Mechanisms associated with the expression of cisplatin resistance in a human ovarian tumor cell line following exposure to fractionated X-irradiation in vitro.

Interactions between cisplatin (CDDP) and irradiation are of potential significance for the combined modality treatment of cancer. Previous data have indicated that following in vitro exposure to X-irradiation certain tumour cells expressed resistance to CDDP. To identify parameters associated with this CDDP resistance, the human ovarian carcinoma cell line SK-OV-3/P was pre-exposed to fractionated X-irradiation (total dose: 50 Gy) in vitro. The resultant subline (SK-OV-3/DKR-10) proved 2-fold resistant to CDDP, but not to acute X-irradiation. Consistent with unaltered dihydrofolate reductase and thymidylate synthase activities, SK-OV-3/DXR-10 cells were neither cross-resistant to methotrexate nor to 5-fluorouracil. Verapamil (6.6 microM) significantly (P less than 0.05) enhanced CDDP-induced cytotoxicity in the resistant DXR-10 subline, but not in the parental cells. Total glutathione levels were significantly (P less than 0.01) lower in the resistant subline and BSO pretreatment failed to influence cytotoxicity, whilst related enzyme activities were not consistently modified in the SK-OV-3/DXR-10 cells. Resistance in these cells was associated with significantly decreased cisplatin uptake (P less than 0.002). Immediately following drug exposure the total platination level of the DNA, quantitated immunochemically, was higher (P less than 0.05) in the resistant subline indicative of increased tolerance to DNA damage. After an 18 h post-treatment incubation the parental cell line appeared proficient in the removal of the intrastrand adduct Pt-AG, but deficient in removing the major adduct Pt-GG and the difunctional Pt-(GMP)2 lesion, whilst the DXR-10 resistant subline appeared proficient in removal of all four Pt-DNA adducts. DNA polymerases alpha and beta activities, however, were comparable in both cell lines. These data implicate both enhanced repair and increased tolerance of DNA damage as mechanisms of resistance to CDDP resulting from in vitro exposure of a human ovarian carcinoma cell line to fractionated X-irradiation.     

Segmental intestinal muscular thinning: a possible cause of intestinal obstruction in the newborn

Intestinal obstruction proximal to a transition zone without an interposed physical barrier usually indicates Hirschsprung disease. The authors report one case of focal small bowel muscular thinning just distal to a transition zone that produced clinical and radiographic findings that simulated long-segment Hirschsprung disease in a 2-day-old infant.     

Very low versus undetectable maternal serum alpha-fetoprotein values and fetal death

Very low maternal serum alpha-fetoprotein (MSAFP) levels (less than 10 ng/mL) are known to be associated with non-viable pregnancies, including conditions such as fetal death, molar pregnancies, and non-pregnancies. There has not been agreement, however, as to whether very low MSAFP levels indicate already existing fetal deaths or are actually predictive. We analysed 230 pregnancies with MSAFP levels less than 10 ng/mL from among 15,807 women (1.5 per cent) screened consecutively during a three-year period and identified 26 non-viable pregnancies, 22 of which were diagnosed sonographically as part of the screening process (17 missed abortions, 3 blighted ova, 2 non-pregnancies). Furthermore, 20 of these 22 pregnancies were associated with essentially undetectable MSAFP levels (less than 5 ng/mL). Our data indicate that pregnancies with MSAFP values less than 5 ng/mL are the group most strongly associated with fetal non-viability and that very low MSAFP values are not strongly predictive for fetal death.     

Human balance and posture control during standing and walking

The common denominator in the assessment of human balance and posture is the inverted pendulum model. If we focus on appropriate versions of the model we can use it to identify the gravitational and acceleration perturbations and pinpoint the motor mechanisms that can defend against any perturbation.

We saw that in quiet standing an ankle strategy applies only in the A/P direction and that a separate hip load/unload strategy by the hip abd/adductors is the totally dominant defence in the M/L direction when standing with feet side by side. In other standing positions (tandem, or intermediate) the two mechanisms still work separately, but their roles reverse. In the tandem position M/L balance is an ankle mechanism (invertors/evertors) while in the A/P direction a hip load/unloading mechanism dominates.

During initiation and termination of gait these two separate mechanisms control the trajectory of the COP to ensure the desired acceleration and deceleration of the COM. During initiation the initial acceleration of the COM forward towards the stance limb is achieved by a posterior and lateral movement of the COP towards the swing limb. After this release phase there is a sudden loading of the stance limb which shifts the COP to the stance limb. The COM is now accelerated forward and laterally towards the future position of the swinging foot. Also M/L shifts of the COP were controlled by the hip abductors/adductors and all A/P shifts were under the control of the ankle plantar/dorsiflexors. During termination the trajectory of both COM and COP reverse. As the final weight-bearing on the stance foot takes place the COM is passing forward along the medial border of that foot. Hyperactivity of that foot's plantarflexors takes the COP forward and when the final foot begins to bear weight the COP moves rapidly across and suddenly stops at a position ahead of the future position of the COM. Then the plantarflexors of both feet release and allow the COP to move posteriorly and approach the COM and meet it as quiet stance is achieved. The inverted pendulum model permitted us to understand the separate roles of the two mechanisms during these critical unbalancing and rebalancing periods.

During walking the inverted pendulum model explained the dynamics of the balance of HAT in both the A/P and M/L directions. Here the model includes the couple due to the acceleration of the weight-bearing hip as well as gravitational perturbations. The exclusive control of A/P balance and posture are the hip extensors and flexors, while in the M/L direction the dominant control is with the hip abductors with very minor adductor involvement. At the ankle the inverted pendulum model sees the COM passing forward along the medial border to the weight-bearing foot. The model predicts that during single support the body is falling forward and being accelerated medially towards the future position of the swing foot. The model predicts an insignificant role of the ankle invertors/evertors in the M/L control. Rather, the future position of the swing foot is the critical variable or more specifically the lateral displacement from the COM at the start of single support. The position is actually under the control of the hip abd/adductors during the previous early swing phase.

The critical importance of the hip abductors/adductors in balance during all phases of standing and walking is now evident. This separate mechanism is important from a neural control perspective and clinically it focuses major attention on therapy and potential problems with some surgical procedures. On the other hand the minuscule role of the ankle invertors/evertors is important to note. Except for the tandem standing position these muscles have negligible involvement in balance control.     

Shared care: a review of the literature

This review examines broad issues of concern regarding the primary/secondarycare interface. The main purpose was to identify areas of goodpractice which could be adapted for more general use. One ofthe most fundamental aspects identified was communication, whichis discussed in some detail. Also covered are shared prescribingand disease management. The data suggest that the most effectivesystem(s) of shared care has yet to be established. Furtherqualitative and economic evaluations are required, taking intoaccount patient preferences. Although the literature does describecertain practice exemplars, it is clear that inter- and intra-professionalcommunication continues to be a problem. Whilst informationtechnology may provide some of the solutions, it is concludedthat a culture change, which compels health professionals tomake sharing of patient information a much higher priority,is reauired. Keywords. Shared care, seamless care, hospital, general practice, family practice.     

Gender difference in anaerobic capacity: role of aerobic contribution.

The purpose of this study was to evaluate effects of gender on anaerobic and aerobic contributions to high-intensity exercise. A group of 38 subjects (22 women, 16 men) performed modified Wingate tests against resistances of 0.086 kg kg-1 body mass (0.844 N kg-1) for women and 0.095 kg kg-1 body mass (0.932 N kg-1) for men. The aerobic contribution to total work performed was determined from breath-by-breath analyses of expired gases during each test. Total work in 30 s was 30% lower (Student's t test; P < 0.01) in women than men (211 +/- 5 J kg-1 versus 299 +/- 14 J kg-1). Aerobic contribution was only 7% lower (P = 0.12) in women than men (53 +/- 1 J kg-1 versus 57 +/- 2 J kg-1). The anaerobic component of the work performed, determined by subtraction of the aerobic component from total work in 30 s, was 35% lower (P < 0.01) in women than men (158 +/- 5 J kg-1 versus 242 +/- 15 J kg-1). It is concluded that, because women provide a relatively higher (P < 0.01) portion of the energy for a 30-s test aerobically than men (25% versus 20%), total work during a Wingate test actually underestimates the gender difference in anaerobic capacity between women and men.     

Cigarette smoking increases white blood cell aggregation in whole blood.

We studied the effect of chronic cigarette smoking on white blood cell aggregation, increased aggregation predisposes to microvascular occlusion and damage. Current smokers had significantly increased white blood cell aggregation when compared with non smokers. The presence of chronically activated white blood cells in current smokers may be relevant in the pathogenesis of ischaemic vascular disease.     

Central nervous system site of action for the hypotensive effect of clonidine in the cat

The purpose of our study was to determine whether clonidine exerts its centrally mediated hypotensive action at three sites that influence arterial pressure located in the medulla, specifically associated with the intermediate area of the ventrolateral medulla. The "intermediate area" lies approximately 1.5 mm caudal to the border of the trapezoid body (caudal border) and 4 mm lateral to the midline. One of the sites that influence arterial pressure lies in the nucleus reticularis rostroventrolateralis. The second site lies in close proximity to the rostral part of the nucleus reticularis lateralis (rLRN) and also near the A1 area. The third site lies in the most rostral area and medial to the nucleus reticularis rostroventrolateralis, that is in the nucleus paragigantocellularis lateralis. Unilateral microinjections of 0.22 and 0.43 nmol of clonidine into the rLRN produced dose-dependent decreases in arterial pressure. The 0.43 nmol dose of clonidine had no effect when unilaterally or bilaterally microinjected into either the nucleus reticularis rostroventrolateralis or into the nucleus paragigantocellularis lateralis. Microinjection of the alpha-2 adrenoceptor antagonist, idazoxan (16.6 nmol), unilaterally into rLRN had no effect per se, but prevented the hypotensive effect of a subsequent microinjection of clonidine. Similarly, bilateral microinjection of idazoxan into rLRN counteracted the hypotensive effect of i.v. administered clonidine. These data indicate that clonidine acts at alpha-2 adrenoceptors in the rLRN to produce hypotension.     

Asbestos-related focal lung masses: manifestations on conventional and high-resolution CT scans

In 260 asbestos-exposed individuals evaluated by means of computed tomography (CT), 43 unsuspected pulmonary masses were found in 27 individuals. The masses included fissural pleural plaques (n = 10), dense fibrotic bands (n = 3), round atelectasis (n = 11), carcinomas (n = 3), and other presumed benign masses (n = 16). The most helpful features in the diagnosis of rounded atelectasis with CT were (a) contiguity to areas of diffuse pleural thickening, (b) a lentiform or wedge-shaped outline, (c) evidence of volume loss in the adjacent lung, and (d) a characteristic "comet tail" of vessels and bronchi sweeping into the margins of the mass. Less advanced areas of focal atelectasis had fewer classic features. Intrafissural pleural plaques were readily identified with high-resolution CT. In asbestos-related masses, the demonstration of stability over time is necessary. Careful interpretation of CT and high-resolution CT features and close surveillance can obviate the need for biopsy in the majority of instances.     

Renal clearance and protein binding of melphalan in patients with cancer

Summary The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m² over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m². Total melphalan clearance after the 5 mg/m² dose ranged from 66.0 to 272 ml/min per m²; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m²; the fraction unbound in plasma, from 0.0598 to 0.460; and t_1/2, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m² and 15 to 961 ml/min per m² respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose exctreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.This study was supported by a grant from The Queen Elizabeth Hospital Research Foundation