Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.     

Vasopressin in the forebrain of common marmosets (Callithrix jacchus): studies with in situ hybridization, immunocytochemistry and receptor autoradiography

The distribution of vasopressin (AVP) producing cells, their projections and AVP receptors was examined in the brain of common marmosets (Callithrix jacchus) using in situ hybridization, immunocytochemistry and receptor autoradiography. Clusters of cells labeled for AVP mRNA or stained for AVP immunoreactivity (AVP-ir) were found in the paraventricular (PVN), supraoptic (SON) and suprachiasmatic nuclei (SCN) of the hypothalamus. Scattered AVP producing cells were also found in the lateral hypothalamus and the bed nucleus of the stria terminalis (BST). Neither AVP mRNA-labeled nor AVP-ir cells were detected in the amygdala. Although AVP-ir fibers were evident outside of the hypothalamic-neurohypophyseal tract, a plexus of fibers in the lateral septum, as observed in the rat brain, was not detected. Receptor autoradiography using 125I-linear-AVP revealed specific binding for AVP receptors in the nucleus accumbens, diagonal band, lateral septum, the BST, SCN, PVN, amygdala, anterodorsal and ventromedial nucleus of the hypothalamus, indicating sites for central AVP action in the marmoset brain. Together, these data provide a comprehensive picture of AVP pathways in the marmoset brain, demonstrating differences from rodents in the distribution of cell bodies, fibers and receptors.     

Homeless youth and their exposure to and involvement in violence while living on the streets

Sick building syndrome is the term given to a heterogeneous constellation of symptoms that affects workers in modern mechanically ventilated office buildings. Although the cause is unknown, there is evidence that the local environment of the work station is an important determinant of symptoms. In this study, investigators examined the effect of a new, individually controlled ventilation system on workers' symptoms. Investigators studied two groups of workers in one mechanically ventilated office building: (1) a control group at whose worksite no intervention was made and (2) an intervention group. The intervention consisted of installation of a device that allowed each worker control over the ventilation supplied to his or her worksite. Just before, and 4 and 16 mo after installation of this device, workers completed self-administered questionnaires regarding occurrence of symptoms. The new ventilation system resulted in higher air velocities, more variable temperatures, and higher concentrations of airborne dust and fungal spores. Four months after installation, workers with the new ventilation system reported fewer symptoms that were (a) work-related (p < .05) and that were work-related and frequent (p < .05); in addition, they reported fewer symptoms that reduced their capacity to work (p < .01). Sixteen months after installation, workers with the new device reported fewer symptoms than at baseline (although not as significantly), and they indicated that the indoor air quality improved their productivity by 11%, compared with a 4% reduction of productivity among the control group of workers (p < .001). Investigators concluded that the new ventilation system, which provided the workers with individual control over ventilation, was associated with important and sustained reduction in symptoms.     

Exploration of the two‐photon excitation spectrum of fluorescent dyes at wavelengths below the range of the Ti:Sapphire laser

We have studied the wavelength dependence of the two‐photon excitation efficiency for a number of common UV excitable fluorescent dyes; the nuclear stains DAPI, Hoechst and SYTOX Green, chitin‐ and cellulose‐staining dye Calcofluor White and Alexa Fluor 350, in the visible and near‐infrared wavelength range (540–800 nm). For several of the dyes, we observe a substantial increase in the fluorescence emission intensity for shorter excitation wavelengths than the 680 nm which is the shortest wavelength usually available for two‐photon microscopy. We also find that although the rate of photo‐bleaching increases at shorter wavelengths, it is still possible to acquire many images with higher fluorescence intensity. This is particularly useful for applications where the aim is to image the structure, rather than monitoring changes in emission intensity over extended periods of time. We measure the excitation spectrum when the dyes are used to stain biological specimens to get a more accurate representation of the spectrum of the dye in a cell environment as compared to solution‐based measurements.     

PV-Pilot Plants in Europe - Status of Operation

In 1980, the CEC launched a call for tenders for photovoltaic pilot projects. Since mid 1984, all the relating plants are in operation. In late summer 198S, the WIP has been charged to inspect the PV plants, so as to gather information on the operational status of the systems.

This inspection showed that most of the plants are working satisfactorily. Nevertheless, optimization measures are possible for many installations in the field of power management and conditioning systems, data acquisition and recording, battery management and charge controlling, loads and load matching, software, maintenance and documentation.

So far, the PV modules themselves, the support structures and batteries have shown to be trouble-free components of PV systems.

In order to preserve the potential of the PV plants and make good use of it, the Commission sponsors, in the frame of the current photovoltaic R & D Programme, follow-up activities on the existing installations.     

Characterization of the radical trapping activity of a novel series of cyclic nitrone spin traps

alpha-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury. We have prepared a series of novel cyclic variants of PBN and evaluated them for radical trapping activity in vitro. Specifically, their ability to inhibit iron-induced lipid peroxidation in liposomes was assessed, as well as superoxide anion (O2(-.)) and hydroxyl radical ((.)OH) trapping activity as determined biochemically and using electron spin resonance (ESR) spectroscopy. All cyclic nitrones tested were much more potent as inhibitors of lipid peroxidation than was PBN. The unsubstituted cyclic variant MDL 101,002 was approximately 8-fold more potent than PBN. An analysis of the analogs of MDL 101,002 revealed a direct correlation of activity with lipophilicity. However, lipophilicity does not solely account for the difference between MDL 101,002 and PBN, inasmuch as the calculated octanol/water partition coefficient for MDL 101,002 is 1.01 as compared to 1.23 for PBN. This indicated the cyclic nitrones are inherently more effective radical traps than PBN in a membrane system. The most active compound was a dichloro analog in the seven-membered ring series (MDL 104,342), which had an IC50 of 26 mum, which was 550-fold better than that of PBN. The cyclic nitrones were shown to trap (.)OH with MDL 101,002 being 20 25 times more active than PBN as assessed using 2-deoxyribose and p-nitrosodimethylaniline as substrates, respectively. Trapping of (.)OH by MDL 101,002 was also examined by using ESR spectroscopy. When Fenton's reagent was used, the (.)OH adduct of MDL 101,002 yielded a six-line spectrum with hyperfine coupling constants distinct from that of PBN. Importantly, the half-life of the adduct was nearly 5 min, while that of PBN is less than 1 min at physiologic pH. MDL 101,002 also trapped the O2(-.) radical to yield a six-line spectrum with coupling constants very distinct from that of the (.)OH adduct. In mice, the cyclic nitrones ameliorated the damaging effects of oxidative stress induced by ferrous iron injection into brain tissue. Similar protection was not afforded by the lipid peroxidation inhibitor U74006F, thus implicating radical trapping as a unique feature in the prevention of cell injury. Together, the in vivo activity, the stability of the nitroxide adducts, and the ability to distinguish between trapping of (.)OH and O2(-.) suggest the cyclic nitrones to be ideal reagents for the study of oxidative cell injury.     

Making mistakes when predicting shifts in species range in response to global warming

Many attempts to predict the biotic responses to climate change rely on the 'climate envelope' approach, in which the current distribution of a species is mapped in climate-space and then, if the position of that climate-space changes, the distribution of the species is predicted to shift accordingly. The flaw in this approach is that distributions of species also reflect the influence of interactions with other species, so predictions based on climate envelopes may be very misleading if the interactions between species are altered by climate change. An additional problem is that current distributions may be the result of sources and sinks, in which species appear to thrive in places where they really persist only because individuals disperse into them from elsewhere. Here we use microcosm experiments on simple but realistic assemblages to show how misleading the climate envelope approach can be. We show that dispersal and interactions, which are important elements of population dynamics, must be included in predictions of biotic responses to climate change.     

Absence of normal activation of the left anterior fusiform gyrus during naming in left temporal lobe epilepsy

Patients with left temporal lobe epilepsy (TLE) often have impaired naming. We studied 13 patients with left TLE and 10 healthy control subjects with [(15)O]H2O PET during visual confrontation naming. Statistical mapping detected multiple regions of significant cerebral blood flow increases within individuals. The left fusiform gyrus was activated in nine healthy subjects, but only in two patients with TLE (a significant difference, p < 0.001). Other activation sites were more variable in healthy subjects and those with TLE. Impaired naming ability may be associated with a lack of increased cerebral blood flow in the left fusiform gyrus in TLE.     

Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients

PURPOSE: To determine the value of pretransplant studies in predicting day 100 nonrelapse toxic mortality following high-dose therapy. PATIENTS AND METHODS: A retrospective review of 383 consecutive hematopoietic stem-cell transplants was performed with attention to toxic mortality and pretransplant factors. Univariate log-rank analysis was used to yield the most significant cut-off values for individual factors. Multivariate analysis using Cox proportional hazards regression determined factors independently predictive of early toxic death. RESULTS: Nonrelapse toxic mortality before day 100 occurred in 23 of 383 (6.0%) transplant recipients. Factors associated with an increased risk of toxic death by univariate analysis included forced expiratory volume in 1 second (FEV1) less than 78% of predicted (P = .0002), allogeneic versus autologous transplant (P = .0003), diffusion capacity of carbon monoxide less than 52% of predicted (P = .002), serum creatinine concentration greater than 1.1 mg/dL (P = .003), Eastern Cooperative Oncology Group performance status greater than 0 (P = .006), preparative regimen containing total-body irradiation versus chemotherapy alone (P = .006), marrow versus blood stem cell (P = .01), serum ALT greater than 50 IU/L (P = .02), diagnosis of hematologic disorder versus solid tumor (P = .06), serum bilirubin level greater than 1.1 mg/dL (P = .08), left ventricular ejection fraction (P = .09), and growth factor use (P = .09). In the multivariate model, transplant type (relative risk, 4.2), FEV1 (relative risk, 4.5), performance status (relative risk, 3.7), serum creatinine (relative risk, 3.8), and serum bilirubin (relative risk, 3.7) were found to be independent predictors of early toxic mortality. CONCLUSION: The pretransplant evaluation is a useful tool to identify patients at risk for early toxic mortality following high-dose therapy.     

SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model

In contrast to conventional T cells, natural killer (NK) 1.1+ T cell receptor (TCR)-alpha/beta+ (NK1+T) cells, NK cells, and intestinal intraepithelial lymphocytes (IELs) bearing CD8-alpha/alpha chains constitutively express the interleukin (IL)-2 receptor (R)beta/15Rbeta chain. Recent studies have indicated that IL-2Rbeta/15Rbeta chain is required for the development of these lymphocyte subsets, outlining the importance of IL-15. In this study, we investigated the development of these lymphocyte subsets in interferon regulatory factor 1-deficient (IRF-1-/-) mice. Surprisingly, all of these lymphocyte subsets were severely reduced in IRF-1-/- mice. Within CD8-alpha/alpha+ intestinal IEL subset, TCR-gamma/delta+ cells and TCR-alpha/beta+ cells were equally affected by IRF gene disruption. In contrast to intestinal TCR-gamma/delta+ cells, thymic TCR-gamma/delta+ cells developed normally in IRF-1-/- mice. Northern blot analysis further revealed that the induction of IL-15 messenger RNA was impaired in IRF-1-/- bone marrow cells, and the recovery of these lymphocyte subsets was observed when IRF-1-/- cells were cultured with IL-15 in vitro. These data indicate that IRF-1 regulates IL-15 gene expression, which may control the development of NK1+T cells, NK cells, and CD8-alpha/alpha+ IELs.