Gender-specific ischemic tissue tolerance in critically perfused skin

Purpose: The purpose of this study is to determine gender-specific differences in the development of necrosis in persistent ischemic tissue and to analyze whether differences are due to gender-specific loss of vascular reactivity or change in ischemic tolerance. Methods: Hairless mice (skh-1) of both genders were assigned to three groups of adolescent, adult, and senescent age. Critical ischemia was induced by transection of the two distal pedicles of the animal's ear. Microcirculation was assessed over a 5-day period using intravital epifluorescence microscopy. Tissue necrosis, blood flow, functional capillary density (FCD), red blood cell (RBC) velocity, and capillary diameter were analyzed. Results: Induction of persistent ischemia caused an age-dependent demarcation of nonperfused flap tissue. Adult and senescent females developed markedly more necrosis than age-matched males (49 ± 1% vs. 37 ± 3% and 53 ± 3% vs. 44 ± 2%, respectively; p < 0.05), whereas no gender-specific difference in flap necrosis was observed in adolescent animals (31 ± 2% vs. 33 ± 3%). Gender did not affect the amount of microcirculatory dysfunction in the flap. Thus, age-matched females and males exhibited a comparable decrease of FCD, RBC velocity, and capillary dilatory response. Conclusions: Both age and female gender may predispose for an increased susceptibility to develop ischemic tissue necrosis. The increased necrosis in female animals does not apply to an aggravated microvascular dysfunction, but rather to a reduced ischemic tissue toleranc

Selective blockade of endothelin-B receptor improves survival of critically perfused musculocutaneous flaps

Background and aims: Insufficient perfusion of distal flap areas, which may lead to partial necrosis, still represents a challenge in reconstructive surgery. In the process of microvascular and endothelial dysfunction, endothelins (ETs) and their receptors may play an important role. Therefore, the aim of the study was to investigate in a chronic in vivo model the effect of various ET-receptor antagonists in critically perfused flap tissue. Materials and methods: A random pattern musculocutaneous flap was elevated in the back of 25 C57BL/6 mice and fixed into a dorsal skinfold chamber. Repetitive intravital fluorescence microscopy was performed over a 10-day observation period, assessing arteriolar diameter, arteriolar blood flow (aBF), functional capillary density (FCD), the area of tissue necrosis, and the development of newly formed blood vessels. ET-receptor blockers were administrated intraperitoneally 30min before induction of ischemia, as well as daily during the subsequent 4-day period, including (1) BQ-123, a specific ET-A-receptor antagonist (ET-A = 1mg/kg), (2) BQ-788, a selective ET-B-receptor antagonist (ET-B = 1mg/kg), and (3) PD-142893, a nonselective ET-AB-receptor antagonist (ET-AB = 0.5mg/kg). Animals receiving saline only served as controls (n = 7). Results: Despite an increase in aBF during the 10-day observation period (day 1 = 1.92 ± 0.29nl/s; day 10 = 4.70 ± 1.64nl/s), the flaps of saline-treated controls showed a distinct decrease in FCD (94 ± 12cm/cm2). This perfusion failure resulted in flap necrosis of 52 ± 3%. Selective blockade of the ET-B receptor caused a further increase in aBF already at day 1 (2.97 ± 0.42nl/s), which persisted during the following 10-day observation period (day 10 = 5.74 ± 0.69nl/s). Accordingly, adequate FCD could be maintained (day 10 = 215 ± 8cm/cm2; p < 0.05 vs control), resulting in a significant reduction in flap necrosis (day 10 = 25 ± 4%; p < 0,05). In contrast, neither selective blockade of the ET-A receptor nor nonselective ET-A- and ET-B-receptor blockade were able to significantly affect aBF when compared to controls (day 1 = ET-A = 1.39 ± 0.10nl/s; ET-AB = 1.53 ± 0.80nl/s; n.s.). Accordingly, flap necrosis after ET-A- and ET-AB-receptor inhibition did not differ from that of controls (day 10 = ET-A: 46 ± 10%; ET-AB = 51 ± 7%). Conclusion: Our data show that only selective ET-B-receptor inhibition is capable of maintaining nutritive perfusion and, hence, reducing necrosis in critically perfused flap tissue. Accordingly, administration of ET-B-receptor antagonists may be considered in the treatment of critically perfused flap

Microdialysis of the rectus abdominis muscle for early detection of impending abdominal compartment syndrome

Objective: To investigate whether microdialysis is capable of assessing metabolic derangements during intra-abdominal hypertension (IAH), and whether monitoring of the rectus abdominis muscle (RAM) by microdialysis represents areliable approach in the early detection of organ dysfunctions in abdominal compartment syndrome (ACS). Design: Prospective, randomized, controlled animal study. Setting: University animal research facility. Subjects: Fifteen isoflurane-anesthetized and mechanically ventilated Sprague-Dawley rats. Interventions: IAH of 20 mmHg was induced for 3 h and followed by decompression and reperfusion for another 3-h period (n = 10). Five sham-operated animals served as controls. Microdialysis was performed in the anterior gastric wall, liver, kidney, and RAM. The anterior cervical muscles served as distant reference. Glucose, lactate, pyruvate, and glycerol was analyzed throughout the 6-h experiment. Measurements and main results: Prolonged IAH induced significant cardiopulmonary dysfunction and persistent abdominal organ injury. Microdialysis revealed asignificant increase of lactate/pyruvate and glycerol in kidney, intestine and liver, indicating ischemia, energy failure, and cell membrane damage. In addition, at 3 h IAH glucose was significantly decreased in all organs studied. The distant reference did not show any alteration of lactate/pyruvate, glycerol, and glucose over the entire 6-h observation period. In contrast to the other organs, microdialysis of the RAM showed an early and more pronounced increase of lactate, lactate/pyruvate and glycerol already at 1 h IAH. It is noteworthy that lactate, glycerol, and glucose did not completely recover upon decompression of IAH. Conclusions: Our data suggest that continuous microdialysis in the RAM may represent apromising tool for early detecting IAH-induced metabolic derangement

Angiogenesis in tissue engineering : Breathing life into constructed tissue substitutes

Long-term function of three-dimensional (3D) tissue constructs depends on adequate vascularization after implantation. Accordingly, research in tissue engineering has focused on the analysis of angiogenesis. For this purpose, 2 sophisticated in vivo models (the chorioallantoic membrane and the dorsal skinfold chamber) have recently been introduced in tissue engineering research, allowing a more detailed analysis of angiogenic dysfunction and engraftment failure. To achieve vascularization of tissue constructs, several approaches are currently under investigation. These include the modification of biomaterial properties of scaffolds and the stimulation of blood vessel development and maturation by different growth factors using slow-release devices through pre-encapsulated microspheres. Moreover, new microvascular networks in tissue substitutes can be engineered by using endothelial cells and stem cells or by creating arteriovenous shunt loops. Nonetheless, the currently used techniques are not sufficient to induce the rapid vascularization necessary for an adequate cellular oxygen supply. Thus, future directions of research should focus on the creation of microvascular networks within 3D tissue constructs in vitro before implantation or by co-stimulation of angiogenesis and parenchymal cell proliferation to engineer the vascularized tissue substitute in situ

Imprisoned and imperiled: access to HIV and TB prevention and treatment, and denial of human rights, in Zambian prisons

<p>Abstract</p> <p>Background</p> <p>Although HIV and tuberculosis (TB) prevalence are high in prisons throughout sub-Saharan Africa, little research has been conducted on factors related to prevention, testing and treatment services.</p> <p>Methods</p> <p>To better understand the relationship between prison conditions, the criminal justice system, and HIV and TB in Zambian prisons, we conducted a mixed-method study, including: facility assessments and in-depth interviews with 246 prisoners and 30 prison officers at six Zambian prisons; a review of Zambian legislation and policy governing prisons and the criminal justice system; and 46 key informant interviews with government and non-governmental organization officials and representatives of international agencies and donors.</p> <p>Results</p> <p>The facility assessments, in-depth interviews and key informant interviews found serious barriers to HIV and TB prevention and treatment, and extended pre-trial detention that contributed to overcrowded conditions. Disparities both between prisons and among different categories of prisoners within prisons were noted, with juveniles, women, pre-trial detainees and immigration detainees significantly less likely to access health services.</p> <p>Conclusions</p> <p>Current conditions and the lack of available medical care in Zambia's prisons violate human rights protections and threaten prisoners' health. In order to protect the health of prisoners, prison-based health services, linkages to community-based health care, general prison conditions and failures of the criminal justice system that exacerbate overcrowding must be immediately improved. International donors should work with the Zambian government to support prison and justice system reform and ensure that their provision of funding in such areas as health services respect human rights standards, including non-discrimination. Human rights protections against torture and cruel, inhuman or degrading treatment, and criminal justice system rights, are essential to curbing the spread of HIV and TB in Zambian prisons, and to achieving broader goals to reduce HIV and TB in Zambia.</p

Costing Human Rights and Community Support Interventions as a Part of Universal Access to HIV Treatment and Care in a Southern African Setting

Expanding access to antiretroviral therapy (ART) has both individual health benefits and potential to decrease HIV incidence. Ensuring access to HIV services is a significant human rights issue and successful programmes require adequate human rights protections and community support. However, the cost of specific human rights and community support interventions for equitable, sustainable and non-discriminatory access to ART are not well described. Human rights and community support interventions were identified using the literature and through consultations with experts. Specific costs were then determined for these health sector interventions. Population and epidemic data were provided through the Statistics South Africa 2009 national mid-year estimates. Costs of scale up of HIV prevention and treatment were taken from recently published estimates. Interventions addressed access to services, minimising stigma and discrimination against people living with HIV, confidentiality, informed consent and counselling quality. Integrated HIV programme interventions included training for counsellors, ‘Know Your Rights’ information desks, outreach campaigns for most at risk populations, and adherence support. Complementary measures included post-service interviews, human rights abuse monitoring, transportation costs, legal assistance, and funding for human rights and community support organisations. Other essential non-health sector interventions were identified but not included in the costing framework. The annual costs for the human rights and community support interventions are United States (US) $63.8 million (US$1.22 per capita), representing 1.5% of total health sector HIV programme costs. Respect for human rights and community engagement can be understood both as an obligation of expanded ART programmes and as a critically important factor in their success. Basic rights-based and community support interventions constitute only a small percentage of overall programmes costs. ART programs should consider measuring the cost and impact of human rights and community support interventions as key aspects of successful programme expansion

Gender-specific ischemic tissue tolerance in critically perfused skin

PURPOSE: The purpose of this study is to determine gender-specific differences in the development of necrosis in persistent ischemic tissue and to analyze whether differences are due to gender-specific loss of vascular reactivity or change in ischemic tolerance. METHODS: Hairless mice (skh-1) of both genders were assigned to three groups of adolescent, adult, and senescent age. Critical ischemia was induced by transection of the two distal pedicles of the animal's ear. Microcirculation was assessed over a 5-day period using intravital epifluorescence microscopy. Tissue necrosis, blood flow, functional capillary density (FCD), red blood cell (RBC) velocity, and capillary diameter were analyzed. RESULTS: Induction of persistent ischemia caused an age-dependent demarcation of nonperfused flap tissue. Adult and senescent females developed markedly more necrosis than age-matched males (49 +/-1% vs. 37 +/-3% and 53 +/- 3% vs. 44 +/- 2%, respectively; p<0.05), whereas no gender-specific difference in flap necrosis was observed in adolescent animals (31 +/- 2% vs. 33 +/- 3%). Gender did not affect the amount of microcirculatory dysfunction in the flap. Thus, age-matched females and males exhibited a comparable decrease of FCD, RBC velocity, and capillary dilatory response. CONCLUSIONS: Both age and female gender may predispose for an increased susceptibility to develop ischemic tissue necrosis. The increased necrosis in female animals does not apply to an aggravated microvascular dysfunction, but rather to a reduced ischemic tissue tolerance