contractility. Hence, the existence of a myocardial depressant factor in the early phase of experimental AP does not gain support from the present results.

Anabolic steroids alter the haemodynamic effects of endurance training and deconditioning in rats.

The haemodynamic effects of endurance training with or without anabolic steroid treatment (nandrolone decanoate, 5.0 mg kg-1 week-1) were studied before and after a six-week sedentary period in anaesthetized, open-chest rats during isoproterenol and CaCl2 loads. In comparison to the control group (CG I, n = 13) endurance training (TG I, n = 10) increased the resting stroke index significantly, end-diastolic pressure and during CaCl2 infusion the end-diastolic and end-systolic volumes. Peripheral resistance decreased in TG I during both inotropic loads but increased in CG I (P less than 0.01 between the groups). After combined endurance training and anabolic steroid treatment (TSG I, n = 16) the haemodynamic state was similar to that in CG I except peripheral resistance which was even higher than in CG I. The heart weight to body weight ratio was significantly greater both in TG I and TSG I than in CG I. After a six-week deconditioning period the haemodynamic values were essentially similar in endurance trained (TG II, n = 10) and in control rats (CG II, n = 12). After the sedentary period, in the simultaneously trained and anabolic steroid-treated group (TSG II, n = 13) stroke index and end-diastolic volume decreased more during isoproterenol load when compared with TG II or CG II (P less than 0.05 between the groups). Peripheral resistance was higher in the TSG II than in the two other groups. In conclusion, the enhanced pumping performance of the heart by increased left ventricular diastolic filling after endurance training is attenuated by simultaneous anabolic steroid treatment which further increases the peripheral resistance. Detraining reversed the main training effects in six weeks and simultaneous anabolic steroid treatment led to a decreased left ventricular filling and to elevated peripheral resistance after the sedentary period.

The cardiovascular effects of deconditioning after endurance training in rats.

The haemodynamic effects of endurance training and physical deconditioning were studied in anaesthetized rats using aortic and left ventricular pressure recordings and volume measurements by thermodilution method during isoproterenol and CaCl2 loads. The resting stroke volume was significantly larger in the training group (TG I, n = 10) than in the control group (CG I, n = 13). During the CaCl2 infusion stroke index, end-diastolic and end-systolic volumes increased in the TG I, but decreased in the CG I. Both isoproterenol and CaCl2 decreased systemic vascular resistance in the TG I, but increased it in the CG I. After a six-week deconditioning following training period (TG II, n = 10) stroke index, end-diastolic and end-systolic volumes decreased during CaCl2 and isoproterenol infusions similarly to the control deconditioning group (CG II, n = 12). These responses differed significantly from those observed in the TG I. Peripheral resistance increased in both the CG II and the TG II. Cardiac hypertrophy observed during training was partly reversed after the deconditioning period. In conclusion, endurance training improves the pumping performance of the rat heart by enhancing the diastolic filling of the left ventricle and decreasing peripheral resistance during inotropic load. Left ventricular contractility is not affected. A six-week deconditioning period after endurance training returns the haemodynamic changes to sedentary levels.

Acetate-induced changes in cardiac energy metabolism and hemodynamics in the rat.

The hemodynamic and metabolic effects of acetate were studied in rats in vivo and in the isolated perfused heart. Hemodynamic parameters, myocardial phosphagens, inorganic phosphate, and adenosine were measured in vivo. Acetate uptake, coronary flow, O2 consumption, parameters of the cellular energy state, and hypoxanthine compounds and their washout were measured in heart perfusion experiments. Heart rate (HR), cardiac output, and the peak derivative of the left ventricular pressure rise (dP/dtmax) increased significantly during acetate infusion in vivo, but mean arterial pressure, systolic arterial pressure, and systemic vascular resistance decreased. Heart muscle ATP concentrations decreased after 7 min of acetate infusion. In vivo cardiac work load (HR.(peak left ventricular pressure] showed a positive correlation with tissue adenosine concentration and a negative correlation with phosphorylation potential. Acetate uptake in the perfused hearts was about 2.5 mumol/min per gram wet weight. Acetate perfusion increased O2 consumption and coronary flow concomitantly with a decrease in tissue ATP concentration. Tissue AMP and perfusate effluent adenosine concentration and adenosine output increased significantly, perfusate adenosine showing a non-linear positive correlation with coronary flow. The results demonstrate that acetate induces considerable changes in hemodynamics and metabolism in the heart.

Prophylaxis and treatment of anaerobic infections following caesarean section with tinidazole.

The purpose of this prospective, double-blind, placebo-controlled study was to clarify the effect of a single intravenous infusion of 500 mg of tinidazole on infections that followed a caesarean section. 80 consecutive caesarean-section patients and thereafter 72 women undergoing non-elective caesarean section were randomly assigned to two groups, each receiving intravenous infusions at cord clamping. In the entire sample the incidence of endometritis/wound infection in the placebo group was 27.3% (21/77) versus 10.7% (8/75) in the tinidazole group (p less than 0.01). In the non-elective caesarean-section group the incidence of endometritis/wound infection was 39.6% (21/53) in the placebo group versus 14.3% (7/49) in the tinidazole group (p less than 0.01). 27 positive bacterial cultures yielded a pure anaerobic growth in 59% (16/27) of cases, of which 87.5% (14/16) were treated successfully with oral tinidazole.

Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion.

Concentrations of metronidazole and tinidazole were analysed in mother's serum, placental tissue and foetal tissue after a single intravenous infusion of 500 mg of either drug in 21 patients who underwent a first trimester legal abortion. At the time of the evacuation (60 min from the start of the infusion) the concentrations of metronidazole and tinidazole in serum were 13.6 +/- 0.6 micrograms/ml and 13.2 +/- 0.4 micrograms/ml, respectively. In foetal tissue the concentrations of metronidazole and tinidazole reached 66% and 58%, and in placental tissue 26% and 37%, of the respective serum values.

Concentrations of metronidazole and tinidazole in female reproductive organs after a single intravenous infusion and after repeated oral administration.

Concentrations of metronidazole and tinidazole in serum and gynecological organs were analyzed after a single 500 mg intravenous infusion and after three days of treatment with 400 mg t.i.d. of metronidazole or 500 mg b.i.d. of tinidazole. The studies were performed in 67 patients subjected to hysterectomy and/or oophorectomy because of myomatosis uteri, carcinoma uteri or endometriosis. At the time of organ removal (about 30 min after infusion), metronidazole and tinidazole levels in serum were 14.5 +/- 0.45 mg/l and 12.3 +/- 0.38 mg/l, respectively. Concentrations of both drugs in the uterus and Fallopian tube were about the same as the simultaneous serum levels and concentrations in the ovaries about 55% thereof. At steady-state, the concentrations of tinidazole in serum (23.5 +/- 1.0 mg/l) were remarkably higher than those of metronidazole (13.5 +/- 0.84 mg/l) about three hours after the last oral dose. Drug concentrations in organs of the female reproductive tract were 70 to 100% those of the simultaneous serum levels.

Single dose of tinidazole in prophylaxis of infections following hysterectomy.

A single dose of 2 g tinidazole was given preoperatively to 70 patients undergoing elective hysterectomy; 76 patients served as controls. One patient in the drug therapy group and 10 in the control group had a temperature of 38 degrees C at some time after the first postoperative day. One patient in the tinidazole group and seven among the controls had abscess formation. The differences between the tinidazole and the control groups were highly significant. This simple prophylactic procedure reduced treatment costs and minimised infection following hysterectomy.