Molecular neuro-biological and systemic health benefits of achieving dopamine homeostasis in the face of a catastrophic pandemic (COVID- 19): A mechanistic exploration.

In the face of the global pandemic of COVID 19, approaching 1.75 Million infected worldwide (4/12/2020) and associated mortality (over 108, 000 as of 4/12/2020) as well-as other catastrophic events including the opioid crisis, a focus on brain health seems prudent [1] (https://www.coronavirus.gov). This manuscript reports on the systemic benefits of restoring and achieving dopamine homeostasis to reverse and normalize thoughts and behaviors of Reward Deficiency Syndrome (RDS) dysfunctional conditions and their effects on behavioral physiology; function of reward genes; and focuses on digestive, immune, eye health, and the constellation of symptomatic behaviors. The role of nutrigenomic interventions on restoring normal brain functions and its benefits on these systems will be discussed. We demonstrate that modulation of dopamine homeostasis using nutrigenomic dopamine agonists, instead of pharmaceutical interventions, is achievable. The allied interlinking with diverse chronic diseases and disorders, roles of free radicals and incidence of anaerobic events have been extensively highlighted. In conjunction, the role of dopamine in aspects of sleep, rapid eye movement and waking are extensively discussed. The integral aspects of food indulgence, the influence of taste sensations, and gut-brain signaling are also discussed along with a special emphasis on ocular health. The detailed mechanistic insight of dopamine, immune competence and the allied aspects of autoimmune disorders are also highlighted. Finally, the integration of dopamine homeostasis utilizing a patented gene test and a research-validated nutrigenomic intervention are presented. Overall, a cutting-edge nutrigenomic intervention could prove to be a technological paradigm shift in our understanding of the extent to which achieving dopamine homeostasis will benefit overall health.

A comparison of reproductive characteristics of boars generated by somatic cell nuclear transfer to highly related conventionally produced boars.

This study compares the reproductive performance of boars produced by somatic cell nuclear transfer versus conventional breeding. Two different genotypes were selected for comparison: terminal cross line 1 (TX1) and terminal cross line 2 (TX2). The boars selected for comparison from TX1 were three cloned boars, produced by somatic cell nuclear transfer and the conventionally produced progenitor of the clones. The boars selected for comparison from TX2 were a cloned boar produced by somatic cell nuclear transfer and two conventionally produced half sibling boars that were offspring of the progenitor of the clone. Semen from each boar was collected, extended, evaluated and shipped offsite. Upon arrival, the semen was reevaluated and utilized for artificial insemination of 89 commercial gilts, at least 12 gilts per boar, producing 625 piglets. Pregnancy rates were determined at day 30 and 110 of gestation; and farrowing rate and gestation length were recorded. Differences were observed in some of the semen characteristics analyzed with the clones usually possessing superior semen quality to the control, this likely being a result of age differences amongst the clones and controls. Additionally no differences were noted between the clones and controls (progenitor) or between individual boars within genetic line for pregnancy rates, gestation length or any of the litter parameters examined between the clones and controls. These data further support previous reports with limited numbers that the reproductive capabilities of cloned boars are equal to that of conventionally produced boars.

Genetic parameters for various random regression models to describe total sperm cells per ejaculate over the reproductive lifetime of boars.

The objective of this study was to model the variances and covariances of total sperm cells per ejaculate (TSC) over the reproductive lifetime of AI boars. Data from boars (n = 834) selected for AI were provided by Smithfield Premium Genetics. The total numbers of records and animals were 19,629 and 1,736, respectively. Parameters were estimated for TSC by age of boar classification with a random regression model using the Simplex method and DxMRR procedures. The model included breed, collector, and year-season as fixed effects. Random effects were additive genetic, permanent environmental effect of boar, and residual. Observations were removed when the number of data at a given age of boar classification was < 10 records. Preliminary evaluations showed the best fit with fifth-order polynomials, indicating that the best model would have fifth-order fixed regression and fifth-order random regressions for animal and permanent environmental effects. Random regression models were fitted to evaluate all combinations of first- through seventh-order polynomial covariance functions. Goodness of fit for the models was tested using Akaike's Information Criterion and the Schwarz Criterion. The maximum log likelihood value was observed for sixth-, fifth-, and seventh-order polynomials for fixed, additive genetic, and permanent environmental effects, respectively. However, the best fit as determined by Akaike's Information Criterion and the Schwarz Criterion was by fitting sixth-, fourth-, and seventh-order polynomials; and fourth-, second-, and seventh-order polynomials for fixed, additive genetic, and permanent environmental effects, respectively. Heritability estimates for TSC ranged from 0.27 to 0.48 across age of boar classifications. In addition, heritability for TSC tended to increase with age of boar classification.

Long-term infection rates associated with the pectoral versus abdominal approach to cardioverter- defibrillator implants.

Infection is an uncommon (0% to 6.7%) but serious complication after implantable cardioverter-defibrillator (ICD) implantation. All ICD primary implants, replacements, or revisions performed at the Massachusetts General Hospital between April 1983 and May 1999 were reviewed. A total of 21 ICD-related infections (1.2%) were identified among 1,700 procedures affecting 1.8% of the 1,170 patients who underwent a primary implant, a generator change, or a revision of their systems. The mean follow-up time was 35 +/- 33 months. Of the 959 patients with long-term follow-up, 19 of the 584 patients (3.2%) with abdominal and 2 of the 375 patients (0.5%) with pectoral systems developed ICD-related infections (p = 0.03). There was no significant difference between the infection rate among the 959 primary ICD implants and the 447 replacements or system revisions. Only 5 of the patients (24%) had systemic signs of infection, including fever (T>100.5) and elevated white blood count >12,000. Cultures from the wound revealed staphylococcal species in 16 patients (76%). Nineteen patients were treated with removal of the entire ICD system in addition to intravenous antibiotics for 2 to 4 weeks. A decrease in the incidence of ICD-related infection has occurred since the advent of transvenous pectoral systems. The main organism responsible for ICD infection is Staphylococcus. The mainstay of ICD infection management consists of complete removal of the entire implanted system.

Left ventricular hamartoma associated with ventricular tachycardia.

Cardiac hamartomas are a rare type of benign tumor affecting the heart. We describe a 33-year-old patient who presented with a wide complex tachycardia. Diagnostic imaging revealed a mass in the patient's left ventricular wall, near the apex of the heart. The mass was surgically resected and appeared benign. Its pathology was that of a hamartoma of mature cardiac myocytes. Postoperative electrophysiology evaluation showed no inducible focus and the patient remains alive and asymptomatic after 2 years of follow-up.

Lead noise with an active-fixation defibrillation lead.

Inappropriate detection and therapy is the most common adverse effect of implantable cardioverter defibrillator therapy. One mechanism is lead artifact, which usually presents late and is due to stress and fatigue of the lead components. Our experience with a defibrillator lead (Endotak Endurance EZ leads, Models 0154/0155/0156) and its method of active fixation is described. Of 20 implants with this lead, four patients were found to have noise that resulted in inappropriate detections in three. No patient received therapy as a consequence of these detections. The artifact appeared soon after implant and resolved in three of four cases by 4 weeks. None of the 16 remaining patients developed noise after this time. This is a unique lead problem that resolves with time, but it may result in inappropriate therapies and difficult management decisions in high risk patients with ventricular arrhythmias.

Variation of clinical target volume definition in three-dimensional conformal radiation therapy for prostate cancer.

PURPOSE: Currently, three-dimensional conformal radiation therapy (3D-CRT) planning relies on the interpretation of computed tomography (CT) axial images for defining the clinical target volume (CTV). This study investigates the variation among multiple observers to define the CTV used in 3D-CRT for prostate cancer. METHODS AND MATERIALS: Seven observers independently delineated the CTVs (prostate +/- seminal vesicles [SV]) from the CT simulation data of 10 prostate cancer patients undergoing 3D-CRT. Six patients underwent CT simulation without the use of contrast material and serve as a control group. The other 4 had urethral and bladder opacification with contrast medium. To determine interobserver variation, we evaluated the derived volume, the maximum dimensions, and the isocenter for each examination of CTV. We assessed the reliability in the CTVs among the observers by correlating the variation for each class of measurements. This was estimated by intraclass correlation coefficient (ICC), with 1.00 defining absolute correlation. RESULTS: For the prostate volumes, the ICC was 0.80 (95% confidence interval [CI]: 0.56-0.96). This changed to 0.92 (95% CI: 0.75-0.99) with the use of contrast material. Similarly, the maximal prostatic dimensions were reliable and improved. There was poor agreement in defining the SV. For this structure, the ICC never exceeded 0.28. The reliability of the isocenter was excellent, with the ICC exceeding 0.83 and 0.90 for the prostate +/- SV, respectively. CONCLUSIONS: In 3D-CRT for prostate cancer, there was excellent agreement among multiple observers to define the prostate target volume but poor agreement to define the SV. The use of urethral and bladder contrast improved the reliability of localizing the prostate. For all CTVs, the isocenter was very reliable and should be used to compare the variation in 3D dosimetry among multiple observers.

A comparison of multileaf-collimator and alloy-block field shaping.

PURPOSE: The purpose of this report was to compare the dose distribution at a field edge defined with divergent alloy blocks to the distribution obtained with a multileaf collimator (MLC). The comparison is made for simple block replacement situations. METHODS AND MATERIALS: A tertiary multileaf collimator mounted on a linear accelerator operating at 6 MV was compared to divergent alloy blocks positioned at the level of the blocking tray. The leaves of the MLC were positioned to give maximum stepping (leaf displacement equals leaf width), and the blocking produced the same field shape. Three different treatment plans were compared: single field, opposed fields, and a four-field "box." Dose distributions were determined using radiographic film scanned with a laser densitometer with a 0.45-mm spot size. One experiment was repeated using radiochromic film with reduced energy dependence. Dose distributions were examined on the isocenter plane, and on planes displaced by 1.0 and 2.5 cm. The effect of daily setup variations was also studied by comparing a single fraction treatment with a fractionated treatment consisting of 15 fields slightly displaced relative to each other. The magnitude of these displacements was determined using available literature on treatment reproducibility. RESULTS: For a single field plan, maximum stepping of an MLC-defined edge produces an obvious undulating dose pattern compared to an alloy block edge. At the isocenter plane, this pattern is unchanged when parallel opposed fields are used. However, blurring occurs for both MLC and block edges when planes displaced from the isocenter are examined. The gradient for the block edge is 8%/mm for opposed fields and a plane 2.5 cm from the isocenter, compared to 15%/mm for the isocenter plane. Adding two additional fields does not change the dose pattern in the isocenter plane, but does reduce the gradient across the steepest portion of the penumbra to 8%/mm, and shifts the isodose line with the most pronounced stepping to higher values (from 50 to 80%). Introducing daily setup variations results in a reduction of the sharp dose gradient along the sides of a single field, and around the periphery of the beam at the isocenter plane of opposed fields. Smaller changes are found for edges already blurred by other factors. Radiochromic film was generally noisier than radiographic film, but comparison of the two films did not show a significant difference, indicating that the energy dependence of the radiographic film was not a problem. CONCLUSIONS: The obvious dose stepping seen on a portal image of a single field with MLC shaping is shown to be partially erased by the addition of other fields, and for planes away from the isocenter. However, the effects of daily setup variations must be included to more effectively blur dose stepping along the external envelope of a single field or near the isocenter plane of opposed fields. This result conflicts with attempts to improve immobilization.

Warping CT scans from nontreatment to treatment position.

This paper describes a cost-effective technique that optimally utilizes all available diagnostic studies for three-dimensional treatment planning. A simulator unit modified to produce cross-sectional images (simulator-CT unit) is used to create a reference data set with the patient in the treatment position. Registration software (qsh) brings other diagnostic studies into agreement with this reference data set. Two cases are presented as examples of the use of this technique. Registration of abdominal scans from the same patient demonstrates the warping of a nontreatment position study to the treatment position. The second case is based on paired data sets through the head, in which the diagnostic study was obtained by using a gantry tilt to follow the base of the skull and to avoid sections passing through the teeth. The registration software provides a method for combining diagnostic studies into a single "master" data set. The success of the transformation depends on the operator's ability to identify corresponding anatomic landmarks for different data sets and on the magnitude of the variation in the patient's position from one procedure to the next. Limitations in image quality and the number of cross-sections obtainable from a simulator-CT unit can be partially overcome by using the described technique. Thus, the information contained in nontreatment position diagnostic tests can be used accurately for treatment planning at limited cost.

The site of acute myocardial infarction is related to the coronary territory of transient defects on prior myocardial perfusion imaging.

BACKGROUND: Prior studies have established the prognostic value of myocardial perfusion imaging. In particular, the presence and extent of transient defects have been shown to predict future cardiac events including acute myocardial infarction. However, the relationship between the location of the perfusion defect and the site of subsequent myocardial infarction remains unclear. METHODS AND RESULTS: Review of prior records of consecutive patients admitted with acute myocardial infarction identified 34 patients whose prior myocardial perfusion imaging studies had demonstrated transient defects and no interval revascularization. The coronary artery territory of the transient defects was identified and related to the site of subsequent acute myocardial infarction. To reduce the potentially confounding effect of progression of coronary artery disease between the time of the myocardial perfusion imaging study and subsequent infarction, patients were divided into those less than 2 years and those 2 years or greater between imaging and infarction. Among patients with a transient defect and less than 2 years between infarction and imaging, 11 (79%) of 14 had a myocardial infarction in the same coronary territory as their prior transient defect (p < 0.0005). This association decreased to only five (25%) of 20 when the interval was 2 years or greater (difference not significant). Among 22 patients who had undergone prior coronary angiography, myocardial infarction occurred in the same coronary territory as the most severe angiographic stenosis in 12 (54%). The association was not related to the time interval between angiography and infarction. CONCLUSIONS: There is a strong association between the coronary territory of transient defects on myocardial perfusion imaging and the site of subsequent myocardial infarction when the duration is less than 2 years. These observations support the concept that the hemodynamic significance of a coronary lesion is an important factor in the pathophysiology of acute myocardial infarction.

Field edge smoothing for multileaf collimators.

PURPOSE: To smooth the scalloped dose pattern that occurs for stepped leaves at a treatment field edge defined by a multileaf collimator. METHODS AND MATERIALS: Fields with centers shifted slightly in space were superimposed to blur the staggered dose distribution at the field edge. Film dosimetry was used to monitor changes. The dose distribution for a single field position was compared to the distribution for one and three shifts. Three depths were examined and divergent alloy blocks were included in the comparison. RESULTS: The structure that appears at an edge for a single field when leaves are staggered was nearly eliminated when the field was shifted three times to give a total of four different positions. However, shifting the field one time so that two fields were superimposed gave an intermediate result with only slight improvement in the undulating dose distribution. For the four superimposed fields, the 50% isodose pattern converged to a smoothed line running along the center of the original undulating pattern. The 80 and 20% isodoses did not converge to the center of their scalloped patterns. Instead, these isodose lines were spread leaving a larger penumbra width than a divergent alloy block. CONCLUSIONS: Shifting and adding fields is an effective method for smoothing the staggered dose distribution that results when the leaves of a multileaf collimator are stepped to form an irregular field pattern. However, the width of the penumbra for the combined fields is wider than the penumbra for a cerrobend block.

The use of digitally reconstructed radiographs for three-dimensional treatment planning and CT-simulation.

PURPOSE: Recent interest in computed tomography-simulation (CT-simulation) suggests the possibility of a shift to digital images for field verification. This article examines the quality of Digitally Reconstructed Radiographs (DRRs) to determine if they can reasonably be substituted for conventional simulator films, and suggests techniques to improve these images. METHODS AND MATERIALS: Special developmental software and computer hardware allowed extremely rapid reformatting of CT data to produce images geometrically equivalent to treatment unit portal films. The technique uses a trilinear interpolation algorithm and gives a 512 x 512 DRR for any arbitrary beam direction. Resolution in line pairs/cm (lp/cm) for both simulator radiographs and DRRs was measured with a special test phantom. Patient data was reformatted to illustrate methods for improving the quality of the DRR. RESULTS: The equipment used for this study reformats 50 512 x 512 CT scans in 8 s. The resolution for a DRR is limited by the voxel size of the CT scans. For typical voxel dimensions, the resolution was found to be 7 lp/cm transverse and 1.0 lp/cm longitudinal compared to 21.0 lp/cm for a simulator radiograph. Patient movement during the scan procedure further degrades the DRR. The reduced quality of this image makes it more difficult to discern structures, and it may not always be possible to perform essential tasks such as counting vertebral bodies. However, viewing the treatment field superimposed on a DRR displayed with a step function to include only bone aided in the identification of relevant landmarks. Switching between soft tissue, bone, or air windows takes less than 10 s on the equipment used for this study, and the use of different display techniques improved the viewer's ability to evaluate field positioning. CONCLUSIONS: A DRR cannot match the spatial resolution of a radiograph taken with a short exposure and small focal spot, but the ability to change the display mode for the DRR increases the usefulness of these images. Fast reformatting is particularly important when evaluation of field position requires the comparison of each portal image to a series of DRRs.

Evolution of drug resistance in CCRF-CEM human leukemia cells selected by intermittent methotrexate exposure.

A clinically relevant mechanism of acquired methotrexate (MTX) resistance is decreased MTX polyglutamate (MTXGn) synthesis (McCloskey et al. J. Biol. Chem. 266:6181, 1991) secondary to deficient folylpolyglutamate synthetase (FPGS) activity. Earlier studies showed that this mechanism resulted after intermittent MTX treatment, but did not define its evolution in populations or its clonal frequency of occurrence and heterogeneity. We thus studied evolution of resistance in CCRF-CEM human leukemia cell populations and clones after repeated treatment with 30 microM MTX for 24 h. In populations, MTX resistance was detectable after 1 treatment and increased in degree as total cycles increased to 7. Defective MTXGn synthesis in populations was the only resistance mechanism detected, and FPGS activity in extracts decreased with treatment cycle. After 1 treatment, defective MTXGn synthesis was the major (27/48 clones) form of resistance; 18 clones were sensitive, while 1 clone with a DHFR-related change, no clones with decreased MTX uptake, and 2 complex phenotypes were observed. Sporadic clones with DHFR-mediated resistance appeared up to cycle 4, but defective MTXGn synthesis remained the major resistance mechanism. The degree of clonal resistance tended to increase with treatment cycle, but 1 clone in cycle 2 was similar to the clones from cycle 7. No change in FPGS gene copy number or restriction pattern, or FPGS mRNA level or size (2.3 Kb) was detected in populations. Decreased FPGS activity must result from decreased translation, increased protein turnover, or a point mutation affecting catalysis.

A procedure for successful nonsurgical embryo transfer in swine.

The current study was undertaken to develop a successful procedure for the nonsurgical transfer of pig embryos. A total of 663 embryos were surgically collected on Day 4 or 5 from 55 donors, of which 542 embryos of acceptable quality were nonsurgically transferred to 46 recipients. Nonsurgical recipient gilts were sedated 15 min prior to transfer with 20 mg im acepromazine maleate. A disposable insemination spirette with an attached 3-way stopcock was manipulated into the cervix of each gilt. Embryos were expelled from a tomcat catheter into the spirette, and 10 to 12 ml of Whitten's medium were used to flush embryos through the spirette into the reproductive tract. Sixteen (34.8%) recipient gilts did not return to estrus before Day 36, and 10 (21.7%) gilts farrowed with an average litter size of 4.3 +/- 0.7. Embryos were collected from an additional 20 donors and were surgically transferred to an additional 19 recipients. Surgical transfers conducted at the same time as the nonsurgical transfers resulted in 12 (63.2%) gilts farrowing and 7.1 +/- 0.6 pigs were born per litter. In conclusion, a procedure has been developed for nonsurgical transfer of swine embryos which simplifies the process of embryo transfer and which may increase the potential for utilization of embryo transfer technologies by swine producers.

Combining multileaf fields to modulate fluence distributions.

PURPOSE: A method for modulating beam fluence from a linear accelerator is discussed. The beam modulation is accomplished remotely using a multileaf collimator and does not require entering the treatment room. METHODS AND MATERIALS: The multileaf collimator is used to define a series of field shapes that are superimposed at a fixed gantry angle to produce any desired fluence pattern. A heuristic technique for deriving the field shapes and corresponding monitor unit settings is described. The technique has been tested on randomly generated fluence distributions and on distributions with a limited number of peaks and valleys. The second type of distribution more closely simulates fluence patterns obtained with dose optimization software. Estimates of the time required to use this approach to treat a four-field plan are given and compared to the technique of placing a physical compensator in each beam. RESULTS: It has been demonstrated that complex fluence patterns within a 15 x 15 cm2 field can be achieved with less than 20 fields. Estimates show that this technique is faster than entering the treatment room to change physical compensators. Some limitations of the method are discussed. CONCLUSION: Optimized distributions that conform the dose to irregularly shaped target volumes that wrap around critical structures are possible using superimposed multileaf fields. A method for defining the field shapes is presented.

A new technique for positioning tangential fields.

PURPOSE: A technique that eliminates the use of a mechanical "breast-bridge" for positioning tangential fields for treatment of the intact breast or chest wall has been developed. METHODS AND MATERIALS: Treatment set-up parameters are determined using measuring capabilities (gantry angles and source-skin distances) available on a standard simulator unit. A programmable scientific calculator is used to determine field geometry from polar coordinates for various points on the patient's skin. The calculator program determines the field size, a depth and lateral shift from a skin reference point to the isocenter for the tangential fields, and the gantry angles. The program provides additional information which facilitates the simulation process: First, the coordinates of the isocenter for the tangential fields are expressed relative to couch coordinates for an initial arbitrary isocenter so that the "auto go to" capability available on some simulators can be used. Second, the coordinates of the medial and lateral entry points can be edited when the first set of tangents are not accepted. This part of the program allows quick and efficient adjustment of the fields to obtain adequate treatment volume coverage and a minimum of irradiated lung or heart. RESULTS: Simulation of more than 300 patients has shown the technique to be a practical and efficient method for positioning tangential fields for breast or chest wall irradiation. CONCLUSION: The technique described here takes full advantage of the capabilities of the new generation of computer controlled simulators, and offers an alternative to previous methods employing a mechanical "breast-bridge."

Reproductive performance in relation to uterine and embryonic traits during early gestation in Meishan, large white and crossbred sows.

Previous studies have shown that females of the Chinese Meishan breed and of their F1 cross with European Large White pigs are very prolific, producing about four more piglets per litter than control Large White females. The main cause of this prolificacy is enhanced prenatal survival for a given ovulation rate in Meishan and F1 females and this is controlled by genes of the mother, not those of the conceptus. The objectives of this study were to determine whether genotypic differences in embryo survival were apparent in the period immediately after attachment and to compare embryonic and uterine development at this time. Sows in their third parity (20 Large White, 14 Meishan, 25 Large White x Meishan F1 and 25 Meishan x Large White F1) were killed 20-22 days after mating and their reproductive tracts recovered for further study. There were significant differences between the purebred sows, and crossbred sows were approximately intermediate for the number of corpora lutea (20.7 +/- 0.9, 27.8 +/- 1.1, 22.4 +/- 0.8 and 23.3 +/- 0.8 for the four genotypes, respectively), the number of embryos (15.2 +/- 0.9, 23.4 +/- 1.1, 17.2 +/- 0.8 and 18.8 +/- 0.8, respectively) and the proportionate embryo survival (0.74 +/- 0.04, 0.84 +/- 0.04, 0.78 +/- 0.03 and 0.82 +/- 0.03, respectively). There was a negative association within genotype between embryo survival and the number of corpora lutea. Adjusting for the genotypic difference in the number of corpora lutea increased the genotypic differences in embryo survival.(ABSTRACT TRUNCATED AT 250 WORDS)