Differential Effects of Pharmacologic and Mechanical Support on Right-Left Ventricular Coupling.

BACKGROUND: Percutaneous ventricular assist devices are increasingly relied on to maintain perfusion for cardiogenic shock patients. Optimal medical management strategies however remain uncertain from limited understanding of interventricular effects. This study analyzed the effects of pharmacologic and left-sided mechanical support on right ventricular function. METHODS: A porcine model was developed to assess biventricular function during bolus pharmacologic administration before and after left-sided percutaneous ventricular assist and in cardiogenic shock. RESULTS: The presence of mechanical support increased right ventricular load and stress with respect to the left ventricle. This shifted and exaggerated the relative effects of commonly used vasoactive agents. Furthermore, induction of cardiogenic shock led to differential pulmonary vascular and right ventricular responses. CONCLUSIONS: Left ventricular ischemia and mechanical support altered interventricular coupling. Resulting impacts of pharmacologic agents indicate differential right heart responses and sensitivity to treatments and the need for further study to optimize biventricular function in shock patients.

Steady Flow Left Ventricle Unloading Is Superior to Pulsatile Pressure Augmentation Venting During Venoarterial Extracorporeal Membrane Oxygenation Support.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) shunts venous blood to the systemic arterial circulation to provide end-organ perfusion while increasing afterload that may impede left ventricle (LV) ejection and impair cardiac recovery. To maintain flow across the aortic valve and reduce risk of lethal clot formation, secondary mechanical circulatory support (MCS) devices are increasingly used despite limited understanding of their effects on cardiac function. This study sought to quantify the effects of VA-ECMO and combined with either intraaortic balloon pump (IABP) or percutaneous ventricular assist device (pVAD) on LV physiologic state and perfusion metrics in a porcine model of acute cardiogenic shock. Shock was induced through serial left anterior descending artery microbead embolization followed by initiation of VA-ECMO support and then placement of either IABP or pVAD. Hemodynamic measurements, LV pressure-volume loops, and carotid artery blood flow were evaluated before and after institution of combined MCS. The IABP decreased LV end-diastolic pressure by a peak of 15% while slightly increasing LV stroke work compared with decreases of more than 60% and 50% with the pVAD, respectively. The pVAD also demonstrated increased coronary perfusion and systemic pressure gradients in comparison to the IABP. Combined support with VA-ECMO and pVAD improves cardiovascular state in comparison to IABP.

A soft robotic sleeve mimicking the haemodynamics and biomechanics of left ventricular pressure overload and aortic stenosis.

Preclinical models of aortic stenosis can induce left ventricular pressure overload and coarsely control the severity of aortic constriction. However, they do not recapitulate the haemodynamics and flow patterns associated with the disease. Here we report the development of a customizable soft robotic aortic sleeve that can mimic the haemodynamics and biomechanics of aortic stenosis. By allowing for the adjustment of actuation patterns and blood-flow dynamics, the robotic sleeve recapitulates clinically relevant haemodynamics in a porcine model of aortic stenosis, as we show via in vivo echocardiography and catheterization studies, and a combination of in vitro and computational analyses. Using in vivo and in vitro magnetic resonance imaging, we also quantified the four-dimensional blood-flow velocity profiles associated with the disease and with bicommissural and unicommissural defects re-created by the robotic sleeve. The design of the sleeve, which can be adjusted on the basis of computed tomography data, allows for the design of patient-specific devices that may guide clinical decisions and improve the management and treatment of patients with aortic stenosis.

Frailty and clinical outcomes following aortic valve replacement.

BACKGROUND AND AIMS: The Norton score is a well-known scale to assess frailty. Frailty and a low Norton score are associated with complications and mortality in hospitalized patients. We aimed to evaluate whether a low Norton score is associated with surgical complications and death after aortic valve replacement (AVR). METHODS: From 2004 through 2020, we performed an observational study in a large tertiary medical center, which included all patients who had undergone isolated AVR surgery. Of the 1469 study patients, 618 patients (42%) had a low (<18) and 851 patients (58%) a high Norton score (≥18). RESULTS: Frailer patients with a low Norton score had higher in-hospital mortality compared to those with a high Norton score (5.5% vs. 0.8%, p < .001). The Norton score was significantly higher among patients who survived compared to those who died (17.5 ± 2.4 vs. 11.5 ± 5.2, p < .001). A low Norton score was associated with a threefold increased risk of in-hospital mortality (odds ratio 3.03; 95% confidence interval [CI] 1.14-0.09, p = .034). Ten-year mortality rate was higher among frailer patients with a low compared with a high Norton score (25.9%, 13.3%; hazard ratio 0.69, CI 0.48-0.82, p < .001). By adding a Norton score to standard prognostic factors (age, gender, comorbidities, left ventricular ejection fraction, functional class) we showed a significant improvement of 59.4% (p < .001) for predicting 1-year mortality, and 40.6% (p < .001) for predicting 10-year mortality. CONCLUSIONS: Our findings show that the admission Norton score is a powerful marker of short- and long-term mortality, and, therefore, should be considered as a risk stratification tool in patients who are candidates for AVR.

Abortive herpes simplex virus infection of nonneuronal cells results in quiescent viral genomes that can reactivate.

Abortive viral infections are usually studied in populations of susceptible but nonpermissive cells. Single-cell studies of viral infections have demonstrated that even in susceptible and permissive cell populations, abortive infections can be detected in subpopulations of the infected cells. We have previously identified abortive infections in HeLa cells infected with herpes simplex virus 1 (HSV-1) at high multiplicity of infection (MOI). Here, we tested 4 additional human-derived nonneuronal cell lines (cancerous or immortalized) and found significant subpopulations that remain abortive. To characterize these abortive cells, we recovered cell populations that survived infection with HSV-1 at high MOI. The surviving cells retained proliferative potential and the ability to be reinfected. These recovered cell populations maintained the viral genomes in a quiescent state for at least 5 wk postinfection. Our results indicate that these viral genomes are maintained inside the nucleus, bound to cellular histones and occasionally reactivated to produce new progeny viruses. We conclude that abortive HSV-1 infection is a common feature during infection of nonneuronal cells and results in a latency-like state in the infected cells. Our findings question the longstanding paradigm that alphaherpesviruses can establish spontaneous latency only in neuronal cells and emphasize the stochastic nature of lytic versus latency decision of HSV-1 in nonneuronal cells.

Coalescing replication compartments provide the opportunity for recombination between coinfecting herpesviruses.

Homologous recombination (HR) is considered a major driving force of evolution because it generates and expands genetic diversity. Evidence of HR between coinfecting herpesvirus DNA genomes can be found frequently both in vitro and in clinical isolates. Each herpes simplex virus type 1 (HSV-1) replication compartment (RC) derives from a single incoming genome and maintains a specific territory within the nucleus. This raises intriguing questions about where and when coinfecting viral genomes interact. To study the spatiotemporal requirements for intergenomic recombination, we developed an assay with dual-color FISH that enables detection of HR between different pairs of coinfecting HSV-1 genomes. Our results revealed that HR increases intermingling of RCs derived from different genomes. Furthermore, inhibition of RC movement reduces the rate of HR events among coinfecting viruses. Finally, we observed correlation between nuclear size and the number of RCs per nucleus. Our findings suggest that both viral replication and recombination are subject to nuclear spatial constraints. Other DNA viruses and cellular DNA are likely to encounter similar restrictions.-Tomer, E., Cohen, E. M., Drayman, N., Afriat, A., Weitzman, M. D., Zaritsky, A., Kobiler, O. Coalescing replication compartments provide the opportunity for recombination between coinfecting herpesviruses.

Paraoxonase 1 (PON1) attenuates sperm hyperactivity and spontaneous acrosome reaction.

BACKGROUND: Sperm capacitation is essential for proper fertilization and is associated with increased sperm hyperactivity (HA) and acrosome reaction (AR). For successful fertilization, AR timing is critical; accordingly, early spontaneous AR may not facilitate fertilization. Paraoxonase 1 (PON1) possesses antioxidant properties which affect sperm capacitation. The association between PON1, semen parameters, and capacitation is not fully understood. OBJECTIVE: To study PON1 activity in relation to human sperm hyperactivity and AR. MATERIALS AND METHODS: Semen samples were collected, and parameters were determined (volume, concentration, total sperm count, percentage total motility, and percentage normal morphology) according to World Health Organization (WHO) guidelines. AR and hyperactivity were evaluated using FITC-PSA, staining, and computer-aided sperm analysis (CASA). PON1 activity was assessed using arylesterase activity assay. RESULTS: Purified PON1 inhibited both sperm hyperactivity and AR in a dose-dependent manner. Native semen PON1 activity was positively associated with higher sperm concentration and negatively associated with spontaneous acrosome reaction (sAR). DISCUSSION AND CONCLUSION: PON1 may have a positive effect on fertility via its ability to prevent early spontaneous sperm capacitation and AR before reaching the female genital tract.

Gene Expression Correlates with the Number of Herpes Viral Genomes Initiating Infection in Single Cells.

Viral gene expression varies significantly among genetically identical cells. The sources of these variations are not well understood and have been suggested to involve both deterministic host differences and stochastic viral host interactions. For herpesviruses, only a limited number of incoming viral genomes initiate expression and replication in each infected cell. To elucidate the effect of this limited number of productively infecting genomes on viral gene expression in single cells, we constructed a set of fluorescence-expressing genetically tagged herpes recombinants. The number of different barcodes originating from a single cell is a good representative of the number of incoming viral genomes replicating (NOIVGR) in that cell. We identified a positive correlation between the NOIVGR and viral gene expression, as measured by the fluorescent protein expressed from the viral genome. This correlation was identified in three distinct cell-types, although the average NOIVGR per cell differed among these cell-types. Among clonal single cells, high housekeeping gene expression levels are not supportive of high viral gene expression, suggesting specific host determinants effecting viral infection. We developed a model to predict NOIVGR from cellular parameters, which supports the notion that viral gene expression is tightly linked to the NOIVGR in single-cells. Our results support the hypothesis that the stochastic nature of viral infection and host cell determinants contribute together to the variability observed among infected cells.

Acute mastoiditis in children: is surgical treatment necessary?

Acute mastoiditis in children remains an otological problem. Although the widespread use of antibiotics has reduced the need for surgical intervention, surgery is frequently used in the treatment of acute mastoiditis and its complications. The charts of 44 patients hospitalized with signs of acute mastoiditis were reviewed. In 43.2 per cent of all patients, acute mastoiditis was the presenting sign of acute middle-ear infection. Post-auricular erythema and protrusion of the auricle were the most frequent signs at presentation. All four signs (post-auricular erythema, oedema, tenderness, and protrusion of the auricle) were present in 40.9 per cent of patients. No bacterial pathogen was isolated in 45.5 per cent of ear cultures. Complicated acute mastoiditis was diagnosed in 13.7 per cent of the patients. Eighty-seven per cent of patients responded well to intravenous antibiotics and myringotomy, and in 11.4 per cent mastoidectomy or abscess drainage were performed. We conclude that nearly all patients with uncomplicated mastoiditis recover following intravenous antibiotics and myringotomy. Mastoidectomy should be performed in selected cases, such as cases of complicated acute mastoiditis.

An outbreak of Trichinella spiralis infection in southern Lebanon.

An outbreak of trichinosis occurred during January 1995 in a south Lebanese village with a population of 800-1000 persons. The estimated number of persons treated for a Trichinella-like illness was 200. Sixty-three persons sought medical attention at a local infirmary: 44 of them were diagnosed as having trichinosis or suspected trichinosis according to their clinical symptoms, signs and laboratory tests. An environmental investigation indicated that the source of infection was pork obtained from a single butcher in the village and consumed uncooked, as an ingredient of 'kubeniye' (a local dish), during Christmas and New Year's meals. Sera of patients, suspected patients, and asymptomatic controls were tested for the presence of anti-Trichinella antibodies. Eight (89%) of the 9 tested patients were positive, 1 (11%) was negative. Among the 7 suspected patients, 2 (28.5%) were positive, 3 (42.9%) had equivocal results, and 2 (28.5%) were negative. Among the 20 asymptomatic persons, 3 (15%) were positive, 12 (60%) negative and 5 (25%) had equivocal results. Specimens from the implicated pork meat were examined by microscopy and were found to contain encysted larvae of Trichinella spiralis. This outbreak of trichinosis is one of the largest reported. Previous outbreaks in Lebanon occurred under very similar circumstances, indicating a need to control and prevent the trading of pork meat that is not under veterinary control, and to increase the awareness of the population for this problem.

Neonatal mastitis--diagnosis and treatment.

Neonatal mastitis is an uncommon infection. Twenty-one neonates with mastitis were treated at the Bnai Zion Medical Center and Hillel Yaffe Hospital during the years 1985-92. Half of them presented with mastitis, and the other half with breast abscess. The most common pathogen was Staphylococcus aureus, which was isolated in 85% of cases. Antibiotic therapy was the initial treatment in all cases except one, and included i.v. orbenin or augmentin. Puncture of six breast abscesses followed the initial antibiotic course, and another five abscesses were treated surgically by incision and drainage. About half the neonates (10 of 21) recovered after antibiotic treatment alone, indicating that aggressive antibiotic therapy is effective in about 50% of cases and, if started immediately upon diagnosis, no additional surgical treatment is necessary. When an abscess was formed, needle aspiration was as effective as incision and drainage.

In vitro construction of cells-containing implants for articular cartilage regeneration.

Regeneration of destroyed articular cartilage can be induced by transplantation of cartilage cells into the defects. The best results are obtained by the use of either fetal allogeneic cells or autogenic ones. Induction of chondrogenesis in residual mesenchymal cells is optimal for obtaining large amounts of autogenic chondrocytes. Further modification of the technique is needed to reconstruct large defects. The cells are grown on biodegradable scaffolds and are later implanted into joint defects.

Implants composed of carbon fiber mesh and bone-marrow-derived, chondrocyte-enriched cultures for joint surface reconstruction.

The current study integrates two distinct approaches in joint resurfacing into a combined type of implant, composed of carbon fiber mesh impregnated and coated with a hyaluronic-acid-based delivery substance containing cultured cells. Rabbit autogeneic chondrocyte-enriched cultures obtained from mesenchymal stem cells (chondroprogenitor cells) derived from adult rabbit bone marrow were grown in vitro under conditions favoring chondrogenesis. The improvement in quality of repair when a combined implant containing both cells and a carbon scaffold was used, in comparison to the utilization of carbon fiber mesh alone, was clearly demonstrated using clinical, histological, biochemical, and biomechanical examinations. Evaluations of the joints were performed at 6 weeks and 6 months after implantation. The repair tissue in the cell-implanted joints consisted of a typical hyaline cartilage, which was more cellular and thicker than the repair tissue in the hyaluronic-acid-impregnated carbon-fiber-implanted control joints. The hyaline cartilage in the experimental group formed a superficial layer above the carbon fibers, flush with the joint surface. In the controls, in which carbon fiber and the delivery substance alone were implanted, a histologically and biochemically fibrous tissue that was inferior biomechanically to the new cartilage was formed by the cells containing implants.