Physical coronary arteriogenesis of cardiac and extracardiac origin

Coronary collaterals are pre-formed connections that provide an alternative route when regular antegrade blood flow to the heart muscle is compromised. In response to a coronary obstruction, coronary collaterals undergo gradual enlargement, variably compensating for impaired antegrade blood flow. As natural bypasses, sufficiently large coronary collaterals can preserve myocardial perfusion and viability in the acute and chronic phases of coronary artery disease. In chronic stable coronary artery disease, medical therapy is complemented by established interventional therapies such as percutaneous coronary intervention and surgical coronary artery bypass grafting. However, new therapeutic options are needed for patients who are not candidates for conventional revascularization due to severe and/or diffuse obstructive coronary artery disease. Promotion of coronary collaterals represents such an alternative treatment option. However, while a multitude of interventions has been shown to be effective in collateral growth promotion, the effect of current interventions is only temporary and therefore recurrent application of the arteriogenic stimulus is necessary to sustain the level of collaterals. Historically, attempts to induce durable improvement of coronary collateral flow have already been made. Experimental and clinical studies examined the efficacy of distal ligation of the internal mammary artery (IMA) to augment blood flow to the coronary circulation. The basis of these studies was the clinical structural and experimental functional documentation of pre-formed connections between the internal mammary arteries and the coronary circulation - extracardiac collaterals. With the advent of coronary artery bypass grafting, the procedure was, however, abandoned. Notably, the clinical studies were based on crude outcome measures, such as symptomatic improvement. The function and in-vivo prevalence of internal mammary-to-coronary-anastomoses was therefore investigated in a clinical study (Project I) for the first time. 120 patients referred for elective coronary angiography for suspected or established coronary artery disease (CAD) underwent 180 pairs of coronary artery balloon occlusions, the first with and the second without simultaneous distal IMA occlusion (thought to augment flow via IMA-to-coronary connections). Collateral function was assessed during coronary balloon occlusion by collateral flow index (CFI), which is the ratio of coronary occlusive to aortic (effective perfusing) pressure, accounting for the back pressure (central venous pressure). Regional myocardial ischemia was assessed by the intracoronary electrocardiogram (ECG). With simultaneous distal IMA occlusion CFI was significantly higher during left IMA with left anterior descending coronary artery (LAD) occlusion and right IMA with right coronary artery (RCA) occlusion than during LAD or RCA occlusionalone. Conversely, during contralateral IMA occlusion, ie RCA with left IMA or LAD or left circumflex coronary artery (LCX) with right IMA occlusion, CFI was not different. Concordantly, myocardial ischemia by intracoronary ECG was lower during LAD or RCA occlusion with simultaneous ipsilateral IMA occlusion nd was not different during contralateral IMA occlusion or with LCX occlusion. In conclusion, it could be demonstrated that there was functional, ischemia-reducing collateral supply from the ipsilateral IMA to the right coronary and the left anterior descending coronary artery. The effect of permanent distal right IMA on coronary collateral function was investigated or the first time in an open-label clinical trial (Project II). 50 patients with stable CAD underwent distal right IMA closure at baseline and determination of right and left coronary function (LAD or LCX) by CFI at baseline and at follow-up 6 weeks after right IMA device closure. CFI in the untreated RCA increased significantly from baseline to follow-up, while CFI in the untreated left coronary remained unchanged. Concordantly, regional myocardial ischemia determined by intracoronary ECG was reduced during a 1-minute coronary balloon occlusion in the RCA but not in the left coronary. In conclusion, permanent distal right IMA closure in this non-randomized study appeared to augment extracardiac right coronary collateral supply. With acute myocardial ischemia, the mainstay of therapy lies in the antegrade technique of prompt percutaneous revascularization. However, a reopened epicardial conduit artery does not guarantee reperfusion of myocardial tissue, which can be impaired by microvascular dysfunction. In this situation of a failed antegrade approach, retrograde treatment approach has been proposed by an intervention in the coronary venous system - intermittent coronary sinus occlusion (CSO). Although the ischemia-relieving effect of CSO is thought to depend on coronary collaterals, its role of coronary collaterals has so far not been clearly defined in humans. The role of coronary collaterals in the anti-ischemic effect of CSO was therefore investigated in a clinical study (Project III) and in a computer simulation (Project IV). In the clinical study, 35 patients with stable coronary artery disease underwent two 2-minute balloon occlusions of a major coronary artery to induce controlled ischemia. CSO was performed randomized to the first or second coronary balloon occlusion.Collateral function was assessed by CFI and regional myocardial ischemia was assessed by the ST-segment shift in the intracoronary ECG. Intermittent coronary sinus occlusion was shown to reduce myocardial ischemia depending on the extent of collateral function. With minimal collateral function, no ischemia-reducing effect of CSO was demonstrated. An anti-ischemic effect of CSO was seen with intermediate collateral function. High collateral function prevented myocardial ischemia in the first place and therefore, no additional effect of CSO was demonstrated. The computer simulation (Project IV) consisted of a lumped-parameter model of a two-branch left coronary system circuit with arterial, capillary and venous compartments. As a key point, arterial collateral connections were an integral part of the model, in contrast to prior computer models. Importantly, the salient features of coronary pressure and flow during non-ischemic and ischemic conditions, as well as during CSO could be reproduced. In particular, the proposed main mechanism of CSO - retrograde flow from the venous to the venular and capillary compartment was reproduced by the model. As a key point, the model predicted retrograde flow to be dependent on the extent of collateral blood flow and contractility. With minimal collateral function, retrograde flow to an ischemic region was low, while it progressively increased with higher collateral function. Accounting for the combination of reduced contractility during ischemia and the level of collateral function, the effect on retrograde flow was much increased. Retrograde flow was predicted to be very low at zero to minimal collateral function and concomitantly severely reduced contractility. Conversely, retrograde flow increased steeply with increasing collateral function and more preserved contractility. In essence, the mathematical model provided a reasonable explanation for the findings from the clinical study (Project III) and could, for the first time, provide an explanation for the role of collaterals in the anti-ischemic effect of CSO

The human coronary collateral circulation: development and clinical importance

Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischaemia. In comparison with other species, the human coronary collateral circulation is very well developed. Among individuals without coronary artery disease (CAD), there are preformed collateral arteries preventing myocardial ischaemia during a brief vascular occlusion in 20-25%. Determinants of such anastomoses are low heart rate and the absence of systemic arterial hypertension. In patients with CAD, collateral arteries preventing myocardial ischaemia during a brief occlusion are present in every third individual. Collateral flow sufficient to prevent myocardial ischaemia during coronary occlusion amounts to one-fifth to one-fourth the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction, and the inverse of collateral supply. Well-developed coronary collateral arteries in patients with CAD mitigate myocardial infarcts and improve survival. Approximately one-fifth of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients. It should aim at growth of large conductive collateral arteries (arteriogenesis). Potential arteriogenic approaches include the treatment with granulocyte colony-stimulating factor, physical exercise training, and external counterpulsatio

Interactive effects of added L-carnitine and chromium picolinate on sow reproductive performance

A total of 599 sows were used to determine the effects of added L-carnitine and/or chromium picolinate on reproductive performance. Experimental treatments were arranged in a 2 × 2 factorial with main effects of added L-carnitine (0 or 50 ppm) and chromium picolinate (0 or 200 ppb). Starting on the first day of breeding, sows were provided a daily top dress containing the carnitine and(or) chromium along with the standard gestation diet. Dietary treatments were administered daily through the initial gestation, lactation, and through a second gestation period (2 parities). During the first parity, there was a carnitine × chromium interaction (P0.05) were observed in number of pigs born alive, still born, mummies, or total born in the first parity. Added dietary L-carnitine decreased (P<0.05) wean to estrus interval, and tended to increase (P<0.08) the number of sows in estrus by d 7. In the second parity, a tendency (P<.08) for a carnitine × chromium interaction was found for first service farrowing rate. Adding carnitine and chromium together in the diet increased first service farrowing rate compared to either product alone. Because of the change in wean-to-estrus interval and farrowing rate, feeding additional dietary carnitine and chromium increased (P<0.04) the percentage of sows that were weaned from parity 1 and farrowed in parity 2. When calculating the total number of pigs and number born alive based on all sows that were started on test, both added carnitine and chromium increased the number of pigs born and born alive. These results show that carnitine and chromium supplementation improved return-to- estrus interval and farrowing rate and, thus, total number born alive over two parities

Targeted microbubbles: a novel application for the treatment of kidney stones

Kidney stone disease is endemic. Extracorporeal shockwave lithotripsy was the first major technological breakthrough where focused shockwaves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: (i) bisphosphonates attach to hydroxyapatite crystals with high affinity; and (ii) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to pre-emptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by virtue of being used as an adjunct to traditional imaging methods, especially useful in high-risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine

Soft Microreactors for the Deposition of Conductive Metallic Traces on Planar, Embossed, and Curved Surfaces

Advanced manufacturing strategies have enabled large‐scale, economical, and efficient production of electronic components that are an integral part of various consumer products ranging from simple toys to intricate computing systems; however, the circuitry for these components is (by and large) produced via top‐down lithography and is thus limited to planar surfaces. The present work demonstrates the use of reconfigurable soft microreactors for the patterned deposition of conductive copper traces on flat and embossed two‐dimensional (2D) substrates as well as nonplanar substrates made from different commodity plastics. Using localized, flow‐assisted, low‐temperature, electroless copper deposition, conductive metallic traces are fabricated, which, when combined with various off‐the‐shelf electronic components, enabled the production of simple circuits and antennas with unique form factors. This solution‐phase approach to the patterned deposition of functional inorganic materials selectively on different polymeric components will provide relatively simple, inexpensive processing opportunities for the fabrication of 2D/nonplanar devices when compared to complicated manufacturing methods such as laser‐directed structuring. Further, this approach to the patterned metallization of different commodity plastics offers unique design opportunities applicable to the fabrication of planar and nonplanar electronic and interconnect devices, and other free‐form electronics with less structural “bloat” and weight (by directly coating support elements with circuitry)

Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing

DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA’s signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies

GAS FLOW ANALYSIS IN LOW ENERGY ARC PUFFER INTERRUPTERS

ABSTRAC

Early Switch from Intravenous to Oral Antibiotics in Skin- and Soft-tissue Infections: An Algorithm-based Prospective Multicentre Pilot Trial.

BACKGROUND: In hospitalized patients with skin and soft tissue infections (SSTIs), intravenous (IV) empiric antibiotic treatment is initiated. The best time point for switching from IV to oral treatment is unknown. We used an algorithm-based decision tree for the switch from IV to oral antibiotics within 48 hours and aimed to investigate the treatment outcome of this concept. METHODS: In a nonrandomized trial, we prospectively enrolled 128 patients hospitalized with SSTI from July 2019 to May 2021 at 3 institutions. Clinical and biochemical response data during the first week and at follow-up after 30 days were analyzed. Patients fulfilling criteria for the switch from IV to oral antibiotics were assigned to the intervention group. The primary outcome was a composite definition consisting of the proportion of patients with clinical failure or death of any cause. RESULTS: Ninety-seven (75.8%) patients were assigned to the intervention group. All of them showed signs of clinical improvement (ie, absence of fever or reduction of pain) within 48 hours of IV treatment, irrespective of erythema finding or biochemical response. The median total antibiotic treatment duration was 11 (interquartile range [IQR], 9–13) days in the invention group and 15 (IQR, 11–24) days in the nonintervention group (P < .001). The median duration of hospitalization was 5 (IQR, 4–6) days in the intervention group and 8 (IQR, 6–12) days in the nonintervention group (P < .001). There were 5 (5.2%) failures in the intervention group and 1 (3.2%) in the nonintervention group after a median follow-up of 37 days. CONCLUSIONS: In this pilot trial, the proposed decision algorithm for early switch from IV to oral antibiotics for SSTI treatment was successful in 95% of cases. Clinical Trials Registration. ISRCTN1524549

Introducing the national COPD resources and outcomes project

<p>Abstract</p> <p>Background</p> <p>We report baseline data on the organisation of COPD care in UK NHS hospitals participating in the National COPD Resources and Outcomes Project (NCROP).</p> <p>Methods</p> <p>We undertook an initial survey of participating hospitals in 2007, looking at organisation and performance indicators in relation to general aspects of care, provision of non-invasive ventilation (NIV), pulmonary rehabilitation, early discharge schemes, and oxygen. We compare, where possible, against the national 2003 audit.</p> <p>Results</p> <p>100 hospitals participated. These were typically larger sized Units. Many aspects of COPD care had improved since 2003. Areas for further improvement include organisation of acute care, staff training, end-of-life care, organisation of oxygen services and continuation of pulmonary rehabilitation.</p> <p>Conclusion</p> <p>Key Points: positive change occurs over time and repeated audit seems to deliver some improvement in services. It is necessary to assess interventions such as the Peer Review used in the NCROP to achieve more comprehensive and rapid change.</p