Structural and functional evidence for the scaffolding effect of alveolar blood vessels.

A contribution of pulmonary blood distension to alveolar opening was first proposed more than 100 years ago. To investigate the contribution of blood distension to lung mechanics, we studied control mice (normal perfusion), mice after exsanguination (absent perfusion) and mice after varying degrees of parenchymal resection (supra-normal perfusion). On inflation, mean tracheal pressures were higher in the bloodless mouse (4.0 ± 2.5 cm H2O); however, there was minimal difference between conditions on deflation (0.7 ± 0.9 cm H2O). To separate the peripheral and central mechanical effects of blood volume, multi-frequency lung impedance data was fitted to the constant-phase model. The presence or absence of blood had no effect on central airway resistance (p > .05). In contrast, measures of tissue damping (G), tissue elastance (H) and hysteresivity (η) demonstrated a significant increase in bloodless mice relative to control mice (p < .001). After varying amount of surgical resection and associated supra-normal perfusion of the remaining lung, there was an increase in G and H. Although the absolute difference in G and H increased with the amount of parenchymal resection, the proportional contribution of blood was identical in all conditions. The presence of blood in the pulmonary vasculature resulted in a constant 64 ± 5% reduction in tissue damping (G) and a 55 ± 4% reduction in tissue elastance (H). This nearly-constant contribution of blood to lung hysteresivity was only reduced by positive end-expiratory pressure (PEEP). To identify a distinct structural subset of vessels in the lung potentially contributing to these observations, vascular casting and scanning electron microscopy of the lung demonstrated morphologically distinct vascular rings at the alveolar opening. Our results suggest that intravascular blood distension, likely attributable to a subset of vessels in the alveolar entrance ring, contributes a measurable scaffolding effect to the functional recruitment of the peripheral lung.

Remodeling of alveolar septa after murine pneumonectomy.

In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends ("E"). Septal retraction, observed in 20-30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling.

Innovative bridging of the rural-urban divide: comparison of scope, safety, and impact of collaborative rural surgery camps and an urban surgical program.

BACKGROUND: In medically under-resourced regions worldwide, non-permanent surgery programs or camps have been conducted to expand access to surgical services. Surgery camp programs have been reported in rural India, primarily in the ophthalmic and obstetric fields; however, the provision of general surgical services in these settings is largely unknown. METHODS: A 12-month retrospective review of non-ambulatory procedures performed at a rural hospital surgery camp program and at an urban hospital in Maharashtra, India, was completed to characterize relative differences in procedural activity, frequency and severity of perioperative complications, and to evaluate efficacy of care. RESULTS: A total of 449 cases performed in rural hospital surgery camps were compared with 344 cases performed in an urban hospital during the course of the study period. The majority of rural surgical cases were elective and of intermediate complexity. Approximately 4% of rural cases were complex-major compared to 17% of urban cases. Intraoperative complications occurred in 0.2% rural cases compared to 5.5% of urban cases; p = 0.01. Postoperative complications were predominantly low grade in both groups. The postoperative complication rate was higher among rural surgical patients (43.4%; 23.5%; p < 0.01), though the Surgical Risk Score was significantly lower in this group (p < 0. 01). Rural surgery camp activity over 12 months achieved diagnostic and/or therapeutic goals in 92.2% of procedures and rendered 1.74-2.69 disability-adjusted life-years (DALYs) averted per patient. CONCLUSIONS: Rural general surgery camps can safely and effectively provide a wide range of surgical services under appropriate collaborative and clinical conditions. Surgery camps may be a safe, temporizing solution to unmet needs until substantial gains in rural healthcare are realized.

Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization.

In most rodents and some other mammals, the removal of one lung results in compensatory growth associated with dramatic angiogenesis and complete restoration of lung capacity. One pivotal mechanism in neoalveolarization is neovascularization, because without angiogenesis new alveoli can not be formed. The aim of this study is to image and analyze three-dimensionally the different patterns of neovascularization seen following pneumonectomy in mice on a sub-micron-scale. C57/BL6 mice underwent a left-sided pneumonectomy. Lungs were harvested at various timepoints after pneumonectomy. Volume analysis by microCT revealed a striking increase of 143 percent in the cardiac lobe 14 days after pneumonectomy. Analysis of microvascular corrosion casting demonstrated spatially heterogenous vascular densitities which were in line with the perivascular and subpleural compensatory growth pattern observed in anti-PCNA-stained lung sections. Within these regions an expansion of the vascular plexus with increased pillar formations and sprouting angiogenesis, originating both from pre-existing bronchial and pulmonary vessels was observed. Also, type II pneumocytes and alveolar macrophages were seen to participate actively in alveolar neo-angiogenesis after pneumonectomy. 3D-visualizations obtained by high-resolution synchrotron radiation X-ray tomographic microscopy showed the appearance of double-layered vessels and bud-like alveolar baskets as have already been described in normal lung development. Scanning electron microscopy data of microvascular architecture also revealed a replication of perialveolar vessel networks through septum formation as already seen in developmental alveolarization. In addition, the appearance of pillar formations and duplications on alveolar entrance ring vessels in mature alveoli are indicative of vascular remodeling. These findings indicate that sprouting and intussusceptive angiogenesis are pivotal mechanisms in adult lung alveolarization after pneumonectomy. Various forms of developmental neoalveolarization may also be considered to contribute in compensatory lung regeneration.

Stretch-induced intussuceptive and sprouting angiogenesis in the chick chorioallantoic membrane.

Vascular systems grow and remodel in response to not only metabolic needs, but also mechanical influences as well. Here, we investigated the influence of tissue-level mechanical forces on the patterning and structure of the chick chorioallantoic membrane (CAM) microcirculation. A dipole stretch field was applied to the CAM using custom computer-controlled servomotors. The topography of the stretch field was mapped using finite element models. After 3days of stretch, Sholl analysis of the CAM demonstrated a 7-fold increase in conducting vessel intersections within the stretch field (p<0.01). The morphometric analysis of intravital microscopy and scanning electron microscopy (SEM) images demonstrated that the increase vessel density was a result of an increase in interbranch distance (p<0.01) and a decrease in bifurcation angles (p<0.01); there was no significant increase in conducting vessel number (p>0.05). In contrast, corrosion casting and SEM of the stretch field capillary meshwork demonstrated intense sprouting and intussusceptive angiogenesis. Both planar surface area (p<0.05) and pillar density (p<0.01) were significantly increased relative to control regions of the CAM. We conclude that a uniaxial stretch field stimulates the axial growth and realignment of conducting vessels as well as intussusceptive and sprouting angiogenesis within the gas exchange capillaries of the ex ovo CAM.

Effect of unilateral diaphragmatic paralysis on postpneumonectomy lung growth.

Respiratory muscle-associated stretch has been implicated in normal lung development (fetal breathing movements) and postpneumonectomy lung growth. To test the hypothesis that mechanical stretch from diaphragmatic contraction contributes to lung growth, we performed left phrenic nerve transections (PNT) in mice with and without ipsilateral pneumonectomy. PNT was demonstrated by asymmetric costal margin excursion and confirmed at autopsy. In mice with two lungs, PNT was associated with a decrease in ipsilateral lung volume (P<0.05) and lung weight (P<0.05). After pneumonectomy, PNT was not associated with a change in activity level, measureable hypoxemia, or altered minute ventilation; however, microCT scanning demonstrated altered displacement and underinflation of the cardiac lobe within the first week after pneumonectomy. Coincident with the altered structural realignment, lung impedance measurements, fitted to the constant-phase model, demonstrated elevated airway resistance (P<0.05), but normal peripheral tissue resistance (P>0.05). Most important, PNT appeared to abrogate compensatory lung growth after pneumonectomy; the weight of the lobes of the right lung was significantly less than pneumonectomy alone (P<0.001) and indistinguishable from nonsurgical controls (P>0.05). We conclude that the cyclic stretch associated with diaphragmatic muscle contraction is a controlling factor in postpneumonectomy compensatory lung growth.

Financial burden of thyroid cancer in the United States: An estimate of economic and psychological hardship among thyroid cancer survivors.

BACKGROUND: Annual cancer-related healthcare expenditure in the United States is estimated to exceed $150 billion by 2020. As the prevalence of thyroid cancer increases worldwide, thyroid cancer survivorship is associated with increasing personal and cumulative costs. Few studies have examined the psychological and material economic costs experienced by thyroid cancer survivors. We seek to estimate the comparative prevalence of financial and psychological hardship among thyroid cancer and non-thyroid cancer patients in the United States. METHODS: The 2011 Medical Expenditure Panel Survey Experiences with Cancer databank was queried to identify thyroid and non-thyroid (colon, breast, lung, prostate) cancer survivors. This survey includes assessments of financial stress, material hardship, and psychological financial hardship. Cancer incidence-based weighted estimates of responses were compared between thyroid and non-thyroid cancer survivors. Independent predictors of material and psychological financial burden were identified through separate multivariate regression models. RESULTS: Thyroid cancer survivors more frequently reported psychological financial burden compared to non-thyroid cancer (46.1% vs 24.0%, P = .04). Material financial hardship (28.1% vs 19.9%, P = .37) and concurrent material and psychological hardship (25.1% vs 12.5%, P = .09) were noted at similar frequencies between thyroid and non-thyroid cancer survivors. However, on multivariate analysis, only younger age and lack of health insurance coverage were independently associated with psychological financial hardship. CONCLUSION: Thyroid cancer survivors report greater psychological financial hardship than non-thyroid cancer survivors. Because this financial burden may be underrecognized in the medical community, further studies should be conducted to aid physicians in better understanding the impact of a thyroid cancer diagnosis.

Pediatric toxic polycystic thyroid.

BACKGROUND: Polycystic thyroid disease (PCTD) is a rare condition and has been described in adults in the setting of subclinical and clinical hypothyroidism. We present the first known case of a pediatric patient with diffuse macrocystic degeneration of the thyroid. CLINICAL PRESENTATION: A 6-year-old previously healthy patient was evaluated after presenting with a 16-month history of an enlarging polycystic thyroid and hyperthyroidism. Markers of autoimmune thyroid disease including thyroid stimulating immunoglobulin (TSI), thyroid stimulating hormone (TSH) receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody were negative. No family history of benign or malignant thyroid or cystic disease was present. The patient underwent a total thyroidectomy without perioperative complication. She remains euthyroid with thyroid hormone replacement therapy. SUMMARY: To our knowledge, this is the first report of PCTD in the pediatric population associated with hyperthyroidism without evidence of autoimmune disease. Somatic activating thyrotropin-receptor gene mutations are known to cause non-autoimmune hyperthyroidism in children, however it is unknown if similar mechanisms are responsible for pediatric PCTD. CONCLUSIONS: Polycystic thyroid degeneration can occur in children and may result in a hyperthyroid state.

Extracellular Assembly of the Elastin Cable Line Element in the Developing Lung.

In the normal lung, a dominant structural element is an elastic "line element" that originates in the central bronchi and inserts into the distal airspaces. Despite its structural importance, the process that leads to development of the cable line element is unknown. To investigate the morphologic events contributing to its development, we used optical clearing methods to examine the postnatal rat lung. An unexpected finding was numerous spheres, with a median diameter of 1-2 µm, within the primary septa of the rat lung. The spheres demonstrated green autofluorescence, selective fluorescent eosin staining, reactivity with carboxyfluorescein succinimidyl ester, and specific labeling with anti-tropoelastin monoclonal antibody-findings consistent with tropoelastin. The sphere number peaked on rat postnatal day 4 (P4) and were rare by P14. The disappearance of the spheres was coincident with the development of the cable line element in the rat lung. Transmission electron microscopy demonstrated no consistent association between parenchymal cells and sphere alignment. In contrast, the alignment of tropoelastin spheres appeared to be the direct result of interactions of scaffold proteins including collagen fibers and fibrillin microfibrils. We conclude that the spatial organization of the cable line element appears to be independent of tropoelastin deposition, but dependent on crosslinking to scaffold proteins within the primary septa. Anat Rec, 300:1670-1679, 2017. © 2017 Wiley Periodicals, Inc.

Elastin Cables Define the Axial Connective Tissue System in the Murine Lung.

The axial connective tissue system is a fiber continuum of the lung that maintains alveolar surface area during changes in lung volume. Although the molecular anatomy of the axial system remains undefined, the fiber continuum of the lung is central to contemporary models of lung micromechanics and alveolar regeneration. To provide a detailed molecular structure of the axial connective tissue system, we examined the extracellular matrix of murine lungs. The lungs were decellularized using a 24 hr detergent treatment protocol. Systematic evaluation of the decellularized lungs demonstrated no residual cellular debris; morphometry demonstrated a mean 39 ± 7% reduction in lung dimensions. Scanning electron microscopy (SEM) demonstrated an intact structural hierarchy within the decellularized lung. Light, fluorescence, and SEM of precision-cut lung slices demonstrated that alveolar duct structure was defined by a cable line element encased in basement membrane. The cable line element arose in the distal airways, passed through septal tips and inserted into neighboring blood vessels and visceral pleura. The ropelike appearance, collagenase resistance and anti-elastin immunostaining indicated that the cable was an elastin macromolecule. Our results indicate that the helical line element of the axial connective tissue system is composed of an elastin cable that not only defines the structure of the alveolar duct, but also integrates the axial connective tissue system into visceral pleura and peripheral blood vessels.

Laser microdissection of the alveolar duct enables single-cell genomic analysis.

Complex tissues such as the lung are composed of structural hierarchies such as alveoli, alveolar ducts, and lobules. Some structural units, such as the alveolar duct, appear to participate in tissue repair as well as the development of bronchioalveolar carcinoma. Here, we demonstrate an approach to conduct laser microdissection of the lung alveolar duct for single-cell PCR analysis. Our approach involved three steps. (1) The initial preparation used mechanical sectioning of the lung tissue with sufficient thickness to encompass the structure of interest. In the case of the alveolar duct, the precision-cut lung slices were 200 µm thick; the slices were processed using near-physiologic conditions to preserve the state of viable cells. (2) The lung slices were examined by transmission light microscopy to target the alveolar duct. The air-filled lung was sufficiently accessible by light microscopy that counterstains or fluorescent labels were unnecessary to identify the alveolar duct. (3) The enzymatic and microfluidic isolation of single cells allowed for the harvest of as few as several thousand cells for PCR analysis. Microfluidics based arrays were used to measure the expression of selected marker genes in individual cells to characterize different cell populations. Preliminary work suggests the unique value of this approach to understand the intra- and intercellular interactions within the regenerating alveolar duct.

Influenza preparedness in low-resource settings: a look at oxygen delivery in 12 African countries.

BACKGROUND: Pandemic influenza poses a serious threat to populations in low and lower-middle income countries that face delays in access to health care and inadequately equipped facilities. Oxygen is first-line therapy for influenza-related hypoxia and a standard component of emergency respiratory resuscitation, yet remains a scarce resource in many countries. METHODOLOGY: A snapshot survey of oxygen supply and associated infrastructure was performed at 231 health centres and hospitals in twelve African countries using the World Health Organization (WHO) Tool for Situational Analysis to Assess Emergency and Essential Surgical Care. WHO Global Initiative for Emergency and Essential Surgical Care, WHO regional and country offices, and local Ministries of Health facilitated data collection from facilities surveyed. Data was stored in the WHO DataCol SQL database and computerized spreadsheet tools were used to generate descriptive statistics. RESULTS: Ninety-nine (43.8%) of facilities surveyed reported uninterrupted access to an oxygen source and 55 (24.6%) possessed a fully functioning oxygen concentrator. Electricity was fully available at only 81 (35.1%) health facilities. CONCLUSIONS: In addition to efforts to secure vaccines and antivirals, future global influenza preparedness efforts should include investments in oxygen and associated equipment and infrastructure at first referral health facilities, to minimize morbidity and mortality from influenza in regions with limited medical resources. Increasing oxygen delivery capacity in these areas may also provide long-term, post-pandemic benefits in the management of other medical conditions of significance, including trauma, neonatal pulmonary hypofunction, and HIV-related and childhood pneumonia.

Laparoscopic surgical treatment for refractory gastric antral vascular ectasia: a case report and review.

Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder of unclear etiology and rare cause of upper gastrointestinal bleeding. Endoscopic findings of hyperemic antral folds with dilated, tortuous vessels extending radially from the pylorus are diagnostic. Ectatic submucosal capillaries, microvascular fibrin thrombosis, and fibromuscular hyperplasia in the lamina propria are distinctive histologic features. Diverse treatment options are available, ranging from conservative medical or endoscopic therapy to surgical resection of affected gastric region. Surgery is the only known curative treatment and is traditionally pursued after failure of conservative therapy, as high postoperative mortality has been reported. A case of refractory GAVE in a 71-year-old female patient after 5 years of conservative management, is presented. The patient underwent successful laparoscopic distal gastrectomy and gastrojejunostomy with resolution of symptomatic anemia and melena. Clinical findings, diagnosis, etiology, and treatment of GAVE are reviewed here, with discussion of safety and efficacy of laparoscopic gastric resection for its treatment.