Appendectomy and asthma: a search for an association in older subjects.

INTRODUCTION: Several risk factors found to be associated with postoperative complications and cancer surgery, which carry a significant morbidity risk to cancer patients. Therefore, prehabilitation is necessary to improve the functional capability and nutritional status of a patient prior to surgery, so that the patient can withstand any postoperative activity and associated deterioration. Thus, this study aims to assess the effectiveness of prehabilitation interventions on the functional status of patients with gastric and oesophageal cancer who underwent esophagectomy and gastrectomy. MATERIAL AND METHODS: An interventional study was carried out among oesophageal and gastric cancer patients who had undergone surgery at the National Cancer Institute of Malaysia. The prehabilitation process took a maximum of two weeks, depending on the patient's optimisation before surgery. The prehabilitation is based on functional capacity (ECOG performance status), muscle function (handgrip strength), cardio-respiratory function (peak flow meter) and nutritional status (calorie and protein). Postoperative outcomes are measured based on the length of hospital stay, complications, and Clavien-Dindo Classification. RESULTS: Thirty-one patients were recruited to undergo a prehabilitation intervention prior to gastrectomy (n=21) and esophagectomy (n=10). Demographically, most of the cancer patients were males (67.7%) with an ideal mean of BMI (23.5±6.0). Physically, the majority of them had physical class (ASA grade) Grade 2 (67.7%), ECOG performance status of 1 (61.3%) and SGA grade B (51.6%). The functional capacity and nutritional status showed a significant improvement after one week of prehabilitation interventions: peak expiratory flow meter (p<0.001), handgrip (p<0.001), ECOG performance (p<0.001), walking distance (p<0.001), incentive spirometry (p<0.001), total body calorie (p<0.001) and total body protein (p=0.004). However, those patients who required two weeks of prehabilitation for optimization showed only significant improvement in peak expiratory flow meter (p<0.001), handgrip (p<0.001), and incentive spirometry (p<0.001). Prehabilitation is significantly associated postoperatively with the length of hospital stay (p=0.028), complications (p=0.011) and Clavien-Dindo Classification (p=0.029). CONCLUSION: Prehabilitation interventions significantly increase the functional capacity and nutritional status of cancer patients preoperatively; concurrently reducing hospital stays and complications postoperatively. However, certain cancer patients might require over two weeks of prehabilitation to improve the patient's functional capacity and reduce complications postoperatively.

Mechanisms Underlying Astrocyte Endfeet Swelling in Stroke.

Astrocyte endfeet envelop the cerebral capillaries that form the blood-brain barrier. Swelling of these endfeet occurs early in cerebral ischemia. It is generally hypothesized that such swelling occurs as the result of factors released from parenchymal brain cells during an ischemic stroke (e.g., K(+) and L-glutamate). In this review of mechanisms that can elicit astrocyte swelling in ischemic stroke, we hypothesize that, instead or in addition, such swelling may be a response to blood-brain barrier dysfunction. Astrocyte endfeet swelling may help form a cuff around a damaged vessel that limits the egress of plasma constituents and blood (hemorrhage) into brain.

Gross patterns of umbilical cord coiling: correlations with placental histology and stillbirth.

INTRODUCTION: The purpose of this study was to define gross patterns of umbilical cord hypercoiling and determine correlations with histological features in the placenta and/or perinatal outcomes such as stillbirth. METHODS: Gross images of placentas with hypercoiled umbilical cords (>3 coils/10 cm) were assigned a major umbilical coiling pattern and the direction (right or left) of the coiling. Definitions of 4 gross coiling patterns were established: undulating, rope, segmented, and linked, each with progressively deeper indentations in cord diameter. Outcome variables obtained from placental pathology reports and maternal medical records included histological abnormalities indicative of significant chronic fetal vascular obstruction, such as fetal vascular thrombi, avascular villi, villous stromal-vascular karyorrhexis, and fetal thrombotic vasculopathy, and stillbirth. RESULTS: 318 placentas/umbilical cords met inclusion criteria. The rope pattern was the most common (52%), followed by the undulating (26%), segmented (19%) and linked (3%) patterns. The segmented and linked gross coiling patterns were significantly correlated with histologic evidence of chronic fetal vascular obstruction and stillbirth, when compared with the ropeand undulating patterns. Cords with right twists were also significantly correlated with histologic evidence of chronic fetal vascular obstruction and stillbirth when compared with cords with left twists. The number of cord coils per 10 cm did not correlate with any of the outcome variables. CONCLUSIONS: Among hypercoiled umbilical cords, specific gross patterns of coiling can be recognized, and patterns with the most significant indentation or pinching of the cord diameter are associated with histological evidence of chronic fetal vascular obstruction and stillbirth.

The thrombomodulin analog Solulin promotes reperfusion and reduces infarct volume in a thrombotic stroke model.

BACKGROUND: Currently there is no approved anticoagulant for treating acute stroke. This is largely because of concern for hemorrhagic complications, and suggests a critical need for safer anticoagulants. Solulin is a soluble analog of the endothelial cell receptor thrombomodulin, able to bind free thrombin and convert it to an activator of the anticoagulant, protein C. OBJECTIVE: Solulin was tested for its ability to inhibit middle cerebral artery occlusion (MCAO) induced by photothrombosis, and to restore MCA patency after establishment of stable occlusion. METHODS: Cerebral blood flow (CBF) was monitored by laser Doppler for 1.5 h after occlusion and again 72 h later. RESULTS: Solulin treatment 30 min before thrombosis resulted in an approximately 50% increase in time to form a stable occlusion. When administered 30 or 60 min after MCAO, Solulin significantly improved CBF within 90 min of treatment. In contrast, none of the vehicle-treated mice showed restoration of CBF in the first 90 min and only 17% did so by 72 h. Solulin treatment was associated with a significant reduction in infarct volume, and was well tolerated with no overt hemorrhage observed in any treatment group. Mechanistic studies in mice homozygous for the factor (F)V Leiden mutation, suggest that Solulin's efficacy derives primarily from the anticoagulant activity of the thrombin-Solulin complex and not from direct anti-inflammatory or neuroprotective effects of Solulin or activated protein C. CONCLUSIONS: Our data indicate that Solulin is a safe and effective anticoagulant that is able to antagonize active thrombosis in acute ischemic stroke, and to reduce infarct volume.

Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke.

The use of tissue plasminogen activator (tPA) as a thrombolytic treatment in ischemic stroke is limited largely due to concerns for hemorrhagic complications. The underlying mechanisms are still unknown, but evidence is beginning to emerge that tPA interacts with key regulators of the neurovascular unit (NVU), and that these interactions may contribute to the undesirable side effects associated with the use of tPA in ischemic stroke. Understanding these connections and tPA's normal function within the NVU may offer new insights into future therapeutic approaches.

Effect of pharmacologic plasminogen activator inhibitor-1 inhibition on cell motility and tumor angiogenesis.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is integrally involved in tumorigenesis by impacting on both proteolytic activity and cell migration during angiogenesis. OBJECTIVES: We hypothesized that an orally active small molecule inhibitor of PAI-1 (PAI-039; tiplaxtinin) could affect smooth muscle cell (SMC) attachment and migration in vitro on a vitronectin matrix, and exhibit antiangiogenic activity in vivo. METHODS: In vitro assays were used to assess the mechanism of inhibition of PAI-1 by PAI-039 using wild-type PAI-1 in the presence or absence of vitronectin and wild-type PAI-1 and specific PAI-1 mutants in SMC adhesion and migration assays. An in vivo tumor angiogenesis model was used to assess the effect of PAI-039 administration on neovascularization in a Matrigel implant. RESULTS: PAI-039 dose-dependently inhibited soluble, but not vitronectin-bound, PAI-1. Cell adhesion assays using PAI-1 mutants unable to bind vitronectin (PAI-1K) or inactivate proteases (PAI-1R) further suggested that PAI-039 inactivated PAI-1 by binding near its vitronectin domain. In a tumor angiogenesis model, PAI-039 treatment of wild-type mice dose-dependently decreased hemoglobin concentration and endothelial cell staining within the Matrigel implant, indicating reduced angiogenesis, but exhibited no in vivo efficacy in PAI-1 null mice. CONCLUSIONS: Administration of an orally active PAI-1 inhibitor prevented angiogenesis in a Matrigel implant. The lack of activity of PAI-039 against wild-type PAI-1 bound to vitronectin and PAI-1K suggests PAI-039 binding near the vitronectin-binding site. Our studies further substantiate a role for PAI-1 in cellular motility and tumor angiogenesis, and suggest for the first time that these effects can be modulated pharmacologically.

Gene therapy vector-mediated expression of insulin-like growth factors protects cardiomyocytes from apoptosis and enhances neovascularization.

IGF-I and IGF-II are single-chain polypeptide growth factors that regulate pleiotropic cellular responses. We have characterized the effect of recombinant IGF proteins, as well as third-generation adenoviral vectors encoding either IGF-I or IGF-II genes, on cardiomyocyte apoptosis and on angiogenesis. We found that endothelial cells cultured in the presence of the extracellular protein laminin exhibit a robust response to IGF-I and -II proteins via enhanced cell migration and angiogenic outgrowth. Furthermore, IGF vectors greatly enhanced neovascularization in an in vivo Matrigel model. Transduction of cardiomyocytes with the IGF adenoviral vectors resulted in a dose- and time-dependent increase in the expression of IGF-I or IGF-II protein. This correlated with abrogation of apoptosis induced by ischemia-reoxygenation, ceramide, or heat shock with optimal inhibition of approximately 80%. We conclude that gene transfer of IGF-I and IGF-II is a plausible strategy for the local delivery of IGFs to treat ischemic heart disease and heart failure by stimulating angiogenesis and protecting cardiomyocytes from cell death.

A genetically modified adenoviral vector exhibits enhanced gene transfer of human smooth muscle cells.

Adenoviral vector-based gene therapy is a promising approach for the treatment of restenosis postangioplasty. However, a high concentration of adenoviral vector can cause cellular activation, damage, and an enhanced immune response. One approach to solving this problem is to increase gene transfer efficiency by directing adenoviral vector entry via an alternate receptor system. We have constructed an adenoviral vector, Av9LacZ, that encodes the beta-galactosidase gene and contains a chimeric fiber protein that redirects viral vector binding to the Ad3 adenoviral receptor on the host cell. We examined the ability of Av9LacZ to transduce primary human smooth muscle cells (SMC) and found that it showed a 10- to 15-fold higher transduction efficiency when compared to the prototypic adenoviral vector currently used for preclinical and clinical studies. While both vectors were able to transduce rabbit, pig and monkey SMCs, the genetically modified vector transduced human SMC with much higher efficiency. SMC obtained from the aorta, coronary, renal, popliteal and pulmonary arteries were all efficiently transduced by Av9LacZ. Consistent with the data obtained from cultured cells, Av9LacZ also transduced fresh human arterial tissues considerably more efficiently than Av1LacZ. We conclude that the large discrepancy between transduction of animal and human cells by conventional vectors supports a cautious extrapolation of the results of in vivo animal studies to man. Furthermore, the genetically modified AV9 vector may deliver better efficacy and studies in large animal models with this vector could be more predictive of therapeutic efficacy in the treatment of human restenosis.

Clinical efforts to modulate angiogenesis in the adult: gene therapy versus conventional approaches.

A gene therapy approach towards the modulation of neovascularization provides important advantages that could be crucial for the success of therapies that target blood vessels. These advantages include sustained local expression and the ability to supply multiple pro- or anti-angiogenic factors. There is potential near-term success in the application of this approach for the treatment of ischemic vascular diseases. Although there is convincing proof of concept in animal models that an anti-angiogenesis gene therapy approach can be used to treat cancer, this is a highly competitive field with small molecules, recombinant proteins and monoclonal antibodies already in clinical trials. The scientific rationale for the use of gene therapy is sound, but realization of its full potential for the treatment of a broad array of diseases will require several challenging technical hurdles to be overcome and safety concerns to be alleviated.

Angiotensin II induces vascular smooth muscle cell replication independent of blood pressure.

The purpose of this investigation was to evaluate the role of blood pressure in the proliferative response of vascular smooth muscle cells to systemic infusion of angiotensin II (Ang II). Our laboratory has previously shown that infusion of Ang II induces smooth muscle cell proliferation in rat mesenteric vessels and carotid arteries. Ang II, a strong vasopressor, raised systolic blood pressure in rats from 120 to 200 mm Hg at a dose of 435 ng x kg(-1) x min(-1) after 1 week of treatment. The question arises as to whether this development of hypertension is a primary contributor to the replicative activities observed in the arterial wall of the mesenteric arteries or the carotid arteries or whether Ang II alone, without an increase in blood pressure, is sufficient to stimulate proliferation in these vessels. In the previous studies, we found that Ang II stimulated smooth muscle cell replication in the carotid artery and in type III and type I mesenteric microvessels. This study demonstrates that although administration of hydralazine normalizes the animals' blood pressures, it does not suppress the mitogenic effect of Ang II. Thus, it appears that Ang II has a direct effect on cell proliferation.

Mitogenic effect of angiotensin II on rat carotid arteries and type II or III mesenteric microvessels but not type I mesenteric microvessels is mediated by endogenous basic fibroblast growth factor.

In this study, anti-basic fibroblast growth factor (anti-bFGF) antibody was used to determine whether the mitogenic effect of angiotensin II in vivo could be blocked by neutralizing bFGF in the vessel wall. Animals, divided into six experimental groups, were given (1) angiotensin II, (2) angiotensin II + anti-bFGF antibody, (3) angiotensin II + normal goat IgG (ngIgG), (4) anti-bFGF antibody, (5) ngIgG, and (6) Ringer's solution. Angiotensin II at 435 ng x kg(-1) x min(-1) was infused into rats continuously for 1 week to induce smooth muscle cell replication, and anti-bFGF antibody or ngIgG was injected intravenously 4 times over the 1-week period at a dose of 60 mg/injection. Bromodeoxyuridine (30 mg/mL) was also continuously infused during the 1-week period. The left carotid artery of all animals was balloon-injured on day 4 of the treatment, and all groups were killed for study on day 7. The results showed that angiotensin II significantly stimulated smooth muscle replication in the balloon-injured carotid artery, intact carotid artery, and three branch levels of the mesenteric vascular tree. Anti-bFGF was able to block the mitogenic effect of angiotensin II in larger vessels but not the smallest (type I) microvessels of the mesenteric arterial tree. This differential response may be attributable to the nature of the lesions in type I vessels versus larger vessels: the type I vascular lesion has a large component of proliferating macrophages, whereas the larger vessels show less injury, few macrophages, and varying levels of smooth muscle replication. Our data suggest that the vessel wall remodeling in the angiotensin II-treated larger vessels involves DNA replication that is dependent on the presence of bFGF.

Angiotensin II induction of osteopontin expression and DNA replication in rat arteries.

We recently identified the adhesive protein osteopontin as a novel smooth muscle cell product overexpressed in rat developing neointima and human atheroma. Although osteopontin is a candidate stimulant for intimal lesion progression because of its chemotactic and calcium binding functions, factors controlling osteopontin expression in arteries remain poorly defined. In vitro, smooth muscle cell expression of osteopontin is associated with cell cycle transit or alterations in cell phenotype, and it is increased by angiotensin II (Ang II) stimulation. In the present studies, we investigated both osteopontin expression and DNA replication in the arterial wall in response to chronic Ang II infusion in vivo. Rat carotid arteries with or without intimal thickening (induced by balloon catheterization) were examined. Ang II (250 ng/kg per minute) or vehicle was coinfused with bromodeoxyuridine (to label replicating DNA in vivo) for 2 weeks beginning 4 weeks after injury. With Ang II, smooth muscle cells overexpressed osteopontin as shown by protein immunohistochemistry, in situ hybridization, and Northern blot analyses. Osteopontin mRNA levels were increased markedly (approximately fivefold) in the normal artery media and injured artery neointima, but levels remained low in the injured artery media, in positive correlation (R2 = 0.88, P < .001) with DNA replication in the smooth muscle layers, further suggesting that osteopontin may be a growth-associated, phenotype-dependent gene for smooth muscle cells. However, osteopontin expression in neointima was not restricted to areas showing DNA replication, suggesting a nonobligatory association. Ang II induced severe hypertension. Arterial osteopontin expression was increased also by chronic catecholamine infusion, a model of vascular growth stimulation showing labile pressure elevations. Osteopontin induction in smooth muscle cells may contribute to Ang II-dependent intimal lesion progression and vascular remodeling events associated with renovascular diseases or hyperadrenergic disorders.