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SUMMARYThe Middle East respiratory syndrome coronavirus (MERS-CoV) is caused by a novel coronavirus discovered in 2012. Since then, 1806 cases, including 564 deaths, have been reported by the Kingdom of Saudi Arabia (KSA) and affected countries as of 1 June 2016. Previous literature attributed increases in MERS-CoV transmission to camel breeding season as camels are likely the reservoir for the virus. However, this literature review and subsequent analysis indicate a lack of seasonality. A retrospective, epidemiological cluster analysis was conducted to investigate increases in MERS-CoV transmission and reports of household and nosocomial clusters. Cases were verified and associations between cases were substantiated through an extensive literature review and the Armed Forces Health Surveillance Branch's Tiered Source Classification System. A total of 51 clusters were identified, primarily nosocomial (80·4%) and most occurred in KSA (45·1%). Clusters corresponded temporally with the majority of periods of greatest incidence, suggesting a strong correlation between nosocomial transmission and notable increases in cases.

The processes operating within a rock weathering system may be described qualitatively in the form of an interaction matrix, comprising those factors which are considered significant in the system and the mechanisms operating between them. A method of assigning site-specific values to the significant factors is developed, enabling a quantitative analysis of the effects of weathering on the rock mass. Applying an integer code to the interactions enables the individual factors9 influence within the system to be assessed. An index for weathering may be derived from this analysis and used, in conjunction with an index for engineering geological properties, to characterize and zone a weathered rock mass.

The results of applying chloroform and KCl to Nitella indicate that a negative variation may be started whenever it is possible to set up along the protoplasm a gradient of potential difference sufficiently steep to produce the necessary outward flow of current. Successive variations may thus be set up.

Cells of Nitella have been studied which behave differently from those described in earlier papers. They show unexpectedly large changes in P.D. with certain concentrations of KCl. This is due to the production of action currents (these are recorded at the spot where KCl is applied). A method is given for the separate evaluation of changes of P.D. due to partition coefficients and those due to mobilities. A new amplifier and an improved flowing contact are described.

In Nitella the substitution of KCl for NaCl changes the P.D. in a negative direction. In some cases this change is lessened by adding solid CaCl(2) to the solution of KCl. This may be due to lessening the partition coefficient of KCl or to decreasing the solubility of an organic substance which sensitizes the cell to the action of KCl. Little or no correlation exists between this effect of calcium and its ordinary antagonistic action in producing a balanced solution which preserves the life of the cell indefinitely. CaCl(2) is negative to NaCl but positive to KCl. The effects of mixtures of KCl, NaCl, and CaCl(2) are discussed. The concentration effect of a mixture of KCl + CaCl(2) shows certain peculiarities due to action currents: these resemble those found with pure KCl. These studies and others on Nitella, Valonia, and Halicystis indicate that mobilities and partition coefficients are variable and can be brought under experimental control.

Treatment of Nitella with distilled water apparently removes from the cell something which is responsible for the normal irritability and the potassium effect, (i.e. the large P.D. between a spot in contact with 0.01 M KCl and one in contact with 0.01 M NaCl). Presumably this substance (called R) is partially removed from the protoplasm by the distilled water. When this has happened a pinch which forces sap out into the protoplasm can restore its normal behavior. The treatment with distilled water which removes the potassium effect from the outer protoplasmic surface does not seem to affect the inner protoplasmic surface in the same way since the latter retains the outwardly directed potential which is apparently due to the potassium in the sap. But the inner surface appears to be affected in such fashion as to prevent the increase in its permeability which is necessary for the production of an action current. The pinch restores its normal behavior, presumably by forcing R from the sap into the protoplasm.

Not only does distilled water take away the irritability of Nitella but it also changes its behavior toward potassium. In normal cells potassium is strongly negative to sodium but after sufficient exposure to distilled water this effect disappears. It can be restored by returning the cells to their normal environment or to a suitable nutrient solution. This change in the protoplasm seems to be chiefly in its outer surface.

Cutting a cell of Nitella sets up a series of rapid electrical responses, transmitted at a rate too rapid to be measured by means of our records. These are followed by slower responses whose speed falls off as the distance from the cut increases, as though they were caused by a mechanical disturbance whose intensity falls off as it travels. The faster responses seem to be due to the motion of sap past protoplasmic surfaces which have suffered little or no alteration (they seem to be similar to the electrical changes following a blow on the end of a soft rubber tube containing Ag-AgCl electrodes). The slower responses appear to be due to alterations in the protoplasm and are usually irreversible.

Suitable concentrations of ethyl alcohol (1 to 1.5 M) applied to a spot on a cell of Nitella lower the P.D. enough to cause action currents. The alcohol then suppresses action currents arriving from other parts of the cell and acts as a block. After the alcohol is removed the normal P.D. and irritability return. Similar experiments on the sciatic nerve and skin of the frog produced only a negative result.

The action curve involves four movements each of which shows considerable variation. These variations can be accounted for on the assumption that the action curve is due to the movement of potassium ions accompanied by an increase in permeability.

Several forms of the action curve are described which might be accounted for on the ground that the outer protoplasmic surface shows no rapid electrical change. This may be due to the fact that the longitudinal flow of the outgoing current of action is in the protoplasm instead of in the cellulose wall. Hence the action curve has a short period with a single peak which does not reach zero. On this basis we can estimate the P.D. across the inner and outer protoplasmic surfaces separately. These P.D.'s can vary independently. In many cases there are successive action currents with incomplete recovery (with an increase or decrease or no change of magnitude). Some of the records resemble those obtained with nerve (including bursts of action currents and after-positivity).

It is shown that disappearance of the light of luminous bacteria may be used as a criterion of cell penetration; that luminous bacteria are cytolyzed by water, hypotonic solutions, and by freely penetrating solutions; that luminous bacteria are not injured by hydrogen or hydroxyl ions in the external solutions within the range of pH values employed with the ammonium salts and that therefore disappearance of the light in isotonic solutions of these salts must be due to penetration of the solute; and that there is a characteristic difference between the effects of strong and of weak acids and alkalies on luminous bacteria.

Health facilities in The Gambia, West Africa.Oxygen treatment is vital in pneumonia, the leading cause of death in children globally. There are shortages of oxygen in developing countries, but little information is available on the extent of the problem. We assessed national oxygen availability and use in The Gambia, a sub-Saharan African country.A government-led team visited 12 health facilities in The Gambia. A modified World Health Organization assessment tool was used to determine oxygen requirements, current provision and capacity to support effective oxygen use.Eleven of the 12 facilities managed severe pneumonia. Oxygen was reliable in three facilities. Requirement and supply were often mismatched. Both oxygen concentrators and oxygen cylinders were used. Suboptimal electricity and maintenance made using concentrators difficult, while logistical problems and cost hampered cylinder use. Children were usually triaged by trained nurses who reported lack of training in oxygen use. Oxygen was given typically by nasal prongs; pulse oximetry was available in two facilities.National data showed that oxygen availability did not meet needs in most Gambian health facilities. Remedial options must be carefully assessed for real costs, reliability and site-by-site usability. Training is needed to support oxygen use and equipment maintenance.

The development of a Lennard - Jones polymer - polymer interaction model is described, appropriate for monolayer polymer coatings on spherical solid particles suspended in a polymer fluid. This model is appropriate for polymer - coated particles interacting at very close proximity (Angstroms). The Lennard - Jones potential, determined from abinitio calculations for polyoxymethylene - polyoxymethylene interactions is added to a Stokesian Dynamics computational model in order to estimate the effect of a polymer coating on the behavior of suspended particles under sheared conditions. The relation between suspension microstructure, viscosity and their time evolution are studied in molecular dynamics - like simulations.

In an effort to develop agents that enhance the oxygen-delivery capability of blood without the risks associated with allogeneic blood transfusions, several products are undergoing development and clinical trials. These oxygen transport agents can be divided into two main groups, perfluorocarbon (PFC) emulsions and modified hemoglobin solutions.Articles from the literature on the development and clinical trials of oxygen therapeutic agents were reviewed.PFCs are synthetic fluorinated hydrocarbons that increase dissolved oxygen in the fluid phase of the blood without binding the oxygen molecule. They enhance oxygen delivery significantly and may be used to augment the technique of intraoperative autologous donation. Two PFC products have been tested in Phase III clinical trials. Hemoglobin-based oxygen carriers (HBOCs) are either cross-linked or microencapsulated hemoglobin molecules. Modification of the human hemoglobin molecule with intra- and inter-molecular cross-linking eliminates renal toxicity and improves the oxygen dissociation characteristics of the molecule. These modifications are necessary because stroma-free hemoglobin (Hb) does not release oxygen in the physiologic range and dissociates into dimers which can be rapidly filtered by the kidney, leading to renal toxicity. In addition to human Hb, bovine hemoglobin is another source of raw material for HBOC products. Recombinant human Hb has also been produced, using an E. coli expression system, for HBOC manufacturing. Four cross-linked hemoglobin products have been tested in Phase III clinical trials.While no product has yet been approved for clinical use, preliminary studies with oxygen therapeutics show promising results, with effective oxygen carrying capacity and acceptable side effect profiles. In the future, the formation of a hybrid product which combines the best features from several of the products currently undergoing development may yield the ideal oxygen therapeutic agent.

Fatty acid (FA) composition and cholesterol (CHL) content from control and Ractopamine (Rac) treated pigs were evaluated. Lipids were extracted from the longissimus (LD) and subcutaneous fat (SC) and methyl esters of the FA were formed for gas chromatography. CHL content of the LD was determined using direct saponification. Pigs were fed 0, 5, 10 or 20 ppm Rac for about 40 kg of grain prior to slaughter. Rac had no consistent effect on the FA composition of SC or muscle (neutral or polar) lipids. CHL content in the LD of treated animals was about 9% lower (P < 0.01) than controls. Rac reduced the CHL content of the LD and had limited effect on the FA profile of muscle or SC fat.

Molecular flexibility is a factor that is not extensively studied in most pharmaceutical research efforts. When it is, the level of effort is high involving the preparation of detailed models supported by either molecular dynamics simulations and/or Nuclear Magnetic Resonance data. While these studies are both powerful and illuminating, they cannot be routinely applied in a drug discovery setting as they are time and expertise intensive. Yet there seems to be little doubt that at least in some cases, molecular flexibility plays a key role in complex formation. A simple, rapid and generally applicable flexibility profiling protocol was applied to two model systems and data describing the internal mobility of carbon atoms were obtained. The protocol utilizes the Model Free approach and NMR data to characterize the internal molecular dynamics of these compounds. The first model system consisted of fluorene and diphenylmethane where the anticipated flexibility trends were observed in the data providing a link between chemical intuition and the experimental results. Data on a second model system, which consisted of two Paclitaxel analogs, showed predictable patterns including dynamical phenyl and methyl groups and a relatively immobile taxane core. Subtle differences in the internal dynamics within the taxane core suggest that it cannot be considered as a rigid structure. Key advantages of using this approach are that no prior knowledge or supposition of dynamical features is required, the protocol can be carried out in most medicinal chemistry laboratories and the data obtained provide a common, empirically derived reference point to discuss the effects of molecular flexibility on activity.

Extended abstract of a paper presented at Microscopy and Microanalysis 2008 in Albuquerque, New Mexico, USA, August 3 – August 7, 2008

A new method for studying cellular uptake has been developed. This method is based on selected reaction monitoring liquid chromatography tandem mass spectrometry analysis of preparations from cell culture. The limit of detection for paclitaxel was approximately 0.1 microM intracellular concentration. This method has been utilized to study the uptake of paclitaxel and an analog (BMS-190616) in normal and multidrug resistant (MDR) cell lines. Paclitaxel and the analog, that had been noted to overcome MDR in animal models, were incubated with normal cells (HCT116) and MDR cells (HCT116(VM)46) at therapeutic concentrations. Intracellular drug concentrations were assayed at intervals from 0 to 1.0 h. Results show that paclitaxel accumulates to a level 12 times greater and BMS-190616 to a level 5 times greater in the normal cells as compared to MDR cells suggesting that paclitaxel is more sensitive to MDR than the analog. Furthermore, the steady state level of BMS-190616 was 4 fold greater than paclitaxel in the MDR cell line suggesting that at least part of this compound's increased therapeutic effect can be attributed to processes of uptake and efflux at the cellular level. These data show that the method is rapid, sensitive and presents a unique advantage over traditional radioisotopic methods in that it can readily be employed on a range of analogs without any additional synthetic effort.

A positive association between agonist-stimulated cyclic AMP production in vitro and both experimentally induced (B16 melanoma) and spontaneous (fibrosarcoma) metastases were found. Five B16 melanoma cell lines producing varying degrees of lung colonization following intravenous injection and three hamster fibrosarcoma cell lines producing a varying number of metastases in lungs and regional lymph nodes after removal of the primary tumour were studied. Agonist-stimulated (forskolin and melanocyte-stimulating hormone), but not basal cyclic AMP accumulation, increased with increasing metastatic potential. This relationship did not extend to other intracellular signalling systems as determined by investigation of basal or foetal-calf stimulated phosphatidylinositol hydrolysis for either tumour type. Intracellular free calcium was also similar in B16 melanoma cell lines of varying metastatic potential.

The nature of the relationship between agonist-stimulated cyclic AMP production and metastatic potential was examined in detail for four B16 melanoma cell lines of varying metastatic potential. Highly metastatic cells (B16 F10C1) appeared to differ from cells of low metastatic potential (B16 F1C29) in the degree to which cyclic AMP production in intact cells was stimulated by protein kinase C activation. No significant difference was found in the adenylate cyclase enzyme activities of the broken cells, irrespective of the agonist used, or in the distribution of cyclic AMP between the intracellular and extracellular compartment. Although B16 F1, F10 and F10C1 cells all produced equally pigmented tumors in vivo, the cells differed in their melanogenic response to cyclic AMP elevating agents in vitro: the least metastatic cells produced least agonist-induced cyclic AMP but this induced greatest tyrosinase activation and melanin production in vitro; conversely, the more metastatic cells produced more cyclic AMP but less tyrosinase activation and melanin production in response to agonist stimulation. Thus, agonist-stimulated cyclic AMP production does not appear to be coupled to the differentiated function of melanogenesis for highly metastatic B16 melanoma cells.

The development of a Lennard-Jones-type polymer-polymer interaction model is described, appropriate for monolayer polymer coatings on spherical solid particles suspended in a polymer fluid. This model is appropriate for polymer-coated particles interacting at very close proximity (angstroms). These molecular forces, derived from ab initio calculations for polyoxymethylene-polyoxymethylene interactions are added to the hydrodynamic forces of a Stokesian dynamics simulation in order to estimate the effect of a polymer coating on the behavior of suspended particles under sheared conditions. The relation between suspension microstructure, shear velocity, and their time evolution are studied in molecular-dynamics-like simulations.

The accumulator technique was used to measure radon and thoron flux density at a variety of locations throughout Australia. This is the first such systematic study of Australia and, in the case of thoron, one of few such studies of any large land mass. Seasonally adjusted arithmetic mean flux densities from Australian soils were estimated to be 22 mBq m−2 s−1 (1.05 atom cm−2 s−1) for radon and 1.7 Bq m−2 s−1 (0.0135 atom cm−2 s−1) for thoron. Consideration of statistical sampling error, and systematic error with the accumulator method, leads to an error estimate of about ±20% for these numbers; projection of total flux to the atmosphere requires consideration of additional sources of error. Only modest correlations with variables easily measured in the field were observed. The strongest correlation was a positive one between flux density and gamma dose rate 1 m above ground. Weaker correlations were seen with soil temperature (positive) and soil moisture (negative at higher moistures). Radon and thoron flux density were strongly correlated, but only a weak correlation (negative) existed between them and vegetation. The amount of radon isotope released to the pore space seems particularly important for controlling the wide variation in observed flux densities, but it remains difficult to predict flux densities based on simple field measurements or information in conventional soil and geological maps.

Tobacco (Nicotiana tabacum cv White Burley) pollen contains high levels of 1-aminocyclopropane-1-carboxylic acid (ACC; ∼2700 nmol/g). Such large amounts, however, do not appear until very late in the development of the anthers. Washing pollen in Kwacks medium (10% sucrose) removes nearly 40% of the pollen-held ACC. Pollination of isolated styles with washed pollen results in lower ethylene production than that of styles pollinated with unwashed pollen. No reduction in viability of washed pollen was observed in situ, although loss of viability occurred in vitro. Physical wounding of the stylar tissue induced a relatively small increase in ethylene production when compared to that induced by pollination. The results suggest that pollen-held ACC may participate in pollination-induced ethylene production in this species; however, further promotion of ethylene biosynthesis must occur in response to some other factor associated with pollination.

Cultured fibroblasts and phytohaemagglutinin-stimulated lymphocytes from a patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria produced much less proline, glutamate, aspartate and carbon dioxide from exogenous 14C-labelled ornithine than did corresponding cells from control subjects.

Cells of Nitella flexilis Ag. lose their power to respond to ordinary electrical stimulation after 2 or 3 days in distilled water. It returns after a day or so when they are replaced in their normal environment, in a suitable nutrient solution, or in a dilute solution of CaCl2. Here anesthesia seems to be produced by removing something from the cell and this raises the question whether other cases of anesthesia may be explained in the same way. The antagonistic action of calcium, in some cases at least, appears to depend on its power to prevent substances from leaching out of the cell.

Several forms of the action curve are described which might be accounted for on the ground that the outer protoplasmic surface shows no rapid electrical change. This may be due to the fact that the longitudinal flow of the outgoing current of action is in the protoplasm instead of in the cellulose wall. Hence the action curve has a short period with a single peak which does not reach zero. On this basis we can estimate the P.D. across the inner and outer protoplasmic surfaces separately. These P.D.'s can vary independently. In many cases there are successive action currents with incomplete recovery (with an increase or decrease or no change of magnitude). Some of the records resemble those obtained with nerve (including bursts of action currents and after-positivity).

The reversible electrical variations hitherto described for plants and animals consist in a reversible loss of positive potential at a stimulated spot by which it becomes more negative. In this paper we describe changes which consist in a reversible loss of negative potential at a stimulated spot whereby it becomes more positive. We suggest that this be called a positive variation. The stimulation was produced in all cases by pinching or bending the cell. This produced a compression wave which traveled along the cell, producing a negative variation at a spot which was positive and a positive variation at a spot which was negative (due to application of 0.1 M KCl). The response produced by the compression wave differs in several respects from an ordinary propagated negative variation and may be termed a positive mechanical variation.

The action of distilled water in producing anesthesia (loss of response to electrical stimulation) in Nitella is hastened by the addition of acid and alkali and retarded by the addition of calcium. The loss of irritability is fully reversible.

Cutting a cell of Nitella sets up a series of rapid electrical responses, transmitted at a rate too rapid to be measured by means of our records. These are followed by slower responses whose speed falls off as the distance from the cut increases, as though they were caused by a mechanical disturbance whose intensity falls off as it travels. The faster responses seem to be due to the motion of sap past protoplasmic surfaces which have suffered little or no alteration (they seem to be similar to the electrical changes following a blow on the end of a soft rubber tube containing Ag-AgCl electrodes). The slower responses appear to be due to alterations in the protoplasm and are usually irreversible.

Sudden local chilling causes action currents to be set up in Nitella and in Chara, an effect which does not follow gradual local chilling. This may be due to a partial solidification of the non-aqueous protoplasmic surfaces which makes them susceptible to rupture by the protoplasmic streaming. This movement continues usually for several minutes after the chilling, whereas if stimulation occurs at all it occurs immediately on chilling. It is found that a chilled spot is much more sensitive to mechanical stimulation than is a spot at room temperature. Chilling is accompanied by a rise of resistance, a lowered rate of recovery following stimulation, and usually by a falling off in the magnitude of the action curve.

Treatment with distilled water removes from Nitella the ability to give the large potential difference between 0.01 M KCl and 0.01 M NaCl which is known as the potassium effect. The potassium effect may be restored by action currents. This might be explained by saying that distilled water removes from the surface a substance, R, which is responsible for the potassium effect and which moves into the surface during the action current and thereby restores the potassium effect.

In normal cells of Nitella replacement of NaCl by KCl makes the P.D. much less positive: this is called the potassium effect. Cells which have lost the potassium effect usually show little or no change of P.D. when NaCl is replaced by KCl but an occasional cell responds after a delay. It seems possible that the delay may be largely due to the time required for potassium to combine with an organic substance, thus forming a compound which sensitizes the protoplasmic surface to the action of potassium.

Mechanical stimulation of Nitella often produces responses resembling propagated negative variations but traveling faster and going past a killed spot. They appear to result from a mechanical disturbance traveling along the cell and stimulating each spot it touches (i.e. the stimulus itself travels). They are called mechanical variations to distinguish them from propagated negative variations. A mechanical disturbance may cause an irreversible change (death wave), but in traveling along the cell it may lose intensity and then produce only a reversible response (mechanical variation) which may eventually change to a propagated negative variation. The all or none law does not apply to incomplete mechanical variations, for the response varies with the strength of the stimulus.

A negative variation in Nitella is unable to pass a spot killed by chloroform but can set up a negative variation beyond this spot when a salt bridge is put around it. It can likewise set up a negative variation in a cell of another plant if connected to it by two salt bridges.

The action curve in Chara seems to depend (as in Nitella) on the outward movement of K+ from the sap. Presumably the increase in permeability in the inner protoplasmic surface and the outward movement of K+ destroy the concentration gradient of K+ across the inner protoplasmic surface. Hence the outwardly directed P.D. disappears, causing the rise (spike) of the action curve. The outer protoplasmic surface is normally insensitive to K+. But when it is made sensitive to K+ by treatment with guanidine the outwardly moving K+ sets up a positive P.D. on reaching the outer surface and this causes the action curve to fall, producing a peak. Then the curve has 2 peaks, the second being due to the process of recovery. The action curve thus comes to resemble that of Nitella in which the outer protoplasmic surface is normally sensitive to K+.

Many forms of irregular rhythm and of partial block occurring in the vertebrate heart can be duplicated in Nitella. In order to observe these phenomena the cells of Nitella are kept for 6 weeks or more in a nutrient solution. They are then exposed for 3 hours or less to 0.01 M NaCl, NaSCN, or guanidine chloride, which reduce the time required for the action current to about 1 second (the normal time is 15 to 30 seconds). A pacemaker is established at one end of the cell by placing it in contact with 0.01 M KCl. This produces action currents at the rate of about 1 a second. Apparently some parts of the cell are unable to follow this rapid pace and hence fall into irregular rhythms (arrhythmia) and fail to register all the impulses (partial block).

During periods of O2 lack in liver of seals, mitochondrial respiration and adenosine triphosphate (ATP) synthesis are necessarily arrested. During such electron transfer system (ETS) arrest, the mitochondria are suspended in functionally protected states; upon resupplying O2 and adenosine diphosphate (ADP), coupled respiration and ATP synthesis can resume immediately, implying that mitochondrial electrochemical potentials required for ATP synthesis are preserved during ischemia. A similar situation occurs in the rest of the cell since ion gradients also seem to be maintained across the plasma membrane; with ion-specific channels seemingly relatively inactive, ion fluxes (e.g., K+ efflux and Ca++ influx) can be reduced, consequently reducing ATP expenditure for ion pumping. The need for making up energy shortfalls caused by ETS arrest is thus minimized, which is why anaerobic glycolysis can be held in low activity states (anaerobic ATP turnover rates being reduced in ischemia to less than 1/100 of typical normoxic rates in mammalian liver and to about 1/10 the rates expected during liver hypoperfusion in prolonged diving). As in many ectotherms, an interesting parallelism (channel arrest coupled with a proportionate metabolic arrest at the level of both glycolysis and the ETS) appears as the dominant hypoxia defense strategy in a hypoxia-tolerant mammalian organ.

SummaryPlasma and erythrocyte lithium levels have been determined repeatedly in twelve patients taking lithium carbonate for affective disorders. In any individual the plot of the plasma lithium level against erythrocyte/plasma ratio is linear, but the ratio can either increase or decrease with increasing plasma lithium concentration. Erythrocyte/plasma ratio is an unsound basis for comparing individual responses to lithium.