The influence of interferon-alpha on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma.

The pharmacokinetics of cyclophosphamide (CP) and its cytotoxic metabolite 4-hydroxycyclophosphamide (4-OHCP) have been studied in multiple myeloma patients treated with the CIB (CP, interferon-alpha (IFN-alpha) and betamethasone) regimen. In the present investigation we aimed to determine whether exposure to CP and its cytotoxic metabolite 4-OHCP is influenced by the concomitant administration of IFN-alpha. Ten patients with previously untreated multiple myeloma entered the study. Each patient received two courses of CIB in randomized order. Interferon was administered either 2 h before the CP infusion in one course or 24 h after the CP infusion in the other course. A cyclophosphamide dose of 750-900 mg/m2 was given as a 2 h constant infusion. Interferon-alpha (10-15 x 10(6) IE) was given subcutaneously. All patients received betamethasone 24 h after CP or later. The elimination of CP was described by monoexponential decay. The administration of IFN-alpha before CP caused a decrease in CP clearance to 63% (P=0.004), a 137% longer half-life (P = 0.004) and a 137% higher peak plasma concentration (P = 0.006) compared to the results obtained when IFN-alpha was administered 24 h after CP. The formation of 4-OHCP was also affected by the administration of IFN-alpha prior to CP, 45% less exposure to 4-OHCP expressed as AUC (P = 0.002) and a 61% lower peak plasma concentration (P = 0.002) compared with that observed when IFN-alpha was administered 24 h after CP. The administration of IFN-alpha after CP resulted in a greater (45%, P = 0.02) decrease in leukocyte count compared with results when IFN-alpha was given before CP. This study demonstrates that the administration of IFN-alpha prior to CP significantly impairs pharmacokinetics of CP and 4-OHCP. When IFN-alpha was administered after CP, a higher exposure to the cytotoxic metabolite 4-OHCP was observed and reflected by a significant decrease in leukocyte count compared to that when IFN-alpha was given before CP. In conclusion, the time of administration of IFN-alpha in relation to concomitant chemotherapy (CP) has to be considered to obtain a higher efficacy of IFN-alpha/alkylating agent combining regimens for induction in multiple myeloma and related disorders.     

Stress reactions among Swedish health care personnel in unifil,South Lebanon 1982–1984

Since 1948 almost 50,000 Swedish men and women have been in military UN service in more than 15 countries under very different circumstances. The stress situation for UN soldiers is quite different form soldiers in other military situations. The UN soldier might be scared by his own aggressiveness, because of his limited opportunities to use his weapons. The mission for the UNIFIL hospital in Naqoura, a few kilometres north of the Israeli border, is to provide the UN forces (5000–6000 soldiers) with hospital care and specialized medical services. Three contingents (N = 421) during three years have been studied by means of, questionnaires, self-rating scales, a personality inventory test (KSP) and personal interviews. The personal interviews were structured and performed during the last mouth of service for each contingent. The UN soldiers were interviewed by six experienced psychiatrists, who were all well acquainted with the Swedish military system. All the interviews took place within the Swedish UN hospital area in south Lebanon, during one week for each group.     

Tumor burden status evaluated by computed tomography scan is of prognostic importance in patients with chronic lymphocytic leukemia

It has been discussed if computed tomography (CT) scan is necessary to perform or not, to provide prognostic information in patients with chronic lymphocytic leukemia. In the current National Institute Chronic lymphocytic leukemia Working Group (NCI-WG) guidelines, CT scan is not recommended outside clinical trials but states that further trials are warranted. Computed tomography scan of lymphadenopathy and/or splenomegaly was detected in totally 74 patients, leading to a modified Rai stage in 9 (12%) patients (from stage I to II). Using CT, 19 patients fulfilled the GELF high tumor burden criteria and/or one bulky node ≥7 cm. CT showed splenomegaly in totally 54 (73%) patients, of which 22 (41%) cases had not had been detected during clinical examination. According to the NCI response criteria for chronic lymphocytic leukemia (CLL), 15 (22%) patients showed a CR and 43 (62%) a PR, while when including CT findings, 12 (17%) fulfilled criteria for CR and 41 (59%) for PR. Patients with a high lymphadenopathy tumor burden according to the GELF criteria at the time of initiation of first-line therapy had a shorter time from response to next therapy or death, 12 months compared with 35 months for patients with less advanced lymphadenopathy (P = 0.002). There was also a trend for a shorter overall survival in the high tumor burden group, 58 months compared to 75 months (P = 0.098). Massive splenomegaly was related to a shorter therapy-free as well as overall survival. In our opinion, clinical examination is not sufficient for evaluation of abdominal lymphnodes and spleen in patients with therapy requiring CLL.     

TGFBR1 variants TGFBR1*6A and Int7G24A are not associated with an increased familial colorectal cancer risk

Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case–control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P=0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P=0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.     

Recombinant erythropoietin and chronic renal failure

The hormone deficiency that underlies anemia in chronic kidney failure can now be corrected. Along with the primary benefit of raising the hematocrit and reversing anemia, dramatic secondary benefits can be achieved. Exercise capacity, neuropsychiatric and sexual function, and overall quality of life are enhanced. Guidelines for management are discussed.     

Biliary excretion of the vasopressin analogue DDAVP after intraduodenal, intrajugular and intraportal administration in the conscious pig

The biliary excretion of the vasopressin analogue 1-deamino-8-D-arginine vasopressin (dDAVP) was determined in the pig after three administration routes, intrajugular venous, intraportal venous and intraduodenal. In all cases the biliary excretion was less than 1% of the administered dose. The plasma/bile concentration ratio was less than 1:1. A significant first-pass effect was found when the liver was exposed to a high intraportal dose of dDAVP. Possible uptake and degradation/biotransformation was evaluated by incubating [3H]dDAVP with liver tissue slices showing that [3H]dDAVP was rapidly removed from the incubation medium. The following conclusions can be drawn from these experiments: 1) The intestinal mucosa constitutes the major barrier to intestinal absorption of dDAVP. 2) dDAVP is excreted in bile in small amounts. 3) Indirect evidence suggests that the dDAVP molecule is degraded/biotransformed in the liver at its C-terminus.     

Passive knee muscle moment arms measured in vivo with MRI

Objective. To determine moment arm lengths from seven knee muscles and the patellar tendon. The knee muscles were the biceps femoris, semitendinosus, semimembranosus, gracilis, sartorius, and the lateral and medial gastrocnemius muscles.

Design. The moment arms were calculated based on MRI measurements.

Background. Moment arm lengths of different muscles with respect to the joint centre of rotation (CR) or the centre of the contact point between joint surfaces are necessary basic data for biomechanical models predicting joint load.

Methods. Ten male and seven female subjects participated. Using a 1.5 Tesla magnetic resonance imaging system, 3-dimensional coordinates of relevant points were recorded from a 3-D volume reconstruction of the right knee at knee flexion angles of 0, 30 and 60 °. Muscular moment arms were calculated in both the sagittal and frontal planes. The recordings were all made during passive mode, which means that no muscular contraction was performed.

Results. All muscles except the lateral gastrocnemius showed statistically significant differences (P < 0.05) of moment arm lengths between gender in the frontal plane. All muscles except biceps femoris and sartorius showed significant differences (P < 0.05) of moment arm lengths between gender in the sagittal plane. Most muscles also showed a linear or quadratic trend of changing moment arms with varying knee angle.

Conclusions. Our results indicate that for most biomechanical analyses involving knee muscles, gender- and angle-specific moment arms should be used.     

Dead-space reduction and tracheal pressure measurements using a coaxial inner tube in an endotracheal tube

OBJECTIVE: To evaluate the effects on CO(2) washout of the coaxial double lumen tube (DLT) as compared to a standard endotracheal tube (ETT) and tracheal gas insufflation (TGI). Precision of tracheal pressure monitoring through the DLT and safety issues, including intrinsic PEEP (PEEPi) formation during DLT ventilation, were also evaluated. DESIGN: Lung model study. SETTING: University research laboratory. MEASUREMENTS AND RESULTS: CO(2) washout was analysed in a lung model by measuring single alveolar CO(2) concentration during DLT ventilation as compared to standard ETT ventilation, at different minute ventilation (6-14 l/min) and different CO(2)-output levels (180 ml/min, 240 ml/min, and 300 ml/min). At a CO(2) output level of 240 ml/min the CO(2) washout was also compared to tidal volume-adjusted continuous TGI and expiratory synchronised TGI. Precision of tracheal pressure monitoring and PEEPi formation during DLT ventilation was evaluated by comparing pressure in each limb above the tube to reference tracheal pressure, varying I:E ratios (1:2, 1:1, and 2:1), tidal volumes (300-700 ml), breathing frequencies (15-25), and compliance (20-50 ml/cmH(2)O). DLT ventilation had the same efficacy in removing CO(2) as continuous and expiratory synchronised TGI, reducing single alveolar CO(2) concentration by 9-21% compared to normal ventilation. Tracheal pressure could be measured through the DLT with high precision. There was only marginal formation of PEEPi at tidal volumes 相似文献