Diabetes and Wound Angiogenesis.

Diabetes Mellitus Type II (DM2) is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes.

MicroCT angiography detects vascular formation and regression in skin wound healing.

Properly regulated angiogenesis and arteriogenesis are essential for effective wound healing. Tissue injury induces robust new vessel formation and subsequent vessel maturation, which involves vessel regression and remodeling. Although formation of functional vasculature is essential for healing, alterations in vascular structure over the time course of skin wound healing are not well understood. Here, using high-resolution ex vivo X-ray micro-computed tomography (microCT), we describe the vascular network during healing of skin excisional wounds with highly detailed three-dimensional (3D) reconstructed images and associated quantitative analysis. We found that relative vessel volume, surface area and branching number are significantly decreased in wounds from day 7 to days 14 and 21. Segmentation and skeletonization analysis of selected branches from high-resolution images as small as 2.5µm voxel size show that branching orders are decreased in the wound vessels during healing. In histological analysis, we found that the contrast agent fills mainly arterioles, but not small capillaries nor large veins. In summary, high-resolution microCT revealed dynamic alterations of vessel structures during wound healing. This technique may be useful as a key tool in the study of the formation and regression of wound vessels.

Guillain-Barre Syndrome Associated With COVID-19 Pneumonia-The First Documented Case in a U.S. Military Intensive Care Unit.

Coronavirus disease 2019 (COVID-19) is a significant cause for intensive care unit (ICU) admission worldwide. Most COVID-19 infections are associated with lower respiratory abnormalities but it has been increasingly associated with extra-pulmonary manifestations. Guillain-Barre syndrome (GBS) is a rarely diagnosed but severe disease associated with COVID-19 infection. We describe the diagnostic process behind diagnosing GBS in an elderly male who developed acute-onset quadriparesis and respiratory muscle failure associated with severe COVID-19 pneumonia in a military ICU. A 69-year-old male was admitted to the ICU for acute hypoxemic respiratory failure due to COVID-19 pneumonia. He was subsequently intubated and treated with dexamethasone and remdesivir with improvement. On hospital day 32, the patient was extubated. Three days later, he developed acute, symmetric limb quadriparesis and respiratory muscle failure requiring reintubation. Analysis of his cerebrospinal fluid showed a cytoalbuminologic dissociation, and electromyography/nerve conduction study showed slowed nerve conduction velocity. These findings are consistent with GBS. Blood cultures, serum polymerase chain reaction testing, and clinical symptoms were not suggestive of other common pathogens causing his GBS. The patient's acute GBS in the setting of recent severe COVID-19 infection strongly suggests association between the two entities, as supported by a growing body of case literature. The patient was subjected to intravenous immunoglobulin treatment and was discharged with greatly improved strength in the upper and lower extremities. Our goal in describing this case is to highlight the need for providers to consider, accurately diagnose, and treat GBS as a consequence of severe COVID-19 infection.

Aneurysmal Aberrant Right Subclavian Artery in an Active Duty U.S. Military Male (Case Report).

We present a rare case of four-vessel aortic arch with an aneurysmal aberrant right retro-esophageal subclavian artery (ARSA) in a healthy, asymptomatic active duty U.S. military male. ARSA has a prevalence of 0.6%-1.4%, of which ∼80%-84% are retro-esophageal ARSAs. Intrathoracic subclavian artery aneurysms are rare and often occur in association with congenital aortic arch anomalies and/or concomitant thoracic aortic pathology. This case adds to three previously documented cases of thoracic aortic disease (TAD) in the U.S. military and is the second documented case of ARSA in the U.S. military. This case highlights successful TAD identification in a service member before clinical decompensation.

Using Reminder Letters to Improve Adherence to Routine Hemoglobin A1C Testing in Adults with Diabetes.

The American Diabetes Association (ADA) recommends hemoglobin A1C (A1C) goals of < 7% for most non-pregnant adults and < 8% for adult patients with extensive or life-limiting comorbidities. A1C testing is indicated every 3-months for patients not meeting goals to assess glycemic control, adjust medications, suggest lifestyle changes, and offer counseling. However, many patients do not adhere to routine testing. A clinic-wide quality improvement (QI) pilot project was implemented using mailed reminder letters to improve patient adherence to routine A1C testing in patients with hemoglobin A1C . 8%. Sixty-eight patients were identified for this letter intervention. Of these, 14 patients (20%) were historically adherent to 3-month interval testing, 31 patients (46%) were historically non-adherent, and 23 (34%) had historical A1C test intervals of less than 3-months because of provider orders. The primary outcome was improvement in A1C testing adherence rates of those who were previously non-adherent. There was a 58% increase overall and a 103% increase in testing rates among women. Statistical significance was not observed at the P = .05 level. However, improvement in adherence rates among women reached the P = .10 significance level. Mailed reminder letters may be useful in improving adherence to routine A1C testing in patients with diabetes. Further study of this intervention in larger groups is needed to provide timely data for the management of diabetes care.

A Case of Cardiac Papillary Fibroelastoma - An Increasingly Described Cardiac Tumor with Fatal Consequences.

Papillary fibroelastomas (PFE) are rare primary cardiac tumors characterized by non-malignant, pedunculated, endocardial lesions with a significant risk of embolic potential and death. With improvements in the imaging quality and availability of transthoracic echocardiograms (TTE), the diagnosis of PFE has become more common in the last 2 decades. PFE is changing from a rare "zebra" diagnosis to one that community providers will encounter in their practice and must appropriately treat to prevent morbidity and mortality. Data shows that there are significant survival and morbidity benefit associated with surgical excision over non-operative management, with the benefit of anticoagulation remaining unclear at this time. We report a case describing the diagnostic workup and management of a 58-year-old woman who presented with an unidentified endocardial mass determined to be a PFE. Based on current literature, we favor a strategy of early surgical excision of PFE for an optimal reduction in mortality and thromboembolic sequelae associated with this pathology.

Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing.

Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-ß, HB-EGF, EGFR, TGF-ß1, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.