Gene therapy with Pellino-1 improves perfusion and decreases tissue loss in Flk-1 heterozygous mice but fails in MAPKAP Kinase-2 knockout murine hind limb ischemia model.

OBJECTIVES: In the United States, over 8.5 million people suffer from peripheral arterial disease (PAD). Previously we reported that Pellino-1(Peli1) gene therapy reduces ischemic damage in the myocardium and skin flaps in Flk-1 [Fetal Liver kinase receptor-1 (Flk-1)/ Vascular endothelial growth factor receptor-2/VEGFR2] heterozygous (Flk-1+/--) mice. The present study compares the angiogenic response and perfusion efficiency following hind limb ischemia (HLI) in, Flk-1+/- and, MAPKAPKINASE2 (MK2-/-) knockout (KO) mice to their control wild type (WT). We also demonstrated the use of Peli1 gene therapy to improve loss of function following HLI. STUDY DESIGN AND METHODS: Femoral artery ligation (HLI) was performed in both Flk-1+/- and MK2-/- mice along with their corresponding WT. Another set of Flk-1+/- and MK2-/- were injected with either Adeno-LacZ (Ad.LacZ) or Adeno-Peli1 (Ad.Peli1) after HLI. Hind limb perfusion was assessed by laser doppler imaging at specific time points. A standardized scoring scale is used to quantify the extent of ischemia. Histology analysis performed includes capillary density, fibrosis, pro-angiogenic and anti-apoptotic proteins. RESULTS: Flk-1+/- and MK2-/- had a slower recovery of perfusion efficiency in the ischemic limbs than controls. Both Flk-1+/- and MK2-/- KO mice showed decreased capillary density and capillary myocyte ratios with increased fibrosis than their corresponding wild types. Ad.Peli1 injected ischemic Flk-1+/- limb showed improved perfusion, increased capillary density, and pro-angiogenic molecules with reduced fibrosis compared to Ad.LacZ group. No significant improvement in perfusion was observed in MK2-/- ischemic limb after Ad. Peli1 injection. CONCLUSION: Deletion of Flk-1 and MK2 impairs neovascularization and perfusion following HLI. Treatment with Ad. Peli1 results in increased angiogenesis and improved perfusion in Flk-1+/- mice but fails to rectify perfusion in MK2 KO mice. Overall, Peli1 gene therapy is a promising candidate for the treatment of PAD.

Deletion of newly described pro-survival molecule Pellino-1 increases oxidative stress, downregulates cIAP2/NF-κB cell survival pathway, reduces angiogenic response, and thereby aggravates tissue function in mouse ischemic models.

INTRODUCTION: In the present study, we aimed to explore the functional role of Pellino-1 (Peli1) in inducing neovascularization after myocardial infarction (MI) and hindlimb ischemia (HLI) using Peli1 global knockout mice (Peli1-/-). Recently we have shown that Peli1, an E3 ubiquitin ligase, induce angiogenesis and improve survivability, with decreased necrosis of ischemic skin flaps. METHODS: Peli1fl/fl and Peli1-/- mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Tissues from the left ventricular risk area were collected at different time points post-MI. In addition, Peli1fl/fl and Peli1-/- mice were also subjected to permanent ligation of the right femoral artery followed by motor function scores, Doppler analysis for blood perfusion and immunohistochemical analysis. RESULTS: Global Peli1 knockout exacerbated myocardial dysfunction, 30 and 60 days after MI compared to wild type (WT) mice as measured by echocardiogram. In addition, Peli1-/- mice also showed decreased motor function scores and perfusion ratios compared with Peli1fl/fl mice 28 days after the induction of HLI. The use of Peli1 in adenoviral gene therapy following HLI in CD1 mice improved the perfusion ratio at 28 days compared to Ad.LacZ-injected mice. CONCLUSION: These results suggest new insights into the protective role of Peli1 on ischemic tissues and its influence on survival signaling.

Increased survivability of ischemic skin flap tissue in Flk-1+/- mice by Pellino-1 intervention.

OBJECTIVE: Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia. METHODS: Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/- mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis. RESULTS: Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/- mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis. CONCLUSION: Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.

Overexpression of Thioredoxin1 enhances functional recovery in a mouse model of hind limb ischemia.

BACKGROUND: There is keen interest in finding nonsurgical treatments for peripheral vascular disease (PVD). Previously, we demonstrated that selective activation of Thioredoxin1 (Trx1), a 12-kDa cytosolic protein, initiates redox-dependent signaling and promotes neovascularization after ischemic heart disease. Therefore, Trx1 might possess immense potential to not only treat murine hind limb ischemia (HLI) through effective angiogenesis but also provide PVD patients with nonsurgical therapy to enhance neovascularization and improve blood perfusion. METHODS: To determine whether activation of Trx1 increases blood perfusion in HLI, two different strategies were used-gene therapy and transgenic model system. In adenoviral-mediated gene therapy, 8- to 12-wk-old mice were divided into two groups: (1) control Adeno-LacZ (Ad-LacZ) and (2) Adeno-Thiroedoxin1 (Ad-Trx1). The mice underwent surgical intervention to induce right HLI followed by injection with Ad-LacZ or Ad-Trx1, respectively. In the second strategy, we used wild-type and transgenic mice overexpressing Trx1 (Trx1Tg/+). All the animals underwent Doppler imaging for the assessment of limb perfusion followed by immunohistochemistry and Western blot analysis. RESULTS: Significant increases in perfusion ratio were observed in all the Trx1 overexpressed groups compared with their corresponding controls. Expressions of heme oxygenase-1, vascular endothelial growth factor, and the vascular endothelial growth factor receptors Flk-1 and Flt-1 were increased in Trx1 overexpressed mice compared with their respective controls. Blood perfusion in the ischemic limb gradually improved and significantly recovered in Trx1Tg/+ and Ad-Trx1 groups compared with their corresponding controls. The capillary and arteriolar density in the ischemic zone were found to be higher in Trx1Tg/+ group compared with wild type. CONCLUSIONS: The overall outcomes of our study demonstrate that Trx1 enhances blood perfusion and increases angiogenic protein expression in a rodent HLI model. These results suggest that Trx1 is a potential target for clinical trials and drug therapy for the treatment of PVD.

Profile of Acute Asthma Exacerbation in Drug Users.

The characteristics of patients who use heroin, cocaine, or both and present with acute asthma exacerbations have not been well studied. In this retrospective study, we aimed to study the demographic characteristics of this patient population, the characteristics of their asthma attack, and the risk factors for the need for invasive mechanical ventilation in this patient population. We reviewed the charts of patients discharged from an inner-city hospital with a diagnosis of acute asthma exacerbation. Individuals who used either heroin or cocaine or both within 24 hours of presenting to the emergency department were identified as a cohort of drug users. The rest were classified as non-drug users. Both groups were compared, and a univariate analysis was performed. To assess the predictive value of drug use for the need for intubation in the presence of confounding factors, logistic regression analysis was performed to identify whether using cocaine or heroin or both was an individual predictor for the need for invasive ventilation. Data from 218 patients were analyzed. Drug users (n = 85) were younger (mean age in years 43.9 vs. 50.5, P < 0.01), predominantly male (63.5% vs. 33.8%, P < 0.01), and more likely to be cigarette smokers (90.6% vs. 57.6%, P < 0.01). A medical history of intubation and admissions to the intensive care unit (ICU) was more common among drug users (56.5% vs. 29.3%, P < 0.01 and 54.1% vs. 38.3%, P < 0.03, respectively). Drug use was associated with increased need for invasive mechanical ventilation (35% vs. 23.3%, P = 0.05). Non-drug users were more likely to be using inhaled corticosteroids (48.9% vs. 32.9%, P = 0.03) and had longitudinal care established with a primary care provider (50.6% vs. 68.9%, P < 0.01). After adjusting for a history of mechanical ventilation, history of ICU admission, use of systemic corticosteroids, smoking, and acute physiological assessment and chronic health evaluation 2 score, drug use remained predictive for the need for mechanical ventilation (P = 0.026). Acute asthma exacerbations triggered by cocaine and heroin should be treated aggressively because they represent a cohort with poor follow-up and undertreated asthma as outpatients and are associated with increased need for invasive mechanical ventilation and ICU admission during acute exacerbation.

Trimodal rescue of hind limb ischemia with growth factors, cells, and nanocarriers: fundamentals to clinical trials.

Peripheral artery disease is a severe medical condition commonly characterized by critical or acute limb ischemia. Gradual accumulation of thrombotic plaques in peripheral arteries of the lower limb may lead to intermittent claudication or ischemia in muscle tissue. Ischemic muscle tissue with lesions may become infected, resulting in a non-healing wound. Stable progression of the non-healing wound associated with severe ischemia might lead to functional deterioration of the limb, which, depending on the severity, can result in amputation. Immediate rescue of ischemic muscles through revascularization strategies is considered the gold standard to treat critical limb ischemia. Growth factors offer multiple levels of protection in revascularization of ischemic tissue. In this review, the basic mechanism through which growth factors exert their beneficial properties to rescue the ischemic limb is extensively discussed. Moreover, clinical trials based on growth factor and stem cell therapy to treat critical limb ischemia are considered. The clinical utility of stem cell therapy for the treatment of limb ischemia is explained and recent advances in nanocarrier technology for selective growth factor and stem cell supplementation are summarized.

Effect of Positive Airway Pressure Therapy on Body Mass Index in Obese Patients With Obstructive Sleep Apnea Syndrome: A Prospective Study.

Because obesity is a common cause of obstructive sleep apnea syndrome (OSAS), weight loss can be an effective treatment. OSAS also may cause weight gain in some patients. Effective treatment of sleep apnea may facilitate weight loss in obese patients. We hypothesize that positive airway pressure (PAP) therapy is associated with weight loss in obese patients with OSAS. This was a single-center observational prospective cohort study. Forty-five patients were diagnosed with OSAS after polysomnographic analysis in sleep laboratory and underwent continuous positive airway pressure titration. Patients were followed for 3 months in terms of change in body mass index (BMI) and compliance with PAP therapy. Of the 45 patients recruited, 3 patients were eliminated because of miss recruitment. Nine patients had incomplete data, and the rest (n = 33) were included for analysis. The mean age was 54.9 ± 16.9 years (mean ± SD), 93.9% were male, and 90.9% were whites. Mean apnea-hypopnea index was 36.3 ± 28.17 events per hour. Mean BMI before treatment was 34.7 ± 3.9 kg/m. Fifteen patients (45.5%) were compliant with therapy of OSAS with PAP. There was no difference in age, gender, neck circumference, BMI, and apnea-hypopnea index of patients compliant to therapy when compared with those who were not. There was a significant decrease in BMI in patients compliant with PAP therapy compared with noncompliant patients (-1.2 ± 0.7 vs. 0.3 ± 0.9 kg/m, P ≤ 0.001). PAP therapy may cause significant loss of weight within 3 months in obese patients with OSAS. Further study is needed to elucidate the physiological basis of this change.

Association of Extubation Failure and Functional Outcomes in Patients with Acute Neurologic Illness.

BACKGROUND: An association between extubation failure and neurologic and functional outcomes in patients with primary neurologic illness has not been investigated rigorously. We plan to conduct a retrospective chart review to study this association. METHODS: A total of 949 unique patients intubated and ventilated for at least 48 h in Neuro ICU (NICU) were obtained. Extubation failure was defined as need for reintubation within 48 h of initial extubation. Independent and dependent association between extubation failure and clinical parameters was assessed. RESULTS: The patients had a median age [interquartile range (IQR)] of 58.5 (23.0) years. 60.5% were male and 81.9% were Caucasian. Extubation failure occurred in 108 (12.8%) patients. There was no difference in age, APACHE 3 score, FOUR score, or GCS score of patients at ICU admission between those who experienced extubation failure and those who did not. Extubation failure was associated with longer NICU and hospital LOS [median (IQR); 13.7 (11.3) vs. 9.1(8.2) days, P < 0.01 and 24.5 (20.0) vs. 16.8 (16.7) days, P < 0.01]. Patients with extubation failure had worse functional outcomes at 6 months as measured by the modified Rankin score [MRS; median (IQR), 5.0 (2.0) vs. 4.0 (3.0), P < 0.01]. After adjusting for confounders, extubation failure was associated with longer hospital and ICU LOS and worse functional outcomes. CONCLUSIONS: In patients with acute neurological illness, extubation failure is associated with longer ICU and hospital stays but does not impact hospital mortality. Patients with extubation failure may experience a worsening of their functional status over time.

Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia.

BACKGROUND: There is an emerging focus on investigating innovative therapeutic molecules that can potentially augment neovascularization in order to treat peripheral arterial disease (PAD). Although prolyl hydroxylase domain proteins 1 and 3 (PHD1 and PHD3) may modulate angiogenesis via regulation of hypoxia inducible factor-1α (HIF-1α), there has been no study directly addressing their roles in ischemia-induced vascular growth. We hypothesize that PHD1(-/-) or PHD3(-/-) deficiency might promote angiogenesis in the murine hind-limb ischemia (HLI) model. STUDY DESIGN: Wild type (WT), PHD1(-/-) and PHD3(-/-) male mice aged 8-12weeks underwent right femoral artery ligation. Post-procedurally, motor function assessment and laser Doppler imaging were periodically performed. The mice were euthanized after 28days and muscles were harvested. Immunohistochemical analysis was performed to determine the extent of angiogenesis by measuring capillary and arteriolar density. VEGF expression was quantified by enzyme-linked immunosorbent assay (ELISA). Bcl-2 and HIF-1α were analyzed by immunofluorescence. Fibrosis was measured by picrosirius red staining. RESULTS: PHD1(-/-) and PHD3(-/-) mice showed significantly improved recovery of perfusion and motor function score when compared to WT after femoral artery ligation. These mice also exhibited increased capillary and arteriolar density, capillary/myocyte ratio along with decreased fibrosis compared to WT. VEGF, Bcl-2 and HIF-1α expression increased in PHD1(-/-) and PHD3(-/-) mice compared to WT. CONCLUSIONS: Taken together these results suggest that PHD1 and PHD3 deletions promote angiogenesis in ischemia-injured tissue, and may present a promising therapeutic strategy in treating PAD.

Use of noninvasive ventilation in adult patients with acute asthma exacerbation.

Noninvasive ventilation (NIV) has been found to be beneficial for respiratory failure in many disease states; however, limited data are available supporting its use in acute asthma exacerbation. A retrospective chart analysis of adult patients admitted for acute asthma exacerbation and treated with NIV between January 2007 and December 2009 at a tertiary care community hospital was done. Ninety-eight patient encounters were identified. Mean age of the patients was 48.3 years, and 46% were male. Nineteen patients failed NIV and required invasive ventilation. There was no significant difference in the mean age, sex, race, and initial blood gas between patients with successful versus failed NIV. Usage of drugs, smoking, and history of past hospital or intensive care unit admission or intubation did not significantly influence the rate of failure of NIV. Patients who needed higher initial FiO2 were more likely to get intubated during their hospital stay (46.2 vs. 20.4%, P = 0.019). Patients who failed NIV were found to have longer duration of hospital stay (6.8 vs. 3.9 days, P= 0.016) and longer intensive care unit stay (4 vs. 0.9 days, P = 0.002). Use of inhalers and other medications was not found to significantly influence the rate of failure of NIV. NIV can be used initially in patients with acute asthma exacerbation, as it is associated with shorter duration of hospital stay and can prevent the morbidity of mechanical intubation. Patients with initial requirement of higher FiO2 were more likely to fail NIV and should be carefully monitored.

Retrospective derivation and validation of a search algorithm to identify extubation failure in the intensive care unit.

BACKGROUND: Development and validation of automated electronic medical record (EMR) search strategies is important in identifying extubation failure in the intensive care unit (ICU). We developed and validated an automated search algorithm (strategy) for extubation failure in critically ill patients. METHODS: The EMR search algorithm was created through sequential steps with keywords applied to an institutional EMR database. The search strategy was derived retrospectively through secondary analysis of a 100-patient subset from the 978 patient cohort admitted to a neurological ICU from January 1, 2002, through December 31, 2011(derivation subset). It was, then, validated against an additional 100-patient subset (validation subset). Sensitivity, specificity, negative and positive predictive values of the automated search algorithm were compared with a manual medical record review (the reference standard) for data extraction of extubation failure. RESULTS: In the derivation subset of 100 random patients, the initial automated electronic search strategy achieved a sensitivity of 85% (95% CI, 56%-97%) and a specificity of 95% (95% CI, 87%-98%). With refinements in the search algorithm, the final sensitivity was 93% (95% CI, 64%-99%) and specificity increased to 100% (95% CI, 95%-100%) in this subset. In validation of the algorithm through a separate 100 random patient subset, the reported sensitivity and specificity were 94% (95% CI, 69%-99%) and 98% (95% CI, 92%-99%) respectively. CONCLUSIONS: Use of electronic search algorithms allows for correct extraction of extubation failure in the ICU, with high degrees of sensitivity and specificity. Such search algorithms are a reliable alternative to manual chart review for identification of extubation failure.

Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement.

The period of the year from spring to fall, when clocks in most parts of the United States are set one hour ahead of standard time, is called daylight saving time, and its beginning and ending dates and times are set by federal law. The human biological clock is regulated by the timing of light and darkness, which then dictates sleep and wake rhythms. In daily life, the timing of exposure to light is generally linked to the social clock. When the solar clock is misaligned with the social clock, desynchronization occurs between the internal circadian rhythm and the social clock. The yearly change between standard time and daylight saving time introduces this misalignment, which has been associated with risks to physical and mental health and safety, as well as risks to public health. In 2020, the American Academy of Sleep Medicine (AASM) published a position statement advocating for the elimination of seasonal time changes, suggesting that evidence best supports the adoption of year-round standard time. This updated statement cites new evidence and support for permanent standard time. It is the position of the AASM that the United States should eliminate seasonal time changes in favor of permanent standard time, which aligns best with human circadian biology. Evidence supports the distinct benefits of standard time for health and safety, while also underscoring the potential harms that result from seasonal time changes to and from daylight saving time. CITATION: Rishi MA, Cheng JY, Strang AR, et al. Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2024;20(1):121-125.

Is the use of preoperative breast MRI predictive of mastectomy?

BACKGROUND: Several recent studies have described increasing rates of unilateral and bilateral mastectomy among women with newly diagnosed breast cancer. The use of breast magnetic resonance imaging (MRI) has also risen rapidly, leading to speculation that the high false-positive rate and need for multiple biopsies associated with MRI may contribute to more mastectomies. The objective of this study was to determine whether newly diagnosed patients who underwent preoperative MRI were more likely to undergo mastectomy compared with those who did not have a preoperative MRI. METHODS: A retrospective review was performed of all newly diagnosed patients with breast cancer at our academic breast center from 2004 to 2009. RESULTS: The proportion of newly diagnosed patients with breast cancer having MRI prior to surgery increased from 6% in 2004 to 73% in 2009. Of 628 patients who underwent diagnostic MRI, 369 (59%) had abnormal results, 257 (41%) had one or more biopsies, and 73 had additional sites of cancer diagnosed. Patients with a malignant biopsy, or those with an abnormal MRI who did not undergo biopsy, had an increased mastectomy rate (P<0.01). However, patients with a normal MRI or a benign biopsy actually had a decreased mastectomy rate (P<0.05). Although there was a trend toward more bilateral mastectomies, the overall mastectomy rate did not change over this time period. CONCLUSIONS: Although there is a strong relationship between the result of an MRI and the choice of surgery, the overall effect is not always to increase the mastectomy rate. Some patients who were initially considering mastectomy chose lumpectomy after an MRI.

HIF-prolyl hydroxylases and cardiovascular diseases.

Prolyl hydroxylases belong to the family of iron- and 2-oxoglutamate-dependent dioxygenase enzyme. Several distinct prolyl hydroxylases have been identified. The hypoxia-inducible factor (HIF) prolyl hydroxylase termed prolyl hydroxylase domain (PHD) enzymes play an important role in oxygen regulation in the physiological network. There are three isoforms that have been identified: PHD1, PHD2 and PHD3. Deletion of PHD enzymes result in stabilization of HIFs and offers potential treatment options for many ischemic disorders such as peripheral arterial occlusive disease, myocardial infarction, and stroke. All three isoforms are oxygen sensors that regulate the stability of HIFs. The degradation of HIF-1α is regulated by hydroxylation of the 402/504 proline residue by PHDs. Under hypoxic conditions, lack of oxygen causes hydroxylation to cease HIF-1α stabilization and subsequent translocation to the nucleus where it heterodimerizes with the constitutively expressed ß subunit. Binding of the HIF-heterodimer to specific DNA sequences, named hypoxia-responsive elements, triggers the transactivation of target genes. PHD regulation of HIF-1α-mediated cardioprotection has resulted in considerable interest in these molecules as potential therapeutic targets in cardiovascular and ischemic diseases. In recent years, attention has been directed towards identifying small molecule inhibitors of PHD. It is postulated that such inhibition might lead to a clinically useful strategy for protecting the myocardium against ischemia and reperfusion injury. Recently, it has been reported that the orally absorbed PHD inhibitor GSK360A can modulate HIF-1α signaling and protect the failing heart following myocardial infarction. Furthermore, PHD1 deletion has been found to have beneficial effects through an increase in tolerance to hypoxia of skeletal muscle by reprogramming basal metabolism. In the mouse liver, such deletion has resulted in protection against ischemia and reperfusion. As a result of these preliminary findings, PHDs is attracting increasing interest as potential therapeutic targets in a wide range of diseases.

Rapid eye movement related obstructive sleep apnea: Where do we stand?

Rapid eye movement (REM) related obstructive sleep apnea (OSA) is defined by the presence of episodes of apnea or hypopnea predominantly or exclusively during REM sleep. Epidemiology of this disorder shows a complex interaction with age, sex, and body mass index. The prevalence is variable and depends on the criteria used to define this disorder. Moreover, the clinical significance of this entity remains poorly defined. However, episodes of apnea or hypopnea encountered during REM sleep are longer and are associated with a more profound drop in oxygen saturation than non-REM sleep. Likewise, this disorder may be independently associated with hypertension and poor glycemic control. More importantly, positive airway pressure therapy as currently prescribed may not treat the majority of apnea episodes during REM sleep. The treatment is further complicated by the different definitions used for the diagnosis of this disorder and the lack of consensus if patients with this diagnosis should be treated if their overall apnea-hypopnea index does not meet the threshold for the clinical diagnosis of OSA. The definition and treatment used for the diagnosis and management of REM-related OSA needs to be standardized. Moreover, a consensus needs to be developed as to whether patients with this disorder should be treated if their overall apnea-hypopnea index does not meet the threshold for the clinical diagnosis of OSA. Further investigation may help answer if this disorder is independently associated with neurocognitive and cardiometabolic adverse outcomes and help guide the therapeutic approach.

Heat shock protein A12B gene therapy improves perfusion, promotes neovascularization, and decreases fibrosis in a murine model of hind limb ischemia.

BACKGROUND: Heat shock protein A12B expressed in endothelial cells is important and required for angiogenesis to form functional vessels in ischemic tissue. We have previously shown the cardioprotective effects of heat shock protein A12B overexpression in a rat model of diabetic myocardial infarction. In this study, we aim to explore the role of heat shock protein A12B in a surgically-induced murine hind-limb ischemia model. MATERIALS AND METHODS: Adult 8- to 12-week-old C57BL/6J mice were divided into 2 groups: treated with Adeno.LacZ (control group) and with Adeno.HSPA12B (experimental group) and, with both groups subjected to right femoral artery ligation. Immediately after surgery, mice in both groups received either Adeno.HSPA12B or Adeno.LacZ (1 × 109 plaque forming units) in both the semimembranosus and gastrocnemius muscles of the right limb. The left limb served as the internal control. Both groups underwent serial laser Doppler imaging preoperatively, and again postoperatively until 28 days. Immunohistochemical analysis was performed 3 and 28 days post-surgery. RESULTS: Mice in the Adeno.HSPA12B gene therapy group showed improved motor function and a significantly higher blood perfusion ratio on postoperative days 21 and 28, along with better motor function. Immunohistochemical analysis showed increased expression of vascular endothelial growth factor, thioredoxin-1, heme oxygenase, and hypoxia-inducible factor 1α, along with a decreased expression of A-kinase-anchoring protein 12 and thioredoxin-interacting protein levels. The Adeno.HSPA12B-treated group also showed increased capillary and arteriolar density and an increased capillary-myocyte ratio, along with reduced fibrosis compared to the Adeno.LacZ group. CONCLUSION: Our study demonstrates that targeted Adeno.HSPA12B gene delivery into ischemic muscle enhances perfusion and angiogenic protein expression. This molecule shows promise for the management of peripheral vascular disease as a potential target for clinical trials and subsequent drug therapy.

Complete lung collapse as a rare complication of sarcoidosis-associated mediastinal lymphadenopathy.

Complete lung collapse associated with sarcoidosis is exceedingly rare. Although lymphoma should be ruled out when patients with mediastinal lymphadenopathy develop lung collapse, sarcoidosis should be considered in the differential, especially when associated with fibrosing mediastinitis.

Endovascular Therapy for Spontaneous Ilio-Iliac Arteriovenous Fistula Due To Iliac Artery Aneurysm Rupture With Multi-Organ Dysfunction.

Iliac artery aneurysms can rarely present with rupture into adjacent iliac vein resulting in arteriovenous fistula leading to acute cardiac failure or multi-organ failure. End-organ damage can be reversed with timely diagnosis and intervention. Endovascular therapy is an attractive option to treat this pathology besides allowing for a quick recovery and mitigating the risk of mortality associated with open surgical treatment options. We report treatment of this pathology with Endovascular repair with preservation of ipsilateral hypogastric artery flow using an iliac branch graft device. The postoperative course was complicated by type 3 endoleak due to the separation of components between iliac branch graft and aortic stent graft with resultant recurrence of the fistula. Additional endovascular techniques, including placement of a venous stent and stent grafts to bridge the components, was used to treat the endoleak. We present this report due to the unique nature of the recurrent arteriovenous fistula, technical complexity, and resultant multi-organ dysfunction.