Assessing the impact of coordinated COVID-19 exit strategies across Europe.

As rates of new coronavirus disease 2019 (COVID-19) cases decline across Europe owing to nonpharmaceutical interventions such as social distancing policies and lockdown measures, countries require guidance on how to ease restrictions while minimizing the risk of resurgent outbreaks. We use mobility and case data to quantify how coordinated exit strategies could delay continental resurgence and limit community transmission of COVID-19. We find that a resurgent continental epidemic could occur as many as 5 weeks earlier when well-connected countries with stringent existing interventions end their interventions prematurely. Further, we find that appropriate coordination can greatly improve the likelihood of eliminating community transmission throughout Europe. In particular, synchronizing intermittent lockdowns across Europe means that half as many lockdown periods would be required to end continent-wide community transmission.

Factors at scene and in transfer related to the development of hypothermia in major burns.

There is a paucity of evidence regarding incidence and causes of hypothermia in patients with major burns and its impact on outcomes. This paper identifies contributing factors to hypothermia and its relationship with the severity of physiological scoring systems on admission to a tertiary centre. Patients with burns >20% TBSA admitted between March 2010 and July 2013 comprised this retrospective survey. Data relating to causative factors at time of burn, during transfer, physiological outcome scores (BOBI, SOFA, RTS and APACHE II), length of hospital stay and mortality were collected. SPSS statistical software was used for analysis. The study included 31 patients (medians: age 32 years, burn size 30% TBSA). 13% (n=4) of patients died during hospital admission. 42% (n=13) of patients had a temperature <36.0C on arrival. Temperature on arrival at the burns centre was related to the severity of all physiological scores (p=<0.001). There was no difference between groups in terms of mortality in hospital (p=0.151) or length of hospital stay (p=0.547). Our results show that hypothermia is related to burn severity and patient physiological status. They do not show a relationship between hypothermia and external factors at the time of the burn. This paper prompts further investigation into the prevention of hypothermia in patients with major burns.

Il n'existe que peu de données sur l'incidence et les causes de survenue d'une hypothermie chez les brûlés, ni de son incidence sur le devenir. Cette étude répertorie les facteurs contribuant à l'hypothermie à l'admission dans un centre de référence et sa relation avec les scores de gravité initiaux. Cette étude rétrospective a concerné les patients brûlés sur plus de 20% de SCT admis entre mars 2010 et juillet 2013. Les données concernant les causes d'hypothermie au moment de la brûlure et pendant le transfert, les scores de gravité (BOBI, SOFA, RTS et APACHE II), la durée de séjour et la mortalité ont été relevées. Trente et un dossiers ont été étudiés (âge médian 32 ans, surface brûlée 30%). Quatre (13%) d'ente eux décédés. Treize (42%) avait une température <36°C à l'admission et il existait une corrélation entre la température et les scores de gravité (p<0.001). Il n'y avait pas de différence en termes de mortalité ni de durée de séjour. Cette étude montre que l'hypothermie est corrélée à la gravité de la brûlure et à la gravité générale des patients. On ne retrouve pas de relation entre les facteurs environnementaux au moment de la brûlure et l'hypothermie. Des données supplémentaires sont nécessaires pour la prévention de l'hypothermie liée à la brûlure.

Use of the glucosidase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol as a probe to investigate hypertrehalosemic hormone-mediated change in carbohydrate and lipid metabolism in the cockroach, Periplaneta americana.

The glucosidase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DIA) was used to investigate the action of hypertrehalosemic hormone (HTH) on carbohydrate, neutral lipid, and phospholipid metabolism in the hemolymph and fat body of the cockroach, Periplaneta americana. DIA blocked the hypertrehalosemic and hyperglycemic effects of HTH, as well as the decrease in hemolymph neutral lipid and phospholipid normally induced by HTH. DIA diminished the accumulation of neutral lipid in the fat body formed under the influence of HTH and partly blocked the decrease in fat body phospholipid evoked by HTH. The increased incorporation of (14)C-glucose into fat body triacylglycerol in the presence of HTH was decreased by more than two-thirds when DIA was coinjected with the hormone. The results suggest that glucose derived from hemolymph trehalose is an important contributor to the formation of the glycerol backbone of newly formed triacylglycerol in the fat body.

Control of phospholipase A(2) activity in cockroach (Periplaneta americana) fat body trophocytes by hypertrehalosemic hormone: the role of calcium.

Recently, synthetic HTH-I and HTH-II have been shown to increase the formation of free fatty acids in cockroach (Periplaneta americana) fat body. In this study we show that HTH-II increases PLA(2) activity in dispersed trophocytes, thus implying that phospholipid is a potential source of the fatty acids. The increase in HTH-induced PLA(2) activity is triggered by an increase in [Ca(2+)](i) but extracellular Ca(2+) is also required for a maximal Ca(2+) signal: an effect that can be blocked by the introduction of BAPTA into the trophocytes. Treating trophocytes with ryanodine blocks the increase in PLA(2) activity that follows treatment of the cells with HTH-II. This indicates that the Ca(2+) release channels are distinct from those that respond to inositol trisphosphate. Thapsigargin, which releases Ca(2+) to the cytosol from an intracellular store, increases PLA(2) activity. The data show that the enzyme is translocated from the cytosol to the plasma membrane.

Stimulation of trehalose efflux from cockroach (Periplaneta americana) fat body by hypertrehalosemic hormone is dependent on protein kinase C and calmodulin.

Protein kinase C and calmodulin play key roles in cockroach fat body during activation of phosphorylase and trehalose efflux by HTH-II. The data support the view that an increase in cytosolic Ca2+ is prerequisite for enhanced activity of protein kinase C and calmodulin. Chelation of Ca2+ (i) with BAPTA blocks HTH-II-induced trehalose efflux from the fat body whereas thapsigargin, which raises [Ca2+]i to the same level as HTH-II, produces only a small, yet significant increase in trehalose efflux. Sphingosine, an inhibitor of protein kinase C, inhibits HTH-II-induced trehalose efflux in a concentration-dependent manner. Trehalose efflux is not activated by the protein kinase C activators OAG or PMA alone but in the presence of thapsigargin both agents increase trehalose efflux to a level comparable to that obtained with HTH-II. Thapsigargin has only a moderate activating effect on phosphorylase but in combination with OAG produces an activation indistinguishable from that provoked by HTH-II. Each of the structurally different calmodulin inhibitors, trifluoperazine, W-7, and calmidazolium, blocks completely the action of HTH-II on trehalose efflux, thus confirming the importance of calmodulin in HTH-II initiated trehalose efflux.

Characterization of cockroach (Periplaneta americana) fat body phospholipase A(2) activity.

A phospholipase has been identified in the fat body of the American cockroach, Periplaneta americana, which removes fatty acid from the sn-2 acyl position of an artificial substrate. The enzyme has been characterized using a crude preparation obtained by low-speed centrifugation of the homogenized tissue. With 1-hexadecanoyl-2-(1-pyrenedecanoyl)-sn-glycero-3-phosphocholine as the substrate, the K(m) has been estimated to be 1.17 microM and the v(max) 113.5 pmol/min/mg protein. The phospholipase has a pH optimum close to 7 and shows maximal activity at 50 degrees C. Activity of the phospholipase has been determined in cytosolic and plasma membrane fractions. The specific activity of the latter fraction is approximately twice that of the cytosol. The enzyme in both fractions is Ca(2+)-independent. Arch.

Regulation of phospholipase A(2) activity in cockroach (Periplaneta americana) fat body by hypertrehalosemic hormone: evidence for the participation of protein kinase C.

Phospholipase A(2) (PLA(2)) associated with the membrane fraction of trophocytes from Periplaneta americana fat body increases by as much as 100% when the cells are incubated with hypertrehalosemic hormone (HTH-II). Activation with HTH-II is approximately halved by inclusion of the PKC inhibitor sphingosine in the incubation medium. Because activation of PLA(2) by HTH-II is blocked by the GDP analogue GDP-beta-S, and the unactivated enzyme is activated by the GTP analogue GTP-gamma-S it is likely that a G protein is involved in activation of the enzyme. Activation of PLA(2) was also achieved by treating the trophocytes with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol in the presence of thapsigargin. This supports the view that protein kinase C is also involved in the activation process.

Inositol trisphosphate mediates the action of hypertrehalosemic hormone on fat body of the American cockroach, Periplaneta americana.

The rate of synthesis of inositol trisphosphate (InsP(3)) in trophocytes derived from disaggregated cockroach (Periplaneta americana) fat body increases following treatment of the cells with hypertrehalosemic hormone I or II (HTH-I, -II) in vitro. Trophocytes preloaded with [3H]inositol display a significant increase in InsP(3) synthesis as early as 15 s after addition of the hormone. When the trophocytes are pre-incubated with LiCl and subsequently incubated with HTH the [3H] content of the InsP(3) fraction is greater than that found with HTH alone. This is taken as evidence that inositol monophosphate phosphatase is part of the mechanism for clearing InsP(3) from the cytosol. In contrast to HTH, octopamine, which is also capable of exerting a hypertrehalosemic effect in the cockroach, does not increase the synthesis of InsP(3). 1-Octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3)), a potent and selective inhibitor of phosphatidylinositol phospholipase C, blocks the activation of phosphorylase by HTH-I as well as the hypertrehalosemic effect induced by the hormone.

Regulation of intracellular calcium in dispersed fat body trophocytes of the cockroach, Periplaneta americana, by hypertrehalosemic hormone.

Incubation of trophocytes from dissaggregated fat body of Periplaneta americana with either of the hypertrehalosemic hormones, HTH-I or HTH-II, leads to an increase in the cytosolic concentration of Ca(2+) from approximately 80 to approximately 310nM with a rise time of approximately 110s. The Ca(2+) concentration then declines to the resting level during the ensuing 5min. In the absence of extracellular Ca(2+) the increase in [Ca(2+)](i) due to HTH is limited to approximately 100nM. The calmodulin inhibitors calmidazolium and W-7 also limit to a similar degree the ability of HTH to increase [Ca(2+)](i). Phorbol 12-myristate 13-acetate, an activator of protein kinase C, was shown to block Ca(2+) entry through the plasma membrane. Additional evidence to support the view that HTH enhances Ca(2+) influx has been obtained by measuring the quenching of fura-2 fluorescence when Ca(2+) is replaced with Mn(2+).

State-dependent expression of pressure diuresis in conscious rats.

In 1967, Guyton and Coleman modeled pressure diuresis as the underlying, essential, long-term mechanism that regulates arterial pressure when sodium intake changes. Other mechanisms that influence renal function interact with pressure diuresis to achieve sodium balance and determine the blood pressure. Increases in sodium intake suppress sodium conserving mechanisms and activate natriuretic mechanisms; decreases in sodium intake have the opposite effect. If the Guyton-Coleman model is correct, then pressure diuresis should be more readily detected in animals on a high-salt diet than in animals on a low-salt diet. We measured spontaneous changes in arterial pressure and urine flow in conscious rats fed low-salt (0. 4% NaCl) and high-salt (8.0% NaCl) chow. For 10 rats fed a high-salt diet, arterial pressure and urine flow were positively correlated in 19 of 32 (59%) trials. In 10 rats fed a low-salt diet, a positive correlation was observed in 10 of 33 (30%) trials. Chi-square analysis revealed that differences in Na+ content of the diet were significantly associated with the probability of a positive relationship between blood pressure and urine flow. These results support the hypothesis that the expression of pressure diuresis across time is dependent on the state of sodium balance.

Hormonal activation of phosphorylase in cockroach fat body trophocytes: A correlation with trans-membrane calcium flux.

This study is an investigation of the temporal relationship between transmembrane Ca(2+) fluxes, and glycogen phosphorylase activation in dispersed trophocytes from the fat body of the cockroach, Periplaneta americana. Phosphorylase is maximally activated within 5 min after treating the trophocytes with either of the hypertrehalosemic hormones, Pea-HTH-I and Pea-HTH-II. Activation caused by Pea-HTH-II is sustained for a longer period than that produced by Pea-HTH-I. Chelation of extracellular Ca(2+) with EGTA blocks the activation of phosphorylase by HTH. Similarly, chelation of intracellular Ca(2+) with Quin 2 greatly diminishes the phosphorylase activating effect of both HTHs. The data support the view that an increase in the intracellular Ca(2+ )concentration is required for the activation of phosphorylase and that extracellular Ca(2+) is an essential, although not necessarily sole, source of Ca(2+) for this purpose. Using (45)Ca(2+) to trace the movement of Ca(2+) following a challenge with either Pea-HTH-I or -II, it was shown that (45)Ca(2+)influx nearly doubled during the first 30 s. At this time, the trophocytes begin to expel Ca(2+) at a rate higher than that of untreated cells and this state persists for approximately 4 min. The Ca(2+) fluxes are consistent with its postulated role in the activation of phosphorylase. Arch.

Evidence for the participation of arachidonic acid metabolites in trehalose efflux from the hormone activated fat body of the cockroach (Periplaneta americana).

The hypertrehalosemic hormones, HTH-I and HTH-II, activate trehalose synthesis and increase the rate of sugar efflux from Periplaneta americana fat body in vitro. These processes are unaffected by the diacylglycerol, 1-oleyl-2-acetyl-sn-glycerol, an activator of protein kinase C. Similarly, H-7 and spingosine, inhibitors of protein kinase C, are also inactive against trehalose efflux. The possibility that diacylglycerol lipase might generate an active fatty acid species was ruled out because of the failure of the inhibitor RHC-80267 to inhibit trehalose efflux. Activation of trehalose efflux from the intact fat body by HTH-I was strongly inhibited in a concentration dependent manner by the cyclooxygenase inhibitors indomethacin and diclofenac, but not by acetylsalicylic acid. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, also blocked HTH-I activated trehalose efflux in a concentration dependent fashion. The phospholipase A(2) inhibitors mepacrine and 4'-bromophenacyl bromide were also effective in decreasing the efflux of trehalose from HTH-I challenged fat body. The data suggest possible roles for arachidonic acid metabolites in the regulation of trehalose synthesis and in the efflux of the sugar from the fat body.

Fatty acids stimulate trehalose synthesis in trophocytes of the cockroach (Periplaneta americana) fat body.

Trophocytes from the disaggregated fat body of the cockroach (Periplaneta americana) respond to synthetic hypertrehalosemic hormone (HTH) by increasing the rate of trehalose synthesis. The cells give a similar response when incubated with stearic, oleic, linoleic, or arachidonic acid. A maximal increase in trehalose synthesis was obtained with 1-10 microM fatty acids. Synthesis of trehalose by the trophocytes was also increased by 1 microM prostaglandin F2alpha to nearly the same extent as that evoked by HTH. Furthermore, the data show that the trophocytes are capable of converting linoleic acid into arachidonic acid. This suggests that the cells may convert arachidonic acid, formed from the linoleic acid released by the action of HTH, to a prostaglandin which serves as an integral part of the hypertrehalosemic mechanism.

Evidence that free fatty acids in trophocytes of Periplaneta americana fat body may be regulated by the activity of phospholipase A2 and cyclooxygenase.

Previous studies have shown that palmitic, stearic, oleic and linoleic acid levels in trophocytes prepared from the fat body of male Periplaneta americana are increased following treatment of the cells with hypertrehalosemic hormone (HTH). Melittin, an activator of phospholipase A2, mimicked the action of HTH by increasing the free fatty acid content in a concentration-dependent manner. The increase caused by HTH could be eliminated by pretreatment of the trophocytes with 1 mM 4'-bromophenacyl bromide (BPB), an inhibitor of phospholipase A2. BPB also decreases the concentration of free fatty acids in trophocytes not treated with HTH but by a smaller margin. Nordihydroguaiaretic acid (NDGA) and indomethacin, inhibitors of lipoxygenase and cyclooxygenase, respectively, eliminated the increase in free fatty acids evoked by HTH. In the absence of HTH both inhibitors increased the free fatty acid content of the trophocytes, an effect consistent with the known mode of action of these agents. None of the inhibitors tested, all of which blocked HTH activated trehalose synthesis, prevented activation of phosphorylase by HTH. This is taken as evidence that other downstream sites are also important in the regulation of trehalose production by the fat body. It is suggested that the increase in free fatty acids evoked by HTH, or metabolites of those fatty acids, may regulate the synthesis and release of trehalose from the trophocytes because of potential effects on trehalose phosphate synthase, trehalose 6-phosphate phosphatase, and the trehalose transport mechanism in the trophocyte membrane.

The regulation of trehalose metabolism in insects.

Trehalose is a non-reducing disaccharide comprising two glucose molecules. It is present in high concentration as the main haemolymph (blood) sugar in insects. The synthesis of trehalose in the fat body (an organ analogous in function to a combination of liver and adipose tissue in vertebrates) is stimulated by neuropeptides (hypertrehalosaemic hormones), released from the corpora cardiaca, a neurohaemal organ associated with the brain. The peptides cause a decrease in the content of fructose 2,6-biphosphate in fat body cells. Fructose 2,6-biphosphate, acting synergistically with AMP, is a potent activator of the glycolytic enzyme 6-phosphofructokinase-1 and a strong inhibitor of the gluconeogenic enzyme fructose 1,6-biphosphatase. This indicates that fructose 2,6-biphosphate is a key metabolic signal in the regulation of trehalose synthesis in insects. Trehalose is hydrolysed by trehalase (E.C. 3.2.1.28). The activity of this enzyme is regulated in flight muscle, but the mechanism by which this is achieved is unknown. Trehalase from locust flight muscle is a glycoprotein bound to membranes of the microsomal fraction. The enzyme can be activated by detergents in vitro and by short flight intervals in vivo, which indicates that changes in the membrane environment modulate trehalase activity under physiological conditions.

Delay or inhibition of rat lens opacification using pantethine and WR-77913.

Pantethine and the amino phosphorothioate, WR-77913, protected lenses against increased light scattering and opacification during cataract formation in five animal models: (1) radiation, (2) selenite, (3) galactose, (4) streptozotocin and (5) Royal College of Surgeons. In the radiation or selenite models, each test reagent was administered 15 to 30 min prior to initiation of cataract by a single injection of Na2SeO3 or a single exposure to 15 Gy (gray) gamma radiation. In the galactose, streptozotocin and Royal College of Surgeons models where the cataractogenic insult was continuous, repeated administrations of pantethine and WR-77913 were necessary. The results suggested that protein aggregation and lens opacification associated with a variety of physiological and biochemical mechanisms can be delayed or inhibited using a systemic administration of pantethine or WR-77913.

Swim training alters sympathoadrenal and endocrine responses to hemorrhage in borderline hypertensive rats.

Swim training alters cardiovascular, sympathoadrenal, and endocrine responses to hemorrhage in borderline hypertensive rats (BHR). The effects of 10, 20, and 30% blood volume hemorrhages on cardiovascular, sympathoadrenal, and endocrine function in swim-trained (T; 2 h/day, 5 day/wk for 10-12 wk) and age-matched, untrained, sedentary, control (UT) borderline hypertensive rats (BHR) were assessed. Heart rate (HR) in UT BHR was significantly greater during the baseline (rest) period than T BHR. HR increased slightly from baseline in both groups after 10% hemorrhage but was significantly decreased in both groups after 20 and 30% hemorrhages. The decrease was eliminated by atropine (1 mg/kg iv). Systolic (SBP) and diastolic (DBP) blood pressures decreased significantly after 20 and 30% hemorrhages in both T and UT BHR but were not different between the groups at these times. Plasma norepinephrine levels were significantly increased above baseline after 20 and 30% hemorrhages in UT BHR and were significantly greater in UT BHR than T BHR after 30% hemorrhage. Plasma glucose levels increased significantly after 30% hemorrhage in both groups but were significantly greater in UT BHR than T BHR. Both plasma norepinephrine and plasma epinephrine levels showed strong positive correlations with plasma glucose. After 20 and 30% hemorrhages, plasma insulin levels were unchanged in T BHR but were significantly decreased in UT BHR. Plasma insulin levels were significantly less in UT than T BHR after 30% hemorrhage. These results suggest that swim training alters the effect that hemorrhage exerts on endocrine and sympathoadrenal function in BHR.(ABSTRACT TRUNCATED AT 250 WORDS)

The preparation of trophocytes from disaggregated fat body of the cockroach (Periplaneta americana).

A method has been developed for disaggregating the fat body of the adult American cockroach, Periplaneta americana, using collagenase. The yield of cells is sensitive to the osmolarity of the dispersing medium and to the age of the cockroaches from which the fat bodies are taken. Trophocytes uncontaminated with other cells were obtained by taking advantage of the low density of these cells which causes them to float to the top of the dispersion medium. In contrast, the mycetocytes and urocytes being denser than the medium sink to the bottom. The trophocytes retain the ability to respond to the synthetic hyperglycaemic hormones, CCI and CCII, as shown by the activation of phosphorylase and the stimulation of trehalose efflux. The trophocytes incorporated leucine into protein secreted by the cells in a time dependent manner.

Dynamic, short-term coupling between changes in arterial pressure and urine flow.

Pressure diuresis refers to the direct effect of arterial pressure (AP) on the rate of urine flow (UF). On the basis of computer modeling, pressure diuresis has been viewed as a long-term mechanism that acts to set the level of the blood volume and, thus, the steady-state AP. There are no systematic studies, however, on the rapidity with which changes in AP induce changes in UF in vivo. Therefore, we measured the delay between induced changes in AP and the subsequent change in UF. Nine anesthetized rats were instrumented with arterial, venous, and ureteral catheters. AP and UF were measured every 2 s, while acute changes in AP were induced by 1) occlusion of the aorta above or below the renal vessels; 2) brief tail pinch; or 3) intravenous administration of acetylcholine (1 microgram), phenylephrine (1 microgram), or angiotensin II (0.1 microgram). The rapidity of the urinary response to induced changes in AP was determined by calculating the delay between a significant change in AP (+/- 2 SD from baseline) and a significant change in UF. The delay averaged 6.0 +/- 0.5 s for all conditions. Also, examining the relationship between the magnitude of the induced changes in AP and the magnitude of the responses in UF revealed an exponential influence of AP on UF. That is, there were proportionately larger changes in UF compared with AP (< or = 10 times greater magnitude) in response to the experimental interventions.(ABSTRACT TRUNCATED AT 250 WORDS)