Stochastic simulation of successive waves of COVID-19 in the province of Barcelona.

Analytic compartmental models are currently used in mathematical epidemiology to forecast the COVID-19 pandemic evolution and explore the impact of mitigation strategies. In general, such models treat the population as a single entity, losing the social, cultural and economical specificities. We present a network model that uses socio-demographic datasets with the highest available granularity to predict the spread of COVID-19 in the province of Barcelona. The model is flexible enough to incorporate the effect of containment policies, such as lockdowns or the use of protective masks, and can be easily adapted to future epidemics. We follow a stochastic approach that combines a compartmental model with detailed individual microdata from the population census, including social determinants and age-dependent strata, and time-dependent mobility information. We show that our model reproduces the dynamical features of the disease across two waves and demonstrates its capability to become a powerful tool for simulating epidemic events.

Long-term interleukin-2 assessment after conversion from a twice-daily to once-daily tacrolimus regimen in stable kidney recipients.

Conversion to tacrolimus (Tac) to once daily (Tac-O) formulation is commonly followed by a 20% reduction in Tac trough levels in the first month. It is not associated with modifications of renal function but there is the issue of its effects on inflammatory cytokines and on subclinical rejection. The aim of our study was to evaluate long-term interleukins (IL)-2 profiles in stable renal transplant patients after Tac-O conversion. We enrolled 10 stable kidney transplant patients converted to Tac-O. Tac trough levels, serum creatinine concentrations, glomerular filtration rate using the Modification of Diet in Renal Disease formula, C-reactive protein, IL-2 levels, and clinical assessments were performed monthly for 6 months before and 12 months after conversion. Despite the significant reduction in Tac trough levels, we did not observe alterations suggestive of clinical or subclinical acute rejection.

Myocardial protection during aortic surgery: comparison between Bretschneider-HTK and cold blood cardioplegia.

The ideal cardioplegic strategy in thoracic aorta operations requiring long cardiopulmonary bypass and cross-clamp time has not been established. Suboptimal myocardial protection may lead to myocardial damage and possible post-operative complications. We evaluate post-operative cardiac Troponin I (cTnI) release, low cardiac output syndrome (LCOS) and mortality, using a cold crystalloid single-dose intracellular or cold blood multidose cardioplegia in 112 elective or emergent thoracic aorta operation patients. Fifty-four patients (HTK group) received Custodiol® cardioplegic solution and 58 received cold blood cardioplegia (CB group). Cross-clamp time, cardiopulmonary bypass (CPB) time and cTnI peak release were similar in both groups. No differences were found for atrial and ventricular arrhythmias, inotropic support, LCOS and in-hospital mortality. Two-way ANOVA analysis revealed an interactive effect on cTnI peak (p=0.012) of cardioplegic solution type across the cross-clamp time quintile. In the fifth quintile, cross-clamp time patient (>160 min) cTnI peak value was higher in CB patients (p=0.044). HTK and CB cardioplegic solutions assure similar myocardial protection in patients undergoing thoracic aorta operations. In long cross-clamp times, the lower post-operative cTnI release detected using HTK may be indicative of a better myocardial protection in these extreme conditions.

Intravascular pulmonary lymphoma with good response to treatment. A case report.

Intravascular lymphoma is a very rare form of large B cell non-Hodgkin's lymphoma, characterised by the presence of lymphoma cells in the lumina of small vessels only, particularly in the capillaries. We report a 54 year-old female non-smoker, admitted to hospital for further examination of a four month long clinical condition involving high fever, night sweats, unqualified weight loss and progressive dyspnea. Patient's temperature was 38.5 degrees C, pulse 100/min and respiratory 22 cycles/min. Patient's haemoglobin was 9.4 g/dL, she had leukocytosis, elevated LDH and arterial blood gas analysis with moderate hypoxaemia (FiO2 1l/m: PaO2-63.6 mm Hg). Chest X-ray revealed diffuse interstitial changes. All the possible causes of unknown origin fever were excluded. Diagnosis was made through lung biopsy and treatment with combined chemotherapy and rituximab was prescribed leading to a 48 hours clinical remission. We present this case to show how difficult this diagnosis can be and how a good response to therapy is possible.

A dopamine- and protein kinase A-dependent mechanism for network adaptation in retinal ganglion cells.

Vertebrates can detect light intensity changes in vastly different photic environments, in part, because postreceptoral neurons undergo "network adaptation." Previous data implicated dopaminergic, cAMP-dependent inhibition of retinal ganglion cells in this process yet left unclear how this occurs and whether this occurs in darkness versus light. To test for light- and dopamine-dependent changes in ganglion cell cAMP levels in situ, we immunostained dark- and light-adapted retinas with anti-cAMP antisera in the presence and absence of various dopamine receptor ligands. To test for direct effects of dopamine receptor ligands and membrane-permeable protein kinase ligands on ganglion cell excitability, we recorded spikes from isolated ganglion cells in perforated-patch whole-cell mode before and during application of these agents by microperfusion. Our immunostainings show that light, endogenous dopamine, and exogenous dopamine elevate ganglion cell cAMP levels in situ by activating D1-type dopamine receptors. Our spike recordings show that D1-type agonists and 8-bromo cAMP reduce spike frequency and curtail sustained spike firing and that these effects entail protein kinase A activation. These effects resemble those of background light on ganglion cell responses to light flashes. Network adaptation could thus be produced, to some extent, by dopaminergic modulation of ganglion cell spike generation, a mechanism distinct from modulation of transmitter release onto ganglion cells or of transmitter-gated currents in ganglion cells. Combining these observations with results obtained in studies of photoreceptor, bipolar, and horizontal cells indicates that all three layers of neurons in the retina are equipped with mechanisms for adaptation to ambient light intensity.

Manipulation of synaptic sign and strength with divalent cations in the vertebrate retina: pushing the limits of tonic, chemical neurotransmission.

At the first synaptic level of the vertebrate retina, photoreceptor light responses are transmitted to second order neurones through a chemical synapse based on a tonic release of neurotransmitter modulated by graded changes of presynaptic potential. The possibility that such synapses could work through a Ca2+-independent process had been proposed by previous authors, based on the persistence of transmission process in low Ca2+ media containing Co2+ or Ni2+ ions. Recently, we were able to explain these results within the framework of the classical calcium-hypothesis of synaptic transmission by taking into account the modifications of presynaptic surface potential brought about by changes of divalent cation concentrations. Here we report data showing how a surface-charge hypothesis could account for several apparently paradoxical effects of divalent cation manipulations such as: the enhancement of neurotransmitter release induced by low Ca2+ media; the transmission "unblocking" effect of Zn2+, Co2+ and Ni2+; and the reversal of transmission polarity induced by application of low Ca2+ media containing Cd2+ or Mg2+ ions.

Resistance of retinal extracellular space to Ca2+ level decrease: implications for the synaptic effects of divalent cations.

Ion-sensitive microelectrodes were used to measure the variations of [Ca2+]o induced by application of low Ca2+ media in the superfused eyecup preparation of the Pseudemys turtle. The aim of the experiments was to evaluate the possibility, suggested by previous studies, that in the deep, sclerad, layers of the retina [Ca2+]o may remain high enough to sustain chemical synaptic transmission even after prolonged application of low-Ca2+ saline. It was found that, at depths of 100-200 micron from the vitreal surface, [Ca2+ ]o did not fall below 1 mM even after application for periods of 30-60 min of nominally Ca2+-free media, and it was >0.3 mM after 30-min application of media containing EGTA and with a Ca2+ concentration of 1 nM. Previous studies in isolated salamander photoreceptors have shown that a reduction of [Ca2+ ]o to 0.3-1.0 mM may result in a paradoxical increase of Ca2+ influx into synaptic terminals due to the reduced screening of negative charge on the external face of the plasma membrane. On the basis of these results, the persistence or enhancement of synaptic transmission from photoreceptors to horizontal cells observed in various retinas treated with low-Ca2+ media may be accounted for within the classical Ca2+-dependent theory of synaptic transmission without invoking a Ca2+-independent mechanism.

Calcium-independent release of neurotransmitter in the retina: a "copernican" viewpoint change.

The release of synaptic transmitter in chemical synapses is brought about by Ca2+ influx through voltage-dependent Ca2+ channels opened by depolarisation of presynaptic terminals. However, in some preparations transmitter release persists or increases in low-Ca2+ media, and it has therefore been proposed that transmitter release could also occur through a Ca2+-independent, carrier mediated process. In particular it has been suggested that this may be the case for synaptic transmission between photoreceptors and second order neurones of the vertebrate retina. From our recent experiments on synaptic transmission from photoreceptors to horizontal cells of turtle and salamander retinas, it appears that lowering extracellular Ca2+ can actually promote Ca2+ influx through voltage-activated Ca2+ channels via a modification of surface potential of plasma membranes. On the basis of this apparently paradoxical effect of low Ca2+ media, it is possible to reaccommodate the so-called Ca2+-independent release within the framework of Ca2+-dependent synaptic transmission without invoking unconventional mechanisms.

Retinal horizontal cells: old cells, old experiments, new results.

The study of neural interactions in the vertebrate retina carried out after the pioneering studies of Svaetichin has provided important information on the functioning of nerve circuits in the central nervous system. Recently we have investigated the effects of changes of divalent cation concentration on the synaptic transmission between cones and horizontal cells of the turtle retina. Our results seemed apparently in contrast with the classical Ca2(+)-hypothesis of chemical synaptic transmission. Application of low Ca2+ media resulted in a recovery of synaptic transmission after application of divalent cations such as Ca2+, Zn2+ and Ni2+ traditionally considered as Ca2+ channel antagonists. Moreover, in the absence of exogenous divalent cations, low Ca2+ could result in an increase of transmitter release particularly if Mg2+ was omitted from the perfusing medium. These apparently paradoxical results can be reconciled with the postulates of the Ca2(+)-hypothesis of synaptic transmission by taking into account the effects of divalent cations on the fixed charges present at the external surface of cell membrane. It is possible that a similar interpretation could also account for the so-called "Ca2(+)-independent" transmission in other structures of the nervous system.

Calcium-independent synaptic transmission: artifact or fact?

The release of neurotransmitters at classical chemical synapses occurs via Ca2+ influx through voltage-dependent Ca2+ channels, which are opened following depolarization of presynaptic terminals. However, owing to a persistence or increase in the amount of transmitter released in preparations containing low concentrations of Ca2+, it has been proposed that transmitter release could also occur through a Ca(2+)-independent, carrier-mediated process. On the other hand, lowering extracellular [Ca2+] can actually promote Ca2+ influx through voltage-activated Ca2+ channels via a modification of the surface potential of plasma membranes. Therefore, the proposed Ca(2+)-independent transmitter release could be re-accommodated within the framework of the Ca2+ hypothesis of synaptic transmission by taking into account the surface-charge effects.

Low-calcium-induced enhancement of chemical synaptic transmission from photoreceptors to horizontal cells in the vertebrate retina.

According to the classical calcium hypothesis of synaptic transmission, the release of neurotransmitter from presynaptic terminals occurs through an exocytotic process triggered by depolarization-induced presynaptic calcium influx. However, evidence has been accumulating in the last two decades indicating that, in many preparations, synaptic transmitter release can persist or even increase when calcium is omitted from the perfusing saline, leading to the notion of a "calcium-independent release" mechanism. Our study shows that the enhancement of synaptic transmission between photoreceptors and horizontal cells of the vertebrate retina induced by low-calcium media is caused by an increase of calcium influx into presynaptic terminals. This paradoxical effect is accounted for by modifications of surface potential on the photoreceptor membrane. Since lowering extracellular calcium concentration may likewise enhance calcium influx into other nerve cells, other experimental observations of "calcium-independent" release may be reaccommodated within the framework of the classical calcium hypothesis without invoking unconventional processes.

[The effects of sublingual nifedipine on isometric stress in patients with severe aortic insufficiency. An acute hemodynamic study]. / Effetti della nifedipina sublinguale sullo sforzo isometrico in pazienti con insufficienza aortica grave. Studio emodinamico acuto.

We studied the acute hemodynamic effects of nifedipine (N) on handgrip test (Hg) in 10 patients with aortic regurgitation in II NYHA functional class. In basal condition (B) we found a significant increase of mean aortic pressure (AoPmean) in all patients after Hg (101 +/- 9.72 versus 110.3 +/- 6.42 mmHg; p < 0.05). Hg did not induce significant changes of AoPmean after N. Hg increased left ventricular end-diastolic pressure (LVEDP) from 13.3 +/- 6.4 to 20.5 +/- 9.9 mmHg (p < 0.01) before N and from 9.7 +/- 3.2 to 12.8 +/- 5.5 mmHg after N (NS). LVEDP measured during Hg after N showed lower values than those measured before N (12.8 +/- 5.5 versus 20.5 +/- 9.9 mmHg; p < 0.01). Cardiac index (CI) increased by Hg in B (3.7 +/- 0.7 versus 4.0 +/- 1.1 L/min/m2; NS) and after N (4.5 +/- 0.7 versus 4.9 +/- 0.9 L/min/m2; NS). CI increased significantly after N at rest (3.7 +/- 0.7 versus 4.5 +/- 0.7 L/min/m2; p < 0.01) and during Hg (4.0 +/- 1.1 versus 4.9 +/- 0.9 L/min/m2; p < 0.01). The left ventricular stroke work index (LVSWI) decreased during Hg from 74.4 +/- 20.6 to 71.2 +/- 20.0 g.m/m2; NS. N caused an increase at rest to 81.4 +/- 22.5 g.m/m2; NS. LVSWI increased significantly during Hg to 83.5 +/- 26.2 g.m/m2; p < 0.05. Systemic arterial resistances (SAR) significantly decreased after N at rest (1,086.8 +/- 280.8 versus 843.5 +/- 133.1 dyne.s.cm-5; p < 0.01), but increased in B during Hg to 1,220.9 +/- 350.7 dyne.s.cm-5; p < 0.05. A significant reduction of SAR values was observed alter N during Hg (1,220.9 +/- 350.7 versus 838.9 +/- 139.9 dyne.s.cm-5; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

[The acute and 24-hour modifications to the atrial natriuretic factor in patients who have undergone mitral valvuloplasty. The hemodynamic and echocardiographic correlations]. / Modificazioni acute ed a 24 ore del fattore natriuretico atriale in pazienti sottoposti a valvuloplastica mitralica. Correlazioni emodinamiche ed ecocardiografiche.

BACKGROUND: The recent introduction of percutaneous transvenous mitral valvuloplasty (PTMV) for the treatment of mitral stenosis (MS) has provided a unique human model for the study of short-term changes in ANF secretion before and after a reduction in left atrial pressure. This study was designed to investigate the effect of a short-term reduction in left atrial pressure and volume, as determined by echocardiographic study, on ANF and other neurohumoral factor plasma levels (renin and aldosterone). MATERIALS AND METHODS: 10 patients in III FC NYHA, with normal sinus rhythm and MS underwent PTMV. Hemodynamic parameters were measured immediately before and after (20-30 minutes) PTMV. Plasma levels of ANF, aldosterone and plasma renin activity (PRA) were obtained before (24 h) and after (2 h and 24 h) valvuloplasty; echocardiographic left atrial size before (24 h) and 24 h after PTMV. RESULTS: Immediately after PTMV mean left atrial (LA) pressure decreased from 22.3 +/- 6.8 mmHg to 10.0 +/- 2.4 mmHg (p < 0.01); mitral valve area (MVA) increased from 0.99 +/- 0.28 cm2 to 2.17 +/- 0.26 cm2 (p < 0.01). 24 hours after PTMV on echocardiography, LA systolic volume decreased from 59.5 +/- 16.9 cm3 to 42.3 +/- 8.3 cm3 (p < 0.01), LA diastolic volume from 82.6 +/- 15.8 cm3 to 66.5 +/- 12.6 cm3 (p < 0.01), and LA diameter from 48.1 +/- 7.5 mm to 39.2 +/- 4.4 mm (p < 0.01). ANF plasma levels before PTMV were 64.0 +/- 36.9 fmol/ml; 2 and 24 hours after PTMV they fell to 34.2 +/- 21.6 fmol/ml (p < 0.01) and to 20.3 +/- 21.0 fmol/ml (p < 0.01), respectively. PRA values were 15.7 +/- 13.2 ng/ml/h before PTMV; 2 and 24 hours after PTMV they increased to 17.5 +/- 23.2 ng/ml/h (NS) and to 22.3 +/- 16.8 ng/ml/h (p < 0.01). The aldosterone plasma levels were 43.2 +/- 27.9 ng/dl before PTMV and 47.3 +/- 35.8 ng/dl (NS) and 45.3 +/- 28.0 ng/dl (NS) 2 and 24 hours after PTMV. CONCLUSIONS: These results indicate that LA "de-stretching" due to the MVA increase and LA pressure decrease, leads to an abrupt reduction of ANF secretion. According to other studies, PRA increases immediately after PTMV, with a further increase 24 hours after PTMV.

Poor prophylactic lithium response due to antidepressants.

50 manic-depressive patients with rapid cycles received lithium for more than 1 year, during depression they received antidepressant drugs. Response was poor in 36, partial in 6, and good in 8. 21 of the poor responders were persuaded to endure depression without antidepressants; anxiolytics were allowed, 15 stabilized after the end of the untreated depression or after a few milder, shorter episodes; 4 improved partially; 2 were unchanged. 15 other rapid cycle patients started on lithium and stopped antidepressants at the same time. Response was good in 13, partial in 1, and poor in 1. Patients with a course of depression-hypomania (or mania)-free interval also responded poorly to prophylactic lithium when the depression was treated with antidepressants. They responded well when antidepressants were withdrawn. Antidepressants often cause or accentuate a switch from depression to hypomania or mania, and temporary refractoriness to lithium of the hypomania or mania. In this way lithium fails to prevent depression.