Immunodepression reduces learning performance in male laboratory mice (Mus musculus).

Several theoretical and empirical studies have suggested that immunocompetence may act as a constraint on learning, due to a trade-off in investment in the two processes. Here we tested whether experimentally depressing immune responsiveness of male BKW mice using antithymocyte serum (ATS) would lead to reduced learning performance in a radial maze task. Correct choices in the maze were indicated by the presence of familiar odours, incorrect choices by unfamiliar odours. We showed that temporarily depressing cellular immunity led to a reduction in performance in terms of a reduced proportion of correct choices. We also found a positive relationship between the proportion of correct entries over the period of testing and haemagglutination titre, indicating that mice showing greater immune responsiveness performed better in the maze. We conclude that depressing the immune system reduces learning performance in a combined odour/spatial learning task, and that some individuals are better able to compensate for the experimental immunodepression. In contrast to previous studies, there was no evidence that the effect of ATS was mediated by associated changes in corticosterone or testosterone secretion. There were no significant effects of the presence of female odour on learning performance, and therefore no evidence that the down regulation of learning in relation to immune depression was influenced by apparent reproductive opportunity.

Temporal and between-site variation in helminth communities of bank voles ( Myodes glareolus) from N.E. Poland. 2. The infracommunity level.

The relative importance of temporal and spatial effects was assessed in helminth communities of bank voles (Myodes glareolus) in 3 woodland sites in N.E. Poland in the late summers of 1999 and 2002. Among common species the rank order of sites in relation to prevalence and abundance of infection was maintained between surveys. Site effects accounted for most of the deviance (in statistical models), and time was less important, so the exact location from which voles were sampled was of critical importance. The only exception was Syphacia petrusewiczi. In contrast, for derived measures such as species richness and diversity, most deviance was accounted for by host age, and the interaction between site and year was significant, implying that rank order of sites changed between years. Temporal effects on derived measures were generated primarily by a combination of relatively small changes in prevalence and abundance of the common, rather than the rare, species between the years of the study. In the medium-term, therefore, helminth communities of bank voles in N.E. Poland had a stable core, suggesting a substantial strong element of predictability.

Temporal and between-site variation in helminth communities of bank voles ( Myodes glareolus) from N.E. Poland. 1. Regional fauna and component community levels.

Helminth infections were studied in bank voles (Myodes glareolus) from 3 woodland sites in N.E. Poland in the late summers of 1999 and 2002, to assess the temporal stability of derived statistics describing the regional helminth fauna and component community structure, and spatial influence on the latter. Regional helminth fauna changed dramatically between the two years, primarily due to a fall in the abundance of Syphacia petrusewiczi but was partially compensated for by an increase in Mesocestoides lineatus and Cladotaenia globifera. It was dominated by nematodes overall, but more so in 1999 than in 2002 when larval cestodes were more frequent. Most derived parameters for component community structure varied considerably between sites and the two surveys, the hierarchical order for sites not being maintained between surveys. They were susceptible to the disproportionate influence of three relatively rare, unpredictable species with the greatest overall aggregated distribution among hosts. Jaccard's similarity index was less influenced by the rare species, showing greater stability between sites and across years. In conclusion, temporal variation confounded any site-specific characteristics of the summary measures quantified in this study and their usefulness is therefore restricted to the years in which the surveys were conducted.

Odour learning and immunity costs in mice.

There is accumulating evidence that learning is metabolically costly. One way in which this may manifest itself is in trade-offs between learning effort and immune function, with learning increasing susceptibility to infection. We tested this idea in the context of odour learning using outbred (BKW) male laboratory mice. Mice were exposed to three experimental treatments in which they were required to learn different numbers of urinary odours. While treatment affected the extent to which mice habituated to test odours during training, differences were not a simple function of the number of odours. The fact that there was also no significant effect of treatment on the degree of preference for novel over familiar odours in subsequent tests suggests mice retained learned odour profiles equally well regardless of the number of odours. That subsequent infection with Babesia microti increased with the number of odours mice had to learn is then consistent with an increased cost to learning effort when more odours were presented. Analysis within treatments, and relationships with the change in corticosterone concentration over the period of the experiment, suggested that it was a failure to learn, rather than maintaining learning performance, in more difficult learning tasks that led to greater infection. As in a previous study of maze learning in the strain, there was no direct relationship between infection and measures of peripheral antibody (total IgG) titre. The results are discussed in relation to studies in other learning contexts and reported relationships between glucocorticoid hormones and learning outcomes.

A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity.

As part of a drug discovery program to discover more effective platinum-based anticancer drugs, a series of platinum complexes of trans coordination geometry centered on trans-ammine(cyclohexylaminedichlorodihydroxo)platinum(IV) (JM335) has been evaluated in vitro against a panel of cisplatin-sensitive and cisplatin-resistant human tumor cell lines (predominantly ovarian). In vitro, against 5 human ovarian carcinoma cell lines, JM335 was comparably cytotoxic to cisplatin itself and over 50-fold more potent than transplatin (mean 50% inhibitory concentrations: JM335, 3.1 microM; cisplatin, 4.1 microM; transplatin, 162 microM). With the use of seven pairs of human tumor cell lines (parent and subline with acquired resistance to cisplatin and encompassing all of the known major mechanisms of resistance to cisplatin) JM335 exhibited a different cross-resistance pattern to that of its cis isomer (JM149). JM335 showed non-cross-resistance in six of the seven resistant lines, cross-resistance in the A2780cisR line possibly being associated with high levels of glutathione. Preliminary intracellular DNA binding studies showed that in contrast to transplatin, JM335 was efficient at forming DNA-DNA interstrand cross-links. In vivo, JM335 produced growth delays in excess of 15 days against 4 of 6 human ovarian carcinoma xenografts and was unique among the complexes studied in retaining some efficacy against a cisplatin-resistant subline of the murine ADJ/PC6 plasmacytoma. JM335 is the first trans-platinum complex to demonstrate marked antitumor efficacy against both murine and human s.c. tumor models and represents a significant structural lead to complexes capable of circumventing cross-resistance to cisplatin.

Insights from the sharp end of intravenous medication errors: implications for infusion pump technology.

BACKGROUND: Intravenous (IV) medication errors are a common type of error identified in hospitals and can lead to considerable harm. Over the past 20 years there have been several hundred FDA reported incidents involving IV pumps, many of which have led to patient deaths. OBJECTIVE: To determine the actual types, frequency, and severity of medication errors associated with IV pumps. To evaluate the likelihood that smart pump technology without an interface to other systems could have prevented errors. METHODS: Using a point prevalence approach, investigators prospectively compared the medication, dose, and infusion rate on the IV pump with the prescribed medication, doses, and rate in the medical record. Preventability with smart pump technology was retrospectively determined based on a rigorous definition of currently available technology. RESULTS: A total of 426 medications were observed infusing through an IV pump. Of these, 285 (66.9%) had one or more errors associated with their administration. There were 389 documented errors overall; 37 were "rate deviation" errors and three of these were judged to be due to a programming mistake. Most of the documented events would not have caused patient harm (NCC MERP category C). Only one error would have been prevented by smart pump technology without additional interface and software capabilities. CONCLUSION: Medication errors associated with IV pumps occur frequently, have the potential to cause harm, and are epidemiologically diverse. Smart pumps are a necessary component of a comprehensive safe medication system. However, currently available smart pumps will fail to generate meaningful improvements in patient safety until they can be interfaced with other systems such as the electronic medical record, computerized prescriber order entry, bar coded medication administration systems, and pharmacy information systems. Future research should focus on the effectiveness of new technology in preventing latent and active errors, and on new types of error that any technology can introduce.

Synthesis and in vitro and in vivo antitumor activity of a series of trans platinum antitumor complexes.

The synthesis of a series of platinum complexes of trans coordination geometry [centered around the general formula, trans-ammine(amine)dichlorodihydroxoplatinum(IV) plus corresponding tetrachloroplatinum(IV) or Pt(II) counterparts] is described as part of a drug discovery program to identify more effective platinum-based anticancer drugs, particularly targeted toward the circumvention of resistance to cisplatin. Complexes have been evaluated for antitumor activity using in vitro and in vivo tumor models. In vitro against a panel of cisplatin-sensitive and -resistant human tumor cell lines (predominantly ovarian), many of the trans platinum complexes studied (e.g., 1, R = cyclohexyl) exhibited comparable potency to cisplatin and also overcame acquired cisplatin resistance, where resistance was due mainly to either reduced drug uptake or enhanced platinum-DNA adduct removal. Moreover, 14 trans complexes showed significant in vivo antitumor activity against the subcutaneous murine ADJ/PC6 plasmacytoma model; all were platinum(IV) complexes, 13/14 possessing axial hydroxo ligands the other possessing axial ethylcarbamato ligands. Where tested, all of their respective platinum(II) or tetrachloroplatinum(IV) counterparts were inactive. Notably, three dihydroxoPt(IV) complexes (18, 29, 34) (R = c-hexyl, c-heptyl, and 1-adamantyl) retained some efficacy against a cisplatin-resistant variant of the ADJ/PC6. Compounds 18 (trans-[PtCl2(OH)2NH3-(RNH2)]) R = c-C6H11, 22, R = Me3C, 27, R = n-C6H13, 28, R = PhCH2, and 36 (trans-[PtBr2(OH)2NH3(c-C6H11NH2)]) also produced evidence of antitumor activity (> 5 days growth delay) against subcutaneously grown advanced stage human ovarian carcinoma xenografts. These data demonstrate that a series of trans-ammine(amine)dichlorodihydroxoplatinum(IV) complexes are active in vivo against both murine and human subcutaneous tumor models and represent potential leads to a new generation of platinum-based anticancer drug.

Twenty-four-hour preservation of the pig heart by a portable hypothermic perfusion system.

A portable hypothermic perfusion system for storage of hearts has been developed. The system uses the airlift pump principle, whereby the flow of gas maintains circulation of the perfusate through the heart; no other energy source is required. Performance on ex vivo functional testing of 10 pig hearts stored for 20 to 24 hr using this system (group 3) was compared with that of freshly excised hearts (group 1) and hearts stored simply in the perfusate under hypothermic conditions, but not perfused (group 2). Group 2 hearts performed less well on functional testing than those of groups 1 and 3 which showed little statistical difference, suggesting good preservation by hypothermic perfusion. This has been confirmed by orthotopic transplantation of similarly preserved baboon hearts with survival until rejection at a mean of 27 days. The importance of the various constituents of the perfusate and the significance of weight gain during the storage and reperfusion periods are discussed.

Myocardial fibrinolytic activity in allogenic cardiac rejection.

The relationship between alterations in myocardial fibrinolytic activity and the degree of graft tolerance or rejection was studied in 22 nonimmunosuppressed heterotopic cardiac transplants in chacma baboons. Fibrinolysis was evaluated on tissue sections and tissue extracts. Fibrinolytic activity was compared with electrocardiographic voltage alterations and multiple myocardial biopsies and terminal heart specimens were examined by light and electron microscopy. Histopathology and reduction in fibrinolytic activity proved superior to electrocardiographic voltage reductions in assessing early cardiac rejection. The two former modalities correlated well with one another. Myocardial histology showed rejection change earlier than fibrinolytic activity reduction.

Evaluation of endomyocardial biopsy in the diagnosis of cardiac rejection. A study using bioptome samples of formalin-fixed tissue.

The reliability of endomyocardial bioptome samples in detecting cardiac rejection was assessed in 26 formalin-fixed previously transplanted hearts. Thirteen human donor hearts (mean postoperative survival 128 days) and 13 baboon donor hearts (mean survival 16.5 days) were studied. Twenty samples were taken under direct vision from the endomyocardium of each heart with an Olympus bioptome catheter. A total of 397 tissue samples was examined "blindly" histologically (177 human and 220 baboon). The bioptome samples were assigned a histological rejection score and then compared with the score accorded multiple tissue sections from the same heart. Sample scores agreed with tissue section scores as follows: humans 86% (samples showed more severe alterations in 5% and less severe in 9%) and baboons 57% (samples more severe in 40% and less severe in 3%). Only 2 false-negative samples were encountered among 285 tissue samples from hearts showing rejection. Changes of rejection were equally distributed between the left and right ventricles. Endomyocardial sampling proved an accurate means of detecting the presence of rejection. In the baboon hearts the endomyocardium tended to show more severe changes than the rest of the myocardium.

An investigation of the immunosuppressive effects of niridazole and metronidazole in rat and baboon heterotopic cardiac allograft models.

Niridazole alone (at 50 mg/kg/day) and particularly in combination with azathioprine and prednisolone showed potent immunosuppressive activity, far surpassing that produced by conventional agents, in the rat heterotopic cardiac allograft model. Benzoylmetronidazole or metronidazole (at 50 mg/kg/day) either alone or in combination with azathioprine and prednisolone demonstrated little immunosuppressive activity. The potent immunosuppression obtained with niridazole in the rat could not be reproduced in the baboon heterotopic cardiac allograft model in the doses used; niridazole at 50 mg/kg/day seems to be toxic in this animal.

The role of parasite-induced immunodepression, rank and social environment in the modulation of behaviour and hormone concentration in male laboratory mice (Mus musculus).

Peripheral immune responsiveness in male laboratory mice was reduced by infection with the trichostrongyloid nematode Heligmosomoides polygyrus. Responsiveness was also lower among high-ranking (aggressive) males regardless of infection status. Reduced responsiveness in both infected animals and high rankers was associated with elevated serum corticosterone concentration (a potential immunodepressant) and was compounded among high-ranking males by subsequent high aggressiveness. As in previous experiments, only low rankers modulated testosterone secretion in relation to current immunocompetence and corticosterone concentration. The lack of any downregulation of aggression in response to parasite-induced immunodepression contrasted with previous results using antithymocyte serum and may be due to the more localized nature of immunodepression during H. polygyrus infection. However, the additional increase in corticosterone concentration resulting from exposure to female odour and destabilized aggressive social relationships did result in downregulation of aggression among high rankers and of testosterone among mice generally, suggesting that modulation rules of thumb are at least partly dependent on the proximate cues associated with immunodepression.

Maternal effects on the development of social rank and immunity trade-offs in male laboratory mice (Mus musculus).

Social status in randomly constituted groups of male CFLP mice was predictable from early suckling behaviour and rate of weight gain in natal litters. High-ranking males were those that had suckled on more anterior teats and gained weight more quickly. Rank was not predicted by any measures of sibling interaction or hormone (testosterone, corticosterone) concentration. Aggressiveness in eventual high-rankers was associated negatively with the proportion of males in the litter at birth and the amount of maternal attention received. Aggressive social relationships within natal litters did not predict polarized rank relationships in randomized groups. Nevertheless, while still in their natal litters, and in the absence of aggressive rank relationships, eventual rank categories showed the same difference in modulation of testosterone concentration in relation to current immunocompetence (low-rankers modulating, high-rankers not), as has repeatedly been found in randomized groups by earlier studies. The role of maternal condition in determining rank-related life-history development in male mice is discussed.

The consequences of inbreeding for recognizing competitors.

Extreme inbreeding will compromise an animal's ability to discriminate between individuals and, thus, assess familiarity and kinship with conspecifics. In rodents, a large component of individual recognition is mediated through chemical communication. The counter-marking of competitor males' scent marks provides a measure of discrimination between their own scent and that from other individuals. We investigated whether males in common outbred (ICR(CD-1) and TO) and inbred (BALB/c) strains of laboratory mice could recognize the urinary scents of other individuals by measuring their investigation and counter-marking responses. Dominant males of outbred strains investigated and counter-marked scents from other males, whether of the same or another strain. Dominant inbred BALB/c males investigated but did not counter-mark their own strain scents, counter-marking only those from another strain. They did not use environmentally induced status differences in odours to recognize scents from other males. The inability of the inbred mice to discriminate between their own scent marks and those of other males is likely to alter their competitive behaviour, which could influence responses in experiments and the welfare of caged laboratory mice.

Analysis of surgical versus medical therapy in active complicated native valve infective endocarditis.

From 1972 to 1980, 23 patients (Group A) with native valve infective endocarditis underwent surgical intervention, often for multiple indications, during the active stage of the infective process because of progressive class III and IV (New York Heart Association) heart failure (12 patients), persistent severe hypotension (3 patients), uncontrolled infection for over 21 days (11 patients), aortic root abscess (2 patients), and pericarditis (1 patient). Eighty-five patients (Group B) with active native valve endocarditis, matched for severity of illness, were treated medically. Two patients (9%) in Group A and 43 patients (51%) in Group B died during the hospital admission (p less than 0.001). Any difference in long-term cumulative survival rate between the 2 groups was largely due to the beneficial impact of surgical management on the hospital mortality. Of 23 patients in Group A, 11 (48%) had an entirely uncomplicated postoperative course. Long-term mortality rates in those with aortic valve endocarditis treated medically (79%) were significantly higher than in those with mitral valve involvement (47%) (p less than 0.05). Patients with aortic valve involvement treated surgically had a better hospital (p less than 0.005) and long-term (p less than 0.0005) survival rate than those treated medically. Two groups at risk for postoperative complications were identified; 3 of 11 patients (27%) with uncontrolled infection had an early postoperative recurrence, and 4 of 7 patients (57%) with an aortic root abscess had postoperative prosthetic paravalvular regurgitation. Surgery therefore effects a substantial reduction in hospital mortality in patients with complicated active infective endocarditis (9% versus 51%), but patients with preoperative prolonged periods of uncontrolled infection or with aortic root abscess are liable to postoperative complications.

Use of a double atrial-triggered standby pacemaker system for a patient with a biventricular bypass heterotopic cardiac homograft.

In a patient who had a biventricular bypass heterotopic cardiac homograft a double atrial-triggered standby pacemaker system was implanted to allow sequential atrial pacing of both hearts. The system design permitted either the recipient or the donor heart to dictate the rate of its fellow, depending on which heart had the faster spontaneous sinus rate at any time. Alternative methods for achieving sequential pacing are discussed.

Age-dependent changes in the shear wave propagation through human skin.

We studied the potential use of the in vivo frequency response of human volar forearm skin as a means for evaluating skin age. The velocity and damping length of waves on the skin surface were correlated with chronological age. One hundred and fifty subjects from 1 to 95 years of age were studied. For the frequency spectrum from 800 to 2000 Hz, there was a linear correlation between the velocity of propagation and age. At 2000 Hz, the y intercept was 11.4 m/second and the slope was 0.245 m/second/year, r = 0.5500, p less than 1 x 10(-7). There was no correlation of velocity with sex, skin color, obesity, sun exposure, physical activity, or inpatient status.

Antitumor-activity of orally-administered ammine amine platinum (iv) dicarboxylate complexes against a panel of human ovarian-carcinoma xenografts.

The antitumour activity of a series of ten novel ammine/amine platinum (IV) dicarboxylates of general formula [Pt(IV) Cl2 (OCOR1) NH3 (RNH2)] where R1 was an aliphatic or aromatic substituent and R an aliphatic or alicyclic substituent, was evaluated, after oral administration, to nude mice bearing various human ovarian carcinoma xenografts. The tumours were chosen to encompass a wide range in responsiveness to the clinically used platinum-based drugs cisplatin and carboplatin, with tumour growth delays varying from less than 10 days to greater than 60 days. Against two tumour lines, the platinum (IV) ammine/amine dicarboxylate JM221 (R1=C3H7; R= cC6H11) exhibited similar antitumour activity whether administered by the oral or intraperitoneal route. Experiments have been performed using four xenografts to provide a direct comparison of the antitumour effects of three platinum (IV) ammine/amine butyrates (JM216, R=cC6H11; JM225, R=cC5H9; JM269, R=cC7H13; R1=C3H7 for all three) administered by the oral route versus cisplatin and carboplatin administered by the intravenous route at equitoxic q7dx4 schedules. All three dicarboxylates exhibited oral activity broadly comparable to cisplatin and carboplatin and significantly superior to tetraplatin (Ormaplatin; a 1,2 diaminocyclohexane-containing platinum drug currently undergoing clinical evaluation). Average specific growth delay values across the four xenografted lines were 3.45 for cisplatin, 3.9 for carboplatin, 3.2 for JM216, 3.3 for JM225, 3 for JM269 and only 0.55 for tetraplatin. Thus the ammine/amine platinum (IV) dicarboxylates represent a novel class of platinum drug for oral administration capable of exhibiting broadly comparable activity to cisplatin and carboplatin in a panel of human ovarian carcinoma xenografts.

Fistula of the sinus of Valsalva.

Operative repair of sinus of Valsalva aneurysms and fistulas was performed in 10 patients between 1960 and 1976. Associated cardiac defects were corrected in 6 patients. There were no postoperative deaths, and the 8 patients observed to date are still alive and well. Only 2 patients required a second operation. The employment of a transchanber or a transaortic approach or both continues to be a matter of individual preference.

Mitral valve replacement in children.

Mitral valve replacement (MVR) is associated with higher mortality and morbidity rates in children than in adults, and the use of heterograft valves has been encouraged. The results of MVR in 56 consecutive patients, aged 2 to 12 years, presenting between January, 1972, and January 1979, were reviewed to test these beliefs. The etiology of mitral valve disease was rheumatic in 46, congenital in eight, and acute bacterial endocarditis in two. All children were seriously disabled (NYHA Classes III and IV). Cardiac catheterization in 36 patients revealed mixed valve disease in 26, pure mitral regurgitation in seven, and pure mitral stenosis in three. Seventeen Starr-Edwards (SE), five Lillehei (L), Björk-Shiley (BS), eight Hancock (H), and 25 Carpentier-Edwards (CE) mitral prosthesis were inserted. Operative mortality was 2% (1 BS) and late mortality was 10% (three SE, one L, two CE). Serious late complications occurred in 30% of survivors, including 11 instances of calcific valve stenosis (five H, six CE), one case of valve thrombosis (1 L), and two embolic episodes (1 SER, 1 H). Survival curves were similar for patients with heterograft and mechanical valves (92% and 77% at 5 years). Event-free curves showed heterograft valves to have a far higher complication rate than mechanical valves (10% complication free at 4 years compared to 84% free at 5 years). Early operative results in children are excellent, and the overall mortality (10%) compares favorably with figures for MVR in adults. However the long-term durability and choice of prostheses remain problematical, since less than 10% of heterograft valves survive beyond 5 years.