Malignancy: Changes in Circulating Immature and Mature Dendritic Cells During IL-2 Cancer Immunotherapy and Their Relation with Lymphocyte Increase and Clinical Response

Lymphocytosis is the main biomarker predicting the efficacy of subcutaneous IL-2 anticancer immunotherapy. In addition, it has been demonstrated the fundamental role of dendritic cells (DC) in the generation of an effective anticancer immunity. However, the relation between IL-2 and DC system needs to be further understood. This preliminary study was performed in an attempt to analyze changes in circulating DC during IL-2 cancer immunotherapy in relation to lymphocyte variations and clinical efficacy of treatment. The study included 20 metastatic renal cell cancer patients, who underwent subcutaneous low-dose IL-2 immunotherapy (6.000.000 IU/day for 6 days/week for 4 weeks). To evaluate DC, venous blood samples were collected before and after 2 weeks of IL-2 injections, corresponding to the period of maximum lymphocytosis. Immature (CD123(+) ) and mature (CD11c(+) ) DC were measured by FACS and monoclonal antibodies. IL-2 induced a significant increase in the mean number of circulating mature DC, whereas no substantial change occurred in immature DC mean number. The increase in mature DC was associated with a control of disease, whereas no rise was observed in patients who had progressed on IL-2 immunotherapy. Moreover, the increase in mature DC mean number was significantly higher in patients showing evident lymphocytosis, with lymphocyte enhancement greater than 1000 cells/mmc, than in patients with less pronounced lymphocytosis, even though no significant correlation was seen in between mature DC and lymphocyte increase. This preliminary study would suggest that IL-2 may stimulate DC system and that the clinical anticancer efficacy of IL-2 is associated with the increase in circulating mature DC, which could be considered as a new favourable biomarker during IL-2 immunotherapy.     

Fourier Analysis in Patients with Different Pacing Modes

The purpose of this study was to evaluate the usefulness of phase analysis in detecting the altered activation sequence induced by different pacing modes. Radionuclide ventriculography and planar gated blood pool scintigraphy were performed at rest in 56 patients with different pacemakers. This method permitted us to localize the pacemaker impulse site in the right ventricle and its diffusion in the heart. In patients with VVI pacemaker, this technique showed an evident asynchronism of contraction and relaxation of each ventricle and the standard deviation of phase angle (sigma), calculated by computer, is greater during pacing than sinus rhythm for left (LV) and right (RV) ventricles (LV sigma: 17 degrees +/- 4 vs 11 degrees +/- 3, less than 0.001; RV sigma: 31 degrees +/- 7 vs 14 degrees +/- 4, P less than 0.001). In the patients with VVI rate responsive pacemakers, the LV sigma changed from 18.5 +/- 3 under pacing to 11 degrees +/- 3 in sinus rhythm, P less than 0.001, while the RV sigma changed from 30 degrees +/- 8 to 14 degrees +/- 4, P less than 0.001. Instead in the patients with DDD pacemakers, the LV sigma changed from 15.5 degrees +/- 2 under pacing to 11 degrees +/- 3 in sinus rhythm, P less than 0.05, while the RV sigma changed from 29.1 degrees +/- 6 to 14 degrees +/- 4, P less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)     

New Cardiomechanic Pacing Lead Sensor Based on High Frequency Parameters: Experimental Studies in Sheep

Pacing Lead as a High Frequency Cardiomechanic Sensor . Introduction: The purpose of this study was to investigate the possibility of detecting and quantifying ventricular contraction in sheep utilizing the cardiomechanic sensor based upon the high frequency (HF) parameters measurements on bipolar cardiac pacing leads. Measurement of the HF reflection coefficient yields the lead‐bending signal (LBS) caused by myocardial contraction. The correlation between the lead‐bending acceleration (LBA) expressed as the rate of rise of LBS and LV dP/dt should reveal that LBS may be utilized as a cardiomechanic sensor in implantable cardiac electrotherapy devices. Methods and Results: We implanted 3 different pacing leads and tested the measurement system in 9 sheep (42 ± 6 kg) at baseline and during acute hemodynamic intervention with dobutamine infusion and tachycardia induced by VVI pacing at 200 bpm. A stable, consistent, and reproducible LBS was obtained in all sheep during the implantation procedure and 4 months after the implantation during different experimental conditions that included hemodynamic interventions. The dependence between LBA_max and LV dP/dt_max was found to be statistically significant and with high Pearson's correlation coefficient (r = 0.855, P <0.001). We could also observe the hemodynamic deterioration caused by fast ventricular pacing with the decrease of LV dp/dt and LBA compared with sinus rhythm. Conclusion: This study confirms the feasibility and efficacy of the hemodynamic sensor based upon HF lead parameters. Moreover, it was demonstrated that LBA_max is highly correlated to the ventricular contractility and, therefore, can be efficiently used as a hemodynamic and cardiomechanic sensor. (J Cardiovasc Electrophysiol, Vol. 24, pp. 338‐346, March 2013)     

TRANSURETHRAL RESECTION OF PARTIALLY OBSTRUCTED EJACULATORY DUCTS: SEMINAL PARAMETERS AND PREGNANCY OUTCOMES ACCORDING TO THE ETIOLOGY OF OBSTRUCTION

Purpose

We determine how transurethral resection of the ejaculatory ducts performed for infertility affects seminal parameters and pregnancy outcomes in patients with partial ejaculatory duct obstruction due to a congenital or acquired etiological factor.

Materials and Methods

Based on history and physical examination, hormonal profiles, semen analyses, transrectal ultrasonography and vasography findings partial ejaculatory duct obstruction was diagnosed in 14 men a mean of 30 years old who presented for infertility evaluation. Patients were grouped according to congenital or acquired cause of obstruction. Transurethral resection of the ejaculatory ducts was performed using the standard resectoscope loop technique. Clinical outcome was assessed by postoperative analyses of seminal parameters and pregnancy reports.

Results

Transurethral resection of the ejaculatory ducts significantly improved semen quality (ejaculate volume and percentage of sperm motility) in all patients in the congenital group, while all but 1 (83%) had an improved sperm count. Pregnancy was achieved via sexual intercourse by 66% of the patients an average of 5.7 months postoperatively. Of the acquired etiological factor group 37.5% had improved semen quality after transurethral resection of ejaculatory duct and 12.5% achieved pregnancy via sexual intercourse. Postoperative complications occurred at a similar rate in each group (33%). However, complications in the congenital etiology group were minor, while 25% of the men in the acquired group had significant impairment of seminal parameters after transurethral resection of the ejaculatory ducts.

Conclusions

Semen quality improvement and pregnancy outcome after transurethral resection of the ejaculatory ducts for partial ejaculatory duct obstruction differ significantly according to the main etiological cause of obstruction. An equivocal diagnosis of partial obstruction and technical problems during transurethral resection of the ejaculatory ducts may contribute to failure. However, in some cases the reason for failure remains unclear.     

URODYNAMIC AND CLINICAL EVIDENCE OF ACUTE INHIBITORY EFFECTS OF INTRAVESICAL NOCICEPTIN/ORPHANIN FQ ON DETRUSOR OVERACTIVITY IN HUMANS: A PILOT STUDY

PURPOSE: Management of neurogenic incontinence is complex and available treatments are not satisfactory. Nociceptin/orphanin FQ, a recently discovered neuropeptide, has been reported to inhibit the voiding reflex in the rat. These experimental results prompted us to investigate the urodynamic and clinical effects of intravesical instillation of nociceptin/orphanin FQ in humans. MATERIAL AND METHODS: Our study involved 5 normal subjects (group 1) with a mean age of 40.4 years (range 21 to 54) and 9 patients (group 2) 40.4 years (24 to 54). All patients in group 2 presented with detrusor hyperreflexia refractory to standard therapy. They were invited to undergo a filling cystometrogram with saline solution and after 30 minutes, a new one with a solution containing 1 microM. nociceptin/orphanin FQ. The urodynamic parameters that were recorded included bladder capacity, volume threshold for the appearance of detrusor hyperreflexia and maximum bladder pressure. Clinical and urodynamic followup was performed after 15 days. The data were statistically analyzed with 1-way analysis of variance followed by the Dunnett test for multiple comparison considered statistically significant with p <0.05. RESULTS: Intravesical instillation of 1 microM. nociceptin/orphanin FQ in group 1 did not produce significant functional changes. This infusion in group 2 produced a statistically significant increase in mean bladder capacity and volume threshold for the appearance of detrusor hyperreflexia from 164 plus or minus standard deviation (SD) 84 to 301 +/- 118 and 93 plus or minus SD 41 to 231 +/- 104 ml. (p <0.05, respectively). Mean maximum bladder pressure decreased from 79 plus or minus SD 25 to 54 +/- 44 cm. water but was not statistically significant (p = 0.19). After 15 days an absence of clinical improvement was noticed in group 2, and the urodynamic control did not show any significant changes compared to the values before nociceptin/orphanin FQ treatment. No severe symptomatic reactions were observed during infusion of 1 microM. nociceptin/orphanin FQ. CONCLUSIONS: Our results demonstrate that nociceptin/orphanin FQ is able to elicit a robust inhibitory effect on voiding reflex in group 2 but not 1. The ideal dosage, route of administration of nociceptin/orphanin FQ and treatment interval are not yet established.     

Reliability of scoring EMG orofacial events: polysomnography compared with ambulatory recordings

SUMMARY The study of sleep bruxism is usually based on clinical history, signs and symptoms. The recording of electromyographic signals with either ambulatory portable home recorders or with polysomnographic techniques in the laboratory environment allows collection of objective data. The present study showed a 100% agreement with clinical evaluation in the recognition of bruxism episodes from the masseter electromyogram recorded with portable recorders and using the polysomnographic technique. On the contrary, scorers had difficulties in discriminating between different types f episodes (phasic, tonic and mixed), the between-scorers agreement varied between 62% and 63% and the κ-values between 0.43 and 0.33. The ideal time base at which electromyographic signals should be integrated to allow for a good discrimination of bruxism patterns is 0.06 s. The results indicate that portable electromyography recorders are a valuable complement to polysomnographic recordings of orofacial motor activities as they provide a very good recognition rate with adequate time base data collection.     

The Commercial Determinants of Three Contemporary National Crises: How Corporate Practices Intersect With the COVID‐19 Pandemic,Economic Downturn,and Racial Inequity

Policy Points

•  The United States finds itself in the middle of an unprecedented combination of crises: a global pandemic, economic crisis, and unprecedented civic responses to structural racism.
•  While public sector responses to these crises have faced much justified criticism, the commercial determinants of these crises have not been sufficiently examined.
•  In this commentary we examine the nature of the contributions of such actors to the conditions that underpin these crises in the United States through their market and nonmarket activities.
•  On the basis of this analysis, we make recommendations on the role of governance and civil society in relation to such commercial actors in a post‐COVID‐19 world.

The united states finds itself amid three concurrent and interrelated crises. First, at the time of writing, the United States has reported more than 27 million confirmed COVID‐19 cases and more than 500,000 Americans have lost their lives. ¹ Second, in part as a consequence of the physical distancing measures enacted to slow the spread of the pandemic, the United States has faced record unemployment, a rise in the number of Americans unable to afford medical insurance, an end to federal support measures, and an uncertain economic outlook. According to the US Department of Labor, more than 50 million Americans have filed for unemployment benefits since the COVID‐19 pandemic started; more than 10 million Americans remain on state unemployment benefits. ² Third, the country is still contending with how to respond to mass civil protests in 2020 unlike any seen in half a century, triggered by the killing of George Floyd at the hands of police in Minneapolis. This civil unrest reflects centuries of structural racism and has brought unprecedented attention to this problem. ³ , ⁴ , ⁵ In each of these three concurrent crises, the pandemic, ongoing large‐scale unemployment, and civil protests, ⁶ the US federal response has been criticized as being delayed and poorly coordinated, involving downplaying the threat posed by the pandemic and building on longer‐term failures by previous administrations to make investments in public goods that may have facilitated a more robust and effective collective response.By contrast, it would appear that some of the largest entities in corporate America have responded more rapidly to each of the ongoing crises than the federal government has. A number of large companies have engaged in activities that responded to needs emerging from the pandemic, such as producing hand sanitizer, ⁷ setting up COVID‐19 testing sites, ⁸ and partnering on contact tracing. ⁹ Most notably, the pharmaceutical sector has contributed to an unexpectedly and unquestionably successful vaccine development process for SARS‐CoV‐2, with almost 200 million shots already distributed. ¹⁰ In response to the economic downturn, many companies have been adapting their business practices to supply essential services in a time of great disruption. For example, food and other essential businesses have largely kept supply chains for essential goods open, ¹¹ through extending working hours, hiring additional staff, and implementing new means of operating. Several large employers have responded to changing circumstance, aiming to keep as many employees working as possible, often through an embrace of remote working and implementing more permanent shifts into patterns of working. ¹² In response to the global protests around structural racism that erupted in 2020, a number of large companies, including Nike, Reebok, Twitter, and Citigroup, have publicly aligned themselves with the Black Lives Matter movement, ¹³ including committing more than a billion dollars in pledged donations. ¹⁴ In a moment of great national turmoil, when government seems not up to the task, private sector actors have appeared, by contrast, to be better positioned to address the three crises of the moment. This plays neatly into a private sector–centric narrative, and there is little question that much good has come from elements of the private sector during this time.It is certainly true that these visible private sector efforts have contributed to helping populations deal with the consequences of an unprecedented global pandemic. But, given the emerging evidence about the populations at risk for COVID‐19, and why that risk exists to begin with, it is legitimate to ask: in the case of COVID‐19, what was the contribution of the private sector in creating the conditions that made us vulnerable to the pandemic and its consequences to begin with? And, by extension, how can private sector actions align with a durable set of solutions to the crises that characterize this moment?We already know that large, consolidated corporate entities, particularly those that manufacture harmful products, can have profound effects on population health. ¹⁵ , ¹⁶ , ¹⁷ The most obvious way in which this manifests is through “market activity,” that is, the direct consequences of manufacturing and marketing particular products. For example, it is easy to recognize that marketing of cigarettes harms health. However, such actors also influence population health through a range of “nonmarket” activities that shape the political, social, and cultural environments that they operate in. ¹⁸ Examples of this activity include political donations, lobbying, corporate social responsibility initiatives, and legal activity. These activities, often seen as intrinsic to corporate practice, support and protect commercial interests, yet do not necessarily promote population health or structures of governance. Bearing this in mind, it is worth understanding how such activities, both market and nonmarket, have contributed to the vulnerability of the United States to the three crises we now face.