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Background: "Red tides" are harmful algal blooms caused by dinoflagellate microalgae that accumulate toxins lethal to other organisms, including humans via consumption of contaminated seafood. These algal blooms are driven by a combination of environmental factors including nutrient enrichment, particularly in warm waters, and are increasingly frequent. The molecular, regulatory, and evolutionary mechanisms that underlie the heat stress response in these harmful bloom-forming algal species remain little understood, due in part to the limited genomic resources from dinoflagellates, complicated by the large sizes of genomes, exhibiting features atypical of eukaryotes., Results: We present the de novo assembled genome (~ 4.75 Gbp with 85,849 protein-coding genes), transcriptome, proteome, and metabolome from Prorocentrum cordatum, a globally abundant, bloom-forming dinoflagellate. Using axenic algal cultures, we study the molecular mechanisms that underpin the algal response to heat stress, which is relevant to current ocean warming trends. We present the first evidence of a complementary interplay between RNA editing and exon usage that regulates the expression and functional diversity of biomolecules, reflected by reduction in photosynthesis, central metabolism, and protein synthesis. These results reveal genomic signatures and post-transcriptional regulation for the first time in a pelagic dinoflagellate., Conclusions: Our multi-omics analyses uncover the molecular response to heat stress in an important bloom-forming algal species, which is driven by complex gene structures in a large, high-G+C genome, combined with multi-level transcriptional regulation. The dynamics and interplay of molecular regulatory mechanisms may explain in part how dinoflagellates diversified to become some of the most ecologically successful organisms on Earth., (© 2023. The Author(s).)

How cells coordinate their metabolism with division determines the rate of cell proliferation. Dynamic patterns of metabolite synthesis during the cell cycle are unexplored. We report the first isotope tracing analysis in synchronous, growing budding yeast cells. Synthesis of leucine, a branched-chain amino acid (BCAA), increases through the G1 phase of the cell cycle, peaking later during DNA replication. Cells lacking Bat1, a mitochondrial aminotransferase that synthesizes BCAAs, grow slower, are smaller, and are delayed in the G1 phase, phenocopying cells in which the growth-promoting kinase complex TORC1 is moderately inhibited. Loss of Bat1 lowers the levels of BCAAs and reduces TORC1 activity. Exogenous provision of valine and, to a lesser extent, leucine to cells lacking Bat1 promotes cell division. Valine addition also increases TORC1 activity. In wild-type cells, TORC1 activity is dynamic in the cell cycle, starting low in early G1 but increasing later in the cell cycle. These results suggest a link between BCAA synthesis from glucose to TORC1 activation in the G1 phase of the cell cycle., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background : Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive. Methods : Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging. Results : Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation. Conclusion : Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Summary: Mass isotopolome analysis for mode of action identification (MIAMI) combines the strengths of targeted and non-targeted approaches to detect metabolic flux changes in gas chromatography/mass spectrometry datasets. Based on stable isotope labeling experiments, MIAMI determines a mass isotopomer distribution-based (MID) similarity network and incorporates the data into metabolic reference networks. By identifying MID variations of all labeled compounds between different conditions, targets of metabolic changes can be detected., Availability and Implementation: We implemented the data processing in C++17 with Qt5 back-end using MetaboliteDetector and NTFD libraries. The data visualization is implemented as web application. Executable binaries and visualization are freely available for Linux operating systems, the source code is licensed under General Public License version 3., (© The Author(s) 2020. Published by Oxford University Press.)

Continuous cell culture monitoring as a way of investigating growth, proliferation, and kinetics of biological experiments is in high demand. However, commercially available solutions are typically expensive and large in size. Digital inline-holographic microscopes (DIHM) can provide a cost-effective alternative to conventional microscopes, bridging the gap towards live-cell culture imaging. In this work, a DIHM is built from inexpensive components and applied to different cell cultures. The images are reconstructed by computational methods and the data are analyzed with particle detection and tracking methods. Counting of cells as well as movement tracking of living cells is demonstrated, showing the feasibility of using a field-portable DIHM for basic cell culture investigation and bringing about the potential to deeply understand cell motility.

Termination of pregnancy before 12 weeks after the last menstrual period is requested by an important number of women. We review the legal framework of abortion in Switzerland and the most used methods for medical abortion precising their contra-indications and most frequent complications. Very rare but fatal cases of infection following medical abortion (with mifepristone and misoprostol) were recently described. We present their clinical characteristics and discuss the related physiopathological process.

The overall increase in relative survival rates of adult and childhood cancer patients is related to improved chemotherapy and radiotherapy treatment protocols. However, this success is tempered by gonadotoxic effects and uterine damage. The reduced fertility and possible premature menopause can have a profound impact on patients self-esteem and quality of life. Consequently, preservation of fertility or treatments to protect the ovarian function, become a more relevant issue. Advances in assisted reproduction techniques have focused on the following: embryo cryopreservation which is restricted by time and constrains such as, sexual maturity and the presence of a stable partner. Cryopreservation of immature ovarian tissue, the most promising option, with restoration of natural fertility following auto-transplantation or maturation of oocytes in vitro in combination with assisted reproduction.

Women rely on complete and precise information given by doctors and family planning consultants for choosing a suitable contraceptive. Available hormonal contraceptives in Switzerland are presented. Personal and family history are essential for evaluating medical contraindications to combined hormonal methods. Combined pills, vaginal hormonal rings and combined patches share the same contraceptive effects, contraindications and overall cardiovascular risks. Prescribers should prefer second generation pills because of lower risks of venous thromboembolic disease. Non oral methods are generally associated with improved compliance and in the case of vaginal rings, with fewer side effects. Progestogen only contraceptives (pills, implants and intrauterine devices) can be used in patients with known intolerance and/or contraindications to estrogens.

The WHI triggered a great debate on Menopausal Hormonal Therapy. We now know that HT should not be used in cardio-vascular prevention. Many studies have yet been published regarding it's influence on breast cancers. Risks should be modulated in respect with the type of treatment and the targeted population. Only recently menopaused women or women suffering from invalidating menopausal symptoms should benefit from HT. When an HT is needed, the authors recommend the use of trans-cutaneous estrogens combined with natural oral progesterone. Every HT should be prescribed individually, according to the patient's aspirations and expectations.

The relationship between cardiac and vascular abnormalities was studied in 68 patients with established septic shock. At time of hemodynamic evaluation, after initial resuscitation, there was no significant difference in arterial pressure, pulmonary artery pressure, cardiac filling pressures, and cardiac index between the 38 survivors of shock and the 30 patients who died of shock, but the left ventricular stroke work index and the right ventricular (RV) stroke work index were higher in survivors than in those who died (mean +/- SD: 25.0 +/- 9.1 vs 20.1 +/- 9.4 gm/m2 [p less than 0.05] and 6.6 +/- 3.6 vs 4.8 +/- 2.8 gm/m2 [p less than 0.05], respectively). Survivors had also higher thermodilution RV ejection fraction and lower RV end-diastolic volumes than had those who died (43.9% +/- 16.3% vs 31.1% +/- 13.7% [p less than 0.01] and 82 +/- 30 vs 99 +/- 31 ml/m2 [p less than 0.05], respectively). Calculated systemic vascular resistance was similar in the two groups, but vasopressors had been required in 22 (58%) of 38 survivors and 25 (83%) of 30 patients who died (p less than 0.01). Moreover, when the patients were separated into two groups according to their cardiac output, higher or lower than 3 L/min/m2, in both subgroups patients who died had lower blood pressure than had survivors. Blood lactate levels were significantly lower in survivors than in nonsurvivors (5.1 +/- 2.1 vs 8.1 +/- 4.7 mEq/L, p less than 0.01). Final data obtained before recovery of shock or death indicated that the survivors had higher arterial pressure, lower pulmonary artery pressure and right atrial pressure, higher stroke volume, and higher RV ejection fraction than had the patients who died. No survivors but all patients who died had been treated with vasopressors. These data therefore indicate that death as a result of septic shock is characterized by both myocardial depression and altered vascular tone and both are probably interrelated.

The effects of fluid loading on RV function were studied in 41 acutely ill patients monitored with a modified pulmonary artery catheter equipped for measuring RVef. Hemodynamic evaluation was performed before and after infusion of 300 ml of 4.5 percent albumin solution in 30 min. Changes in SI did not correlate with Pra or Ppao but did with RVEDVI. For the entire group, RVef was unchanged (27 +/- 9 vs 27 +/- 9 percent). In the eight patients with an initial RVEDVI greater than 140 ml/m2, the fluid challenge increased Pra and Ppao and reduced LVSWI without any other significant effect. There was no significant correlation between RVEDVI and Pra and only a weak correlation between RVESVI and Ppa. However, there was a highly linear correlation between both RVEDVI and RVESVI and changes in RVEDVI and in RVESVI, suggesting that in the absence of severe pulmonary hypertension RV output is primarily dependent on RV preload.

Bretylium tosylate has been shown effective in the treatment of ventricular fibrillation and in the prevention of its recurrence. However, lidocaine is generally preferred because bretylium could have adverse hemodynamic effects related to its antiadrenergic action. To explore further the differences between these two antiarrhythmic agents, the authors compared the effects of bretylium, lidocaine, and saline on a standardized dog model of ventricular fibrillation followed by electromechanical dissociation (EMD). The protocol included three successive episodes of cardiac arrest in each animal. Three minutes before each episode of ventricular fibrillation, 5 mg/kg of bretylium tosylate (n = 11), 1 mg/kg of lidocaine (n = 9) or saline (n = 12) were administered blindly. There was no difference in the duration of cardiac arrest (bretylium, 8 min 18 sec; lidocaine, 7 min 54 sec; saline, 8 min 20 sec) or the total doses of epinephrine required to resuscitate the animals. Both bretylium and lidocaine appeared to preserve cardiac function 5 minutes after recovery, as stroke volume increased from 17.8 +/- 6.7 to 18.7 +/- 6.7 mL (NS) after bretylium and from 17.7 +/- 7.7 to 19.0 +/- 7.0 mL (NS) after lidocaine, but decreased from 19.0 +/- 5.3 to 14.6 +/- 6.0 mL (P less than .05) after saline. During the first 10 minutes of EMD, ventricular fibrillation or ventricular tachycardia recurred in 4 dogs treated with lidocaine, 3 dogs treated with saline, but no dog treated with bretylium (P less than .05 between bretylium and saline).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute subdural hematoma of the posterior fosa (ASDH-PF) is a clinical rarity with a poor prognosis in teenagers or adults (mortality rate: 71%). We report the third case operated upon with success. The relevant literature is analysed and the characteristics of ASDH-PF are discussed, particularly in connection with the patient's age.

The systemic and renal hemodynamic effects of tertatolol, a new noncardioselective beta blocker without partial agonist activity, given alone or in combination with cyclooxygenase inhibition by acetylsalicylic acid (aspirin), were investigated in eight healthy volunteers. Tertatolol 5 mg, aspirin 1 g, tertatolol 5 mg together with aspirin 1 g and placebo were administered at 1-week intervals in a random order and in a double-blind fashion. Cardiac output was measured by Doppler echography and renal blood flow and glomerular filtration rate (GFR) by constant infusion techniques using (123I) iodohippurate and (51Cr) EDTA, respectively. Measurements were performed before and then successively 2 and 4 hours after oral intake of drugs or placebo. Tertatolol decreased cardiac output by 22% (P less than .05) and heart rate by 17% (P less than .05) without change in blood pressure, renal blood flow, and GFR. The same effects occurred when tertatolol was given together with aspirin. Either placebo or aspirin alone had no effect on systemic and renal hemodynamics. These results suggest that cardiac output is redistributed to the kidneys after tertatolol intake in normal humans. This favorable effect on renal hemodynamics is probably not mediated by a local release of vasodilating prostaglandins.

Humoral vasoactive substances coming from portal blood have been considered as a possible cause of renal dysfunction in cirrhotic patients. We have thus investigated the effect of perfusion of portal blood from anesthetized dogs on the isolated kidney functions. Both kidneys of a dog were simultaneously perfused on 2 Nizet's pump oxygenators, one kidney serving as control for the other. Renal blood flow was decreased in kidneys perfused with portal blood, as compared to the paired control kidneys perfused with sus-hepatic blood (group A experiments). Addition of polymyxin B to the portal blood restored the renal blood flow to the control level (group B experiments). No significant changes appeared between experimental and control kidneys for glomerular filtration rate, urine output, sodium and water excretion, renin activity, angiotensin II levels, plasmatic PGE2 levels, in group A as well as in group B. We conclude that portal blood of dogs contains vasoactive substances reducing renal blood flow; their action is mediated neither by the renin-angiotensin system nor by changes in renal PGE2 production. The complete abolition of this effect by Polymyxin suggests that these substances may be endotoxins.

Measurement of right ventricular ejection fraction (RVEF) by the thermodilution technique has become routinely available at the bedside of the critically ill. We describe 2 patients with tricuspid regurgitation in whom RVEF values were considerably lower by thermodilution than by radionuclide techniques. Discrepancies could be due to the regurgitation of the thermodilution signal and possibly to the different nature of the two measurements (forward stroke volume with the thermodilution technique and total stroke volume with the radionuclide technique). We suggest that lower RVEF measurement by the thermodilution technique could be related to unrecognized tricuspid regurgitation. Measurement of an unexpectedly low RVEF by the thermodilution technique should suggest the presence of tricuspid regurgitation.

The short-term effects of dopexamine hydrochloride, a new synthetic adrenergic agent with predominant beta 2-adrenergic and dopaminergic properties, were studied in nine patients with inadequate cardiac output during the course of an episode of respiratory failure associated with lung infection. Dopexamine at doses up to 5 microgram/kg/min had no significant effect on arterial pressure or cardiac filling pressures, but increased cardiac index from 2.0 +/- 0.2 to 2.6 +/- 0.2 L/min.m2. Left ventricular stroke work increased from 17.3 +/- 15 to 22.1 +/- 2.4 g.m/m2 (p less than 0.01) and systemic vascular resistance index decreased from 3,792 +/- 1,035 to 2,194 +/- 823 dynes.s.cm5.m2 (p less than 0.01). The increase in cardiac output was in part related to an increase in heart rate from 91 +/- 6 to 102 +/- 7 beats/min. Under a mean inspiratory oxygen fraction of 0.48, the PaO2 decreased from 105 +/- 12 to 91 +/- 11 mm Hg (p less than 0.05) as venous admixture increased from 15.8 +/- 1.0 to 18.1 +/- 1.4 percent (p less than 0.05). Accordingly, the combination of inotropic, afterload-reducing and renal vasodilating effects of dopexamine can be useful acutely to increase cardiac output in critical conditions. However, its administration can be limited by a dose-related increase in heart rate. Dopexamine, like other catecholamines, alters blood oxygenation and increases venous admixture.

We reviewed the records of 51 patients. In two-thirds of the cases the main symptom was icterus; one third presented with pain. The whole group underwent a retrograde choledocho-pancreatography. An abnormal papilla was found in 80% of the cases. This finding proved to be of sufficient diagnostic importance without the necessity of an associated choledocho-pancreatography for diagnostic confirmation. Although in the majority of the cases the choledochus proved to be dilated, pancreatic duct enlargment was only noted in 50%. The only treatment in the very elderly patient was endoscopic sphincterotomy. Younger patients underwent a duodeno-pancreatectomy preceded by an endoscopic sphincterotomy. The morbidity and mortality associated with endoscopic opacification of the biliary and pancreatic ducts and sphincterotomy in this setting is much higher than for all other indications in general. For this reason we propose to perform a choledocho-pancreatography only when indispensable for diagnostic purposes (nl. papilla) or when endoscopic sphincterotomy is the chosen treatment modality.

In 15 critically ill patients requiring adrenergic support, right ventricular ejection fraction (RVEF) and right ventricular (RV) volumes were measured by the thermodilution technique receiving 5 micrograms/kg.min of dopamine and after replacement by the same dose of dobutamine. Shift from dopamine to dobutamine resulted in significant increases in stroke index from 28.1 +/- 3.6 to 31.0 +/- 3.8 ml/m2 (p less than .01) and significant decreases in pulmonary artery balloon-occluded pressure from 15.1 +/- 1.0 to 13.9 +/- 1.2 mm Hg (p less than .05) and right atrial pressure (RAP) from 14.0 +/- 1.3 to 12.2 +/- 1.1 mm Hg (p less than .05). RVEF increased slightly but significantly from 21.5 +/- 2.7% to 23.7 +/- 2.9% (p less than .01) so that RV end-diastolic volume (RVEDVI) was unchanged (140 +/- 12 vs. 141 +/- 12 ml, nonsignificant). RVEDVI/RAP ratio increased from 11.3 +/- 1.0 to 12.9 +/- 1.1 ml/mm Hg (p = .037). These results support the view that dobutamine has more favorable effects on RV function than dopamine in critically ill patients in the absence of profound hypotension and also indicates that higher filling pressures under dopamine administration can be related to changes in ventricular pressure/volume relationship.