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Molecular design based on generative models, such as variational autoencoders (VAEs), has become increasingly popular in recent years due to its efficiency for exploring high-dimensional molecular space to identify molecules with desired properties. While the efficacy of the initial model strongly depends on the training data, the sampling efficiency of the model for suggesting novel molecules with enhanced properties can be further enhanced via latent space optimization (LSO). In this paper, we propose a multi-objective LSO method that can significantly enhance the performance of generative molecular design (GMD). The proposed method adopts an iterative weighted retraining approach, where the respective weights of the molecules in the training data are determined by their Pareto efficiency. We demonstrate that our multi-objective GMD LSO method can significantly improve the performance of GMD for jointly optimizing multiple molecular properties.

The effectiveness of nitrosourea fotemustine in treating malignant melanoma, which is an aggressive tumor of melanocytes, pigmented skin cells, was assessed in 169 afflicted patients. The cancer was disseminated throughout the body, including the brain. Nitrosourea fotemustine was given in a dose of 100 milligrams per square meter of body area by intravenous infusion over a one-hour period, every week for three weeks. This was followed by a rest period of four to five weeks. Therapy was maintained at the same dose every three weeks in patients who responded or were stabilized by initial treatment, until their disease progressed. Of 169 patients treated, 153 were assessed for complete response, as indicated by the elimination of the tumor. Treatment with nitrosourea fotemustine resulted in complete responses in three cases and partial responses in 34 patients, thereby producing a response rate of 24.2 percent. The response rates at specific sites were 25 percent within the brain; 19.2 percent in the viscera (or abdominal region); and 31.8 percent at nonvisceral sites. In most cases, the duration of response was 22 weeks, and the response rate in previously untreated patients was 30.7 percent. The main toxic effects of nitrosourea fotemustine were blood-related, and included leukopenia (an abnormal decrease in white blood cells) and thrombocytopenia (an abnormal decrease in platelets, cells involved in blood clotting). These findings suggest that nitrosourea fotemustine is effective and relatively safe in treating disseminated malignant melanoma. (Consumer Summary produced by Reliance Medical Information, Inc.)

The Chromatin Array technique is developed, to enable the simultaneous measurement of the global chromatin accessibility state at the resolution of single genes. The cell line MCF7 is chosen to demonstrate the utility of the Chromatin Array method.

The inversion of inhomogeneous physical states has great technological importance; for example, active noise reduction relies on the emission of an inverted sound wave that interferes destructively with the noise of the emitter1, and inverting the evolution of a spin system by using a magnetic-field pulse enables magnetic resonance tomography2. In contrast to these examples, inversion of a distribution of ferromagnetic or ferroelectric domains within a material is surprisingly difficult: field poling creates a single-domain state, and piece-by-piece inversion using a scanning tip is impractical. Here we report inversion of entire ferromagnetic and ferroelectric domain patterns in the magnetoelectric material Co3TeO6and the multiferroic material Mn2GeO4, respectively. In these materials, an applied magnetic field reverses the magnetization or polarization, respectively, of each domain, but leaves the domain pattern intact. Landau theory indicates that this type of magnetoelectric inversion is universal across materials that exhibit complex ordering, with one order parameter holding the memory of the domain structure and another setting its overall sign. Domain-pattern inversion is only one example of a previously unnoticed effect in systems such as multiferroics, in which several order parameters are available for combination. Exploring these effects could therefore advance multiferroics towards new levels of functionality. The magnetization or polarization of domain states in multiferroics can be reversed while retaining the overall domain pattern, owing to the inherent versatility in coupling the large number of multiferroic order parameters.

Batteries are considered as one of the key flexibility options for future energy storage systems. However, their production is cost‐ and greenhouse‐gas intensive and efforts are made to decrease their price and carbon footprint. We combine life‐cycle assessment, Monte‐Carlo simulation, and size optimization to determine life‐cycle costs and carbon emissions of different battery technologies in stationary applications, which are then compared by calculating a single score. Cycle life is determined as a key factor for cost and CO2emissions. This is not only due to the required battery replacements but also due to oversizing needed for battery types with low cycle lives to reduce degradation effects. Most Li‐ion but also the NaNiCl batteries show a good performance in all assessed applications whereas lead‐acid batteries fall behind due to low cycle life and low internal efficiency. For redox‐flow batteries, a high dependence on the desired application field is pointed out. Batteries to store and score: Optimization of the battery under dynamic charge–discharge scenarios helps minimizing carbon footprint and overall costs. Most Li‐ion but also NaNiCl batteries show a good performance in all assessed applications whereas lead‐acid batteries fall behind due to low cycle life and low efficiency. For redox‐flow batteries, a high dependence on the application field is given. Cycle lifetime is another determining factor.

SHOCK III, an online digital computer system to assist the physician, nurse and paramedical personnel in monitoring and reporting on critically ill patients, is described. [ABSTRACT FROM AUTHOR]

The increasing proportion of renewable resources in electricity mixes, the decentralization of energy supply and the growing use of electric vehicles demands the challenging development of reliable, cost effective and flexible energy storage technologies. One option are electrochemical energy storage systems with high specific power and high specific energy density. One of the most promising electrochemical energy storage systems is the lithium-ion batteries (LIB) which are customized regarding size, weight, specific energy and specific capacity what makes batteries ready for operation under different conditions such as emerging electric power systems, grid support or electric mobility [1]. Even though the lithium-Ion technology for traction batteries is not yet widely applied, experiments and first use experiences show that it is a promising electric energy storage system for electric mobility. However, the environmental impacts of battery production, use and recycling are not well understood. To gain a better understanding about the ecological properties of LIBs material and energy flow analysis (MEFA) is conducted. The MEFA defines the possible sources and consumers of relevant materials, substances, pollutants and energy flows [2, 3]. The presented study analyses the consumed materials and energy as well as the emitted substances and waste heat of different LIBs. The main focus of the MEFA is on the production phase and includes active and passive components and material such as metal-salts, electrode materials, other functional metals (e.g. current collectors, casing, etc.), plastics (e.g. separator) and electrolytes [4--7] and on energy consumption as well.

Concerns for climate change and declining oil reserves lead to a shift of transportation systems in many industrial countries. However, alternative drive concepts contain to some extent critical raw materials. Since the availability of certain raw materials could be decisive for the success of emerging technologies, concerns are growing about the potential limitation of resources. This brought about a growing attention to the subjects of criticality and resource security of raw materials by science, policy and industry. Four of the resulting surveys are described in terms of their framing of criticality, their indicators for evaluating criticality, and their rankings of potentially critical raw materials. Critical raw materials are used in alternative drive concepts because of their specific properties. The focus of our work lies on batteries for electric vehicles with special attention to lithium-ion batteries being one of the most promising candidates for energy storage there. Lithium-ion batteries use as major cathode materials lithium, manganese and cobalt, all of which are potential critical. A material flow model of the global manganese cycle is developed. It could be identified that there is a lack of relevant data for processes and flows. The lack of data impedes a comprehensive view and therefore no final conclusions could be drawn, which advice the need for further research. Using manganese as an example, it could be illustrated how material flow analysis can contribute to compiling relevant preparatory work that can subsequently serve as a basis for a prospective support of a criticality evaluation and to inform stakeholders and policy makers about the effectiveness of various interventions to reduce the risk or the effects of supply chain disruptions.

ABSTRACTExserohilum rostratumwas the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohiluminfection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E. rostratumretrieved from 19 case patients with meningitis or epidural/spinal abscesses, 6 isolates from contaminated NECC vials, and 7 isolates unrelated to the outbreak. Our analysis indicates that all 28 isolates associated with the outbreak had nearly identical genomes of 33.8 Mb. A total of 8 SNPs were detected among the outbreak genomes, with no more than 2 SNPs separating any 2 of the 28 genomes. The outbreak genomes were separated from the next most closely related control strain by ~136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum.

ABSTRACTMicroorganisms may colonize needleless connectors (NCs) on intravascular catheters, forming biofilms and predisposing patients to catheter-associated infection (CAI). Standard and silver-coated NCs were collected from catheterized intensive care unit patients to characterize biofilm formation using culture-dependent and culture-independent methods and to investigate the associations between NC usage and biofilm characteristics. Viable microorganisms were detected by plate counts from 46% of standard NCs and 59% of silver-coated NCs (P= 0.11). There were no significant associations (P> 0.05, chi-square test) between catheter type, side of catheter placement, number of catheter lumens, site of catheter placement, or NC placement duration and positive NC findings. There was an association (P= 0.04, chi-square test) between infusion type and positive findings for standard NCs. Viable microorganisms exhibiting intracellular esterase activity were detected on >90% of both NC types (P= 0.751), suggesting that a large percentage of organisms were not culturable using the conditions provided in this study. Amplification of the 16S rRNA gene from selected NCs provided a substantially larger number of operational taxonomic units per NC than did plate counts (26 to 43 versus 1 to 4 operational taxonomic units/NC, respectively), suggesting that culture-dependent methods may substantially underestimate microbial diversity on NCs. NC bacterial communities were clustered by patient and venous access type and may reflect the composition of the patient's local microbiome but also may contain organisms from the health care environment. NCs provide a portal of entry for a wide diversity of opportunistic pathogens to colonize the catheter lumen, forming a biofilm and increasing the potential for CAI, highlighting the importance of catheter maintenance practices to reduce microbial contamination.

In recent years, lithium received increasing attention as lithium-ion rechargeable batteries appear to be the most promising candidates for future electric vehicles. Several studies forecast a strong increase in demand most likely brought about with the implementation of lithium-ion batteries in the automotive sector. Thus, the availability of lithium could be an important constraint for this emerging technology. Concerning lithium availability the future developments of supply and demand as well as the recycling potential play major roles. In respect of recycling it has to be distinguished in general between dissipative and non-dissipative applications. As several studies (e.g. 1G. Angerer, F. Marscheider-Weidemann, M. Wendl, M. Wietschel, Raw materials for emerging technologies: the case of lithium, Karlsuhe 2009) predict lithium recycling to play an important role for future lithium availability the recyclability of lithium in different applications has to be analysed for estimating the contribution of lithium recycling to future supply.

The development of new technologies is often connected with the use of non-renewable resources. In recent years a qualitative shift in the demand of bulk metals (e.g. Fe, Al, Cu) to more scarce metals (e.g. Te, Ga, Re) is recognisable. Novel technologies and products rely more and more on very specific metals which are indispensable for their function. Although such metals are generally used in low concentrations in products, the demand has raised significantly due to mass production. Some of them are of high importance due to their strategic relevance to emerging innovative technologies.
Lithium so far has gained relatively little attention, although it fulfills the main criteria of a strategically relevant metal. In recent years, however, recognition of lithium increased as a result of the growing market for lithium-based rechargeable batteries in mobile information/communication consumer products and in electric vehicles. Both areas of demand led to a skyrocketed use of lithium in recent years.
Other technologies in the future like fusion power generation will raise lithium consumption at an accelerated rate. It is therefore necessary to determine the availability of lithium in the medium and long term in order to prevent technology failures and to ensure a more sustainable development. The authors will provide a wellfounded knowledge base, outline the availability of worldwide reserves and resources, and describe the structure of present and future demands for lithium.

Abstract: Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Studies show that anti‐apoptotic and neurotrophic agents are suitable candidates to prevent delayed cell death and/or restore neural function. Here we present the nontoxic immunomodulating compound AS101, which has the ability to induce neurite outgrowth and neural differentiation in PC12 cells. The present study shows that components of the ras signaling pathway are crucial for AS101‐induced PC12 differentiation. These include p21ras and its downstream effectors, c‐raf‐1 and MEK, as well as PI3K. Moreover, these components mediate AS101‐induced upregulation of p21waf, which is obligatory for AS101‐induced PC12 differentiation. Furthermore, nitric oxide plays a significant role in these AS101 activities. Finally, we show that AS101 prevents apoptosis of NGF‐differentiated PC12 cells after NGF withdrawal. Taken together, these results suggest that AS101 induces PC12 cell differentiation and survival by activating the ras‐ERK1/2 and ras‐PI3K signal transduction pathways, as well as inducing NO production. Our findings may be important in understanding the regulation of survival/apoptosis of neurons deprived of neurotropic support. Futhermore the data propose that AS101 may have clinical potential in the treatment of neurodegenerative disorders like Parkinson's disease.

We investigate the influence of the cooling epoch on the formation of galaxies in a cold dark matter dominated universe. Isolated haloes, with circular speeds typical of spiral galaxies, have been selected from a low‐resolution numerical simulation for resimulation at higher resolution. Initial conditions for each halo consist of a high‐resolution region containing dark matter and gas, and a nested hierarchy of particles representing the mass distribution of the original low‐resolution simulation. These initial conditions are evolved with two smoothed particle hydrodynamics (SPH) codes, TREESPHGRAPESPH, so that discrepancies due to differences in evolutionary and star formation algorithms can be analysed. In previous SPH simulations, strong outward transport of angular momentum has led to the formation of disc‐like systems with much smaller angular momenta than observed in real disc galaxies. Here we investigate whether this problem can be circumvented if feedback processes prevent disc formation until late epochs. In some of our models, the gas is evolved adiabatically until a specified redshift zcool, at which point the gas is allowed to cool radiatively and star formation may begin. In other models, cooling is continuous throughout the evolution but suppressed by a factor chosen to allow discs to grow roughly linearly with time. The results of varying the cooling epoch for each of five different haloes are analysed. When cooling and star formation are initiated at redshift zcool= 4, stellar discs are destroyed during merger events and we observe catastrophic transport of angular momentum similar to that seen in previous work. With cooling suppressed until zcool= 1, discs can form by the present day with angular momenta comparable to those of observed disc galaxies. We conclude that feedback processes, which prevent gas from collapsing until late epochs, are an essential ingredient in disc galaxy formation.

Helianthus annuusL. plants were exposed for 2 days (13th–15th days of growth) and 30 days (1st–30th days of growth), respectively, to exhaust gas (discontinuously, mean NOXconcentration 30 ppb) and 03 (90 ppb, 1300–1700h) singly or in combination under controlled conditions in fumigation chambers. Extracellular peroxidase activity increased after 2-day fumigation with exhaust gas, O3and exhaust gas plus O3in cotyledons and after 2-day O3fumigation in primary leaves of 15-day-old sunflowers. In leaves of 15-day-old sunflowers up to nine extracellular peroxidase isoenzymes were detectable. Activities of extracellular cationic and anionic peroxidase isoenzymes in cotyledons of 15-day-old sunflowers were, independent of the fumigation variant, predominantly increased. In primary leaves, extracellular cationic and anionic peroxidase isoenzyme activities altered in different ways depending on the fumigation variant. A 30-day fumigation with exhaust gas, O3and exhaust gas plus O3led to decreased extracellular peroxidase activities in all surveyed leaf fractions.

A 95-kDa protein in Xenopus oocytes, Xp95, was shown to be phosphorylated from the first through the second meiotic divisions during progesterone-induced oocyte maturation. Xp95 was purified and cloned. The Xp95 protein sequence exhibited homology to mouse Rhophilin, budding yeast Bro1, and Aspergillus PalA, all of which are implicated in signal transduction. It also contained three conserved features including seven conserved tyrosines, a phosphorylation consensus sequence for the Src family of tyrosine kinases, and a proline-rich domain near the C terminus that contains multiple SH3 domain-binding motifs. We showed the following: 1) that both Xp95 isolated from Xenopus oocytes and a synthetic peptide containing the Src phosphorylation consensus sequence of Xp95 were phosphorylated in vitro by Src kinase and to a lesser extent by Fyn kinase; 2) Xp95 from Xenopus oocytes or eggs was recognized by an anti-phosphotyrosine antibody, and the relative abundance of tyrosine-phosphorylated Xp95 increased during oocyte maturation; and 3) microinjection of deregulated Src mRNA into Xenopus oocytes increased the abundance of tyrosine-phosphorylated Xp95. These results suggest that Xp95 is an element in a tyrosine kinase signaling pathway that may be involved in progesterone-induced Xenopus oocyte maturation.

Although buffer agents alone have failed to improve the success of resuscitation, we now examine the widely held concept that it is the combined effect of alkaline buffer and adrenergic agents that improves outcomes of cardiopulmonary resuscitation. In the present report, the effects of both CO(2)-consuming and CO(2)-generating buffer agents in combination with adrenergic vasopressor drugs were investigated. Ventricular fibrillation was electrically induced in Sprague-Dawley rats weighing between 450 and 550 g. Precordial compression and mechanical ventilation were initiated after 8 min of untreated ventricular fibrillation. Animals were then randomized to receive bolus injections of either inorganic sodium bicarbonate buffer, organic tromethamine buffer, or saline placebo. The beta(1) adrenergic effects of epinephrine were blocked with esmolol. The vasopressor amine was injected 2 min after injection of the buffer agent. Electrical defibrillation was attempted at the end of 8 min of precordial compression. In 15 additional animals, the sequence of administration of the adrenergic vasopressor and buffer agents was reversed such that the adrenergic vasopressor was injected before the buffer agents. All animals were restored to spontaneous circulation. Both bicarbonate and tromethamine significantly decreased coronary perfusion pressure from 26 to 15 mm Hg and reduced the magnitude of the vasopressor effect of the adrenergic vasopressor. When the vasopressor preceded the buffer, declines in coronary perfusion pressure after administration of buffer agents were prevented. In each instance, however, greater impairment of postresuscitation myocardial function and decreased postresuscitation survival were observed after treatment with buffer agents.

Factors related to oxygen availability and requirements were measured on 51 occasions in 14 patients intoxicated with short-acting barbiturates. Patients had no clinical signs of circulatory shock. The cardiac index was normal (3.4±1.1 l/min/m2) but there was a slight decrease of the mean arterial oxygen content (17.2±3.0 ml/100 ml). Oxygen transport was normal (571±199 ml/min/m2). However, the arteriovenous oxygen differences were decreased (3.4±1.0 ml/100 ml). Oxygen consumption was reduced (110±42 ml/min/m2) and the oxygen extraction ratio (oxygen consumption/oxygen transport) was decreased (0.20±0.05), thus confirming a decreased oxygen utilization. Arterial concentration of lactate was normal. Accordingly the observed decrease in oxygen consumption was related to a reduction in oxygen requirements during barbiturate intoxication rather than due to an imbalance between availability and metabolic requirements for oxygen.

Abstract: A peristaltic pump was designed for either manual or computer-controlled operations; it provides flow rates over a large dynamic range (0·01 to 30 ml/min). Driven by a stepper motor in which the stepping rate is determined manually with digital switches or under remote control, the pump is capable of operating in either direction with negative or positive back pressures, thus overcoming problems of unpredictable resistance to flow in needles and catheters through which the fluid is infused. The clamping effect of the pump rollers on the tubing prevents back flow by creating a pressure at the infusion site slightly higher than the intravascular pressures that are physiologically attainable, thus preventing clotting and microembolisation.

The object of this preliminary study is to evaluate the new techniques of measurement by helical CT which allow direct assessment of the volume of a lesion in clinical practice particularly by obtaining direct macroscopic anatomical correlation. Its primary application is anatomical, with measurement of the volumes of organs or anatomical structures, the clinical importance of which relates primarily to oncology. We present our initial results, including their applications and limits, before extending this study to a larger series so that it may be compared with other multicentre evaluations.

Levels of radiation-induced jejunal crypt cell apoptosis were compared in C57BL 6J, C3Hf Kam and C3H HeJ mice. Apoptosis levels were consistently lower in the C3H strains than in C57BL 6J. Although other explanations are possible, the strain difference is most likely to have a genetic basis, and in fact a preliminary analysis of the F2 progeny of C3H HeJ and C57BL 6J mice indicates that more than one gene is involved. Both C3H strains also had lower levels of radiation-induced thymocyte apoptosis than C57BL 6J mice. Jejunal crypt cell apoptosis levels did not co-segregate with thymocyte apoptosis levels in the F2 progeny of C57BL 6J and C3H HeJ mice. These results imply that the genes responsible for the difference in radiation-induced thymocyte apoptosis levels between these two strains are not the same as those responsible for the strain difference in radiation-induced jejunal crypt cell apoptosis levels. The experiments reported here identify strain-specific differences in levels of radiation-induced crypt cell apoptosis and are a first step towards identifying genetic polymorphisms that influence sensitivity of the small intestine to damage from ionizing radiation.

Seventy-four cases of pure acute monoblastic leukemia (AMol) have been retrospectively studied. All patients were treated at Hospital Saint- Louis between 1970 and 1978. Diagnosis was based on morphological and cytochemical features according to the FAB classification. This type of leukemia occurred at any age and in both sexes, with a high frequency of extramedullary involvements. Hyperleukocytosis was very frequent and was significantly correlated with increased blood and urine levels of lysozyme, with renal failure and hypokalemia, and with coagulation abnormalities. AMol still has a poor prognosis, despite a best remission rate (75%) obtained with rubidazone, since the duration of complete remission was short. Central nervous irradiation prolonged remission and prevented meningeal relapses, while 6 meningeal relapses occurred in the patients not irradiated. The high frequency of the extramedullary relapses, including gum and skin, emphasized the question of persistant blast cell sanctuaries after achievement of bone marrow remissions. A more intensive induction with several drugs active against monoblasts could be more efficient and prolong the duration of complete remissions.

Purpose: We defined the efficacy of radiotherapy for the treatment of high grade (Gleason scores 8 to 10) adenocarcinoma of the prostate. Materials and Methods: A total of 50 patients underwent radiotherapy with curative intent for clinically localized prostate cancer with Gleason scores of 8 to 10 at 1 of 4 facilities affiliated with the University of California San Francisco. Patients were considered to have biochemical failure if they had a significant increase in prostate specific antigen (PSA) of 0.5 ng./ml. per year, an increase in PSA to greater than 1.0 ng./ml. or a positive biopsy. Results: Among the 50 patients median PSA was 22.7 ng./ml. (range 1.3 to 93.4). Tumors were clinical stage T1 or T2 in 46 percent of the cases and stage T3 or T4 in 54 percent. The overall actuarial probability of freedom from biochemical failure at 4 years was 23 percent. In a multivariate analysis including all patients pretreatment PSA was the only predictor of PSA failure, with 64 percent free of progression if the pretreatment PSA was 10 ng./ml. or less compared to only 16 percent at 3 years if PSA was more than 10 ng./ml. (p = 0.01). In a multivariate analysis restricted to patients with PSA less than 20 ng./ml. 83 percent of those treated to more than 71 Gy. were free of progression compared to 0 percent for those treated to less than 71 Gy. (p = 0.03). In a multivariate analysis PSA 10 ng./ml. or less (related risk 11.4, p = 0.02), T stage 1 or 2 (relative risk 3.8, p = 0.05) and radiation dose more than 71 Gy. (relative risk 4.0, p = 0.06) were associated with a favorable outcome. Conclusions: At 4 years the freedom from PSA failure following radiotherapy for high grade prostate cancer was comparable to previously reported surgical series. The high failure rate among patients with PSA greater than 20 ng./ml. suggests that these patients should be considered for investigational approaches. The apparent improvement in freedom from progression with the use of higher doses provides reason for optimism.

The aim of the study was to use a virus-free system to transfer the Herpes Simplex Virus-thymidine kinase (HSV-TK) gene in mice bearing melanoma tumours. B16 Fl murine melanoma cells were injected subcutaneously. On days 11 and 14, an intratumoral injection of either naked plasmid containing the HSV-TK gene (pAG0) or pAG0-lipofectamine complexes was given. Ganciclovir (120 mg/kg/day) was given for 5 days starting on day 14. Tumour weight reduction (40–50%) was observed in treated animals versus different control groups. Moreover, histopathological analysis on tumours showed large areas of cavitary necrosis (85%) in treated groups compared to controls (10%). Using a simple and safe method, the results presented here demonstrated that virus-free mediated delivery of the HSV-TK gene is efficient in vivoin murine malignant melanoma.

We show that mouse sperm die spontaneously within 1-2 days in culture and that treatment with either staurosporine (STS) and cycloheximide (CHX) or a peptide caspase inhibitor does not accelerate or delay the cell death. Chicken erythrocytes, by contrast, are induced to die by either serum deprivation or treatment with STS and CHX, and embryonic erythrocytes are more sensitive than adult erythrocytes to both treatments. Although these erythrocyte deaths display a number of features that are characteristic of apoptosis, they are not blocked, or even delayed, by peptide caspase inhibitors, and most of the cells die without apparently activating caspases. A small proportion of the dying erythrocytes do activate caspase-3, but even these cells, which seem to be the least mature erythrocytes, die just as quickly in the presence of caspase inhibitors. Our findings raise the possibility that both mouse sperm and chicken erythrocytes have a death programme that may not depend on caspases and that chicken erythrocytes lose caspases as they mature. Chicken erythrocytes may provide a useful 'stripped down' cell system to try to identify the protein components of such a death programme, which may serve to back-up the conventional caspase-dependent suicide mechanism in many cell types.

Tachykinin peptides such as substance P (SP) function as neurotransmitters and neuromodulators in the mammalian central and peripheral nervous systems. Here, we provide evidence that they may also play an important role in the morphogenesis of some nonneural organs where epithelial-mesenchymal interactions are involved. We show the following. (1) mRNA encoding tachykinin precursor proteins is expressed transiently in condensing mesenchyme during the development of mouse tooth germ, mammary gland, limb bud, external auditory meatus and genital tubercle. (2) In developing tooth germ and mammary gland; mRNA encoding the neutral endopeptidase (NEP) that degrades secreted tachykinins is spatially and temporally co-expressed with tachykinin precursor mRNA. (3) SP and the mRNA encoding SP receptors are also expressed in the developing tooth germ. (4) Tooth development in explant cultures is blocked both by tachykinin-precursor-specific antisense oligonucleotide and by an SP receptor antagonist: in both cases the block is relieved by exogenous SP. Together, these findings suggest a surprising new role for tachykinins in tooth and mammary gland morphogenesis, and possibly also in limb, ear and external genitalia morphogenesis.

The circular genome of Staphylococcus aureus was cut into two fragments by a simple enzymatic method that cleaves a 10-base-pair site. The recognition sequence, A-T-C-G-mA decreases T-C-G-mA-T, was created by the combined use of the methylase M.Cla I (A-T-C-G-mA-T) and the restriction endonuclease Dpn I (G-mA decreases T-C). This technique is insensitive to CpG methylation and in human DNA is predicted to produce fragments that, on average, are greater than five million base pairs. The ability to create such long pieces of DNA should facilitate mapping of large, complex chromosomes.

A patient with refractory human immunodeficiency virus (HIV)-related immune thrombocytopenic purpura (ITP) was treated with 3G8 (anti-CD16) monoclonal antibody on days 1, 3, and 8 (25, 25, and 50 mg were administered intravenously, respectively). Side effects were those expected after the administration of a xenogenic protein, but a severe bone pain occurred from the second injection. At the time of the initiation of the treatment the platelet count was 20,000/mm3 and the absolute CD4 number was 100/mm3. We obtained a long-term correction of thrombocytopenia and, to a lesser extent, there was a stabilization of CD4 lymphocytes for 18 months. We observed a significant stimulation of natural killer (NK) function and an elevation in the serum level of tumor necrosis factor alpha, interferon gamma, and granulocyte- macrophage colony-stimulating factor. This suggests that in HIV-related ITP the removal of platelets is mediated by low-affinity Fc gamma receptors (CD16). The stimulation of NK function and elevation in CD4+ lymphocytes may be related to the production of cytokines by activated human NK cells through the interaction of their CD16-bearing receptor with the 3G8 monoclonal antibody. This observation warrants confirmation and further clinical trials.

A 13-year-old girl had a reversible frontal syndrome secondary to partial complex seizures. She developed sudden and dramatic behavioral changes including sexual disinhibition, loss of concern for personal hygiene, physical and verbal aggression, and pressured and tangential speech. Although the basic neurologic examination was normal, neuropsychological testing revealed selective impairment on tasks sensitive to frontal dysfunction with relatively normal performance on other tests. This case demonstrates that a frontal syndrome can be caused by partial complex seizures and that behavior comparable to that observed in adults with frontal dysfunction may occur in young adolescents.

All authors contrast the poor prognosis of acute granulocytic leukemias (AGLs) with the progress achieved in acute lymphocytic leukemias (ALLs). However, many advances have already been made in the treatment of this disease: the median survival remains poor with present chemotherapy, but survival has been shown to be directly related to the attainment of a complete remission (CR). The indications for such intensive treatment must be individualized according to the age of the patient and the morphological findings of the leukemia.Cytological classification of AGLs is difficult. The cytology of acute promyelocytic and acute monoblastic leukemias (APLs and AMoLs) is now well characterized, but the term acute myeloblastic leukemia (AML) still includes various cytological variants.We shall deal first with the treatment of AML with an overt maturation arrest (high rate of poorly differentiated cells); then we shall consider the specific problems raised by APL and AMoL and the difficulties

Summary HeLa cells are non-permissive for the neurotropic suckling mouse strain of measles virus (MMV), but are permissive for cell-adapted Edmonston strain of measles virus (Edm). Fluorescence and electron microscopy demonstrated no membrane fluorescence and no membrane associated viral components, as well as characteristic lack of nuclear antigen after MMV infection of HeLa cells. This appearance differs markedly from the membrane, cytoplasmic and nuclear fluorescence after Edm infection of HeLa cells. Fluorescence microscopy demonstrates fusion of the two dissimilar syncytia after mixed infection. This suggests Edm envelopment of MMV nucleocapsids may be the means of MMV rescue in this system.

Abstract: A vascular interface system has been designed to relieve the bedside staff in the critical-care environment of time-consuming and unreliable manual operations. The system has made it possible to link a computer-based data acquisition system directly to the patient and provides for automatic haemodynamic monitoring and therapy. The vascular interface system provides access to the patient's vascular sites primarily through pneumatically operated valve assemblies which are biologically (blood) compatible. All connections between catheter and measuring instruments are short, transparent tubes which are easily visible for observation. Operation of the system is simplified through the use of push-button controls with each control assigned a specific procedure (e.g. pressure monitoring, catheter flush and cardiac output). Special safety features built into the system, such as manual override of valve control, ensure continuing operation despite power failure. The existence of the vascular interface system now allows the distribution of blood to a variety of online satellite systems at the bedside. The use of automated equipment frees vital personnel from time-consuming procedures and allows them to return to the real task of observation and patient care.

The features and prognosis of Hodgkin's disease with bone marrow involvement were studied in a series of 53 patients. This form of the disease is characterized by the high incidence of clinical and biological signs reflecting disease activity, common cytopenia (which is rare in other forms), an increased incidence of the lymphocyte depletion histologic type, and extensive lymphoid involvement, often with splenomegaly. In bone marrow biopsy specimens, Sternberg-Reed cells are found in 80% of cases and fibrosis is common, though it always disappears if remission is achieved.

The anthracyclines, of which daunorubin (DNR), rubidazone (RBD), and adriamycin (ADR) are the most commonly used in cancer chemotherapy, belong to the group of intercalating agents capable of inhibiting the replication and transcription of DNA, and of fragmenting DNA and inhibiting the mitochondrial respiratory chain. Their experimental antitumoral activity varies according to the product, the type of tumor, and the route of administration. Following intravenous (IV) injection, they are distributed throughout all body tissues except those of the central nervous system and are metabolized principally in the liver, 90% of the metabolites being excreted in the bile. Excretion is slow, permitting intermittent high-dose therapy. Their principal toxicity is cardiac, presenting as congestive cardiac failure, which occurs when a specific cumulative dose of anthracycline is exceeded. This effect may be due to the formation of free semiquinone radicals from the anthracycline nucleus by the capture of electrons from the mitochondrial respiratory chain.