Lateral arm flap: analysis of its anatomy and modification using a vascularized fragment of the distal humerus

Soft tissue injuries with associated bone defects are difficult to manage and often require prolonged treatment with repeated interventions. Frequently, a free flap is applied as a first step and bone grafting is carried out in a second procedure. Ideally, these two procedures are combined in one operation, utilizing a soft tissue flap with an attached vascularized bone fragment. The lateral arm flap can provide such an osteoseptocutaneous flap and has been utilized clinically with success; however, the vascular anatomy of the flap, especially the humeral fragment, has not been described in detail previously, and there is broad disagreement concerning its innervation. In this study, the arteries and nerves of 24 fresh cadaver arms were dissected after injection of colored latex. The levels of origin of the periosteal arteries of the humerus were also documented. The lateral arm flap has a consistent arterial supply from three septocutaneous perforating branches that are arranged in a predictable pattern. The lateral supracondylar ridge of the humerus is vascularized by direct branches of the posterior branch of the radial collateral artery and by arteries that arise from muscular branches supplying adjacent muscles. The innervation of the lateral arm flap is by the inferior lateral cutaneous nerve of the arm. Knowledge of the consistent vascular anatomy of the lateral humerus and soft tissue of the donor site allows an osteoseptocutaneous flap to be raised safely with an appropriate technique. We recommend use of the lateral arm flap with a humeral fragment for the treatment of combined soft tissue and bone defects when a single step surgical solution is indicated.     

Preferential vascular-based transfer from vagina to the corpus but not to the tubal part of the uterus in postmenopausal women.

BACKGROUND: Vaginal administration of progesterone during infertility treatment has therapeutic advantages over oral administration. However, the reasons for this are poorly defined. To demonstrate a preferential vagina-to-uterus distribution of substances, we investigated cold distribution from vagina to the uterus and rectum. METHOD: In 10 postmenopausal women, thermoprobes were inserted into the uterine cavity and in the rectum at <9 cm or at >9 cm from the anus; temperatures were subsequently measured during 10 min flushing of vagina with cold saline. RESULTS: After 10 min, temperature decreased as follows: uterus, tubal angle: -0.22 +/- 0.07 degrees C, 10 (mean +/- SEM, n); uterus, middle cavity: -1.26 +/- 0.34 degrees C, 9; rectum, <9 cm insertion: -3.69 +/- 0.68 degrees C, 3; rectum, >9 cm insertion: -0.51 +/- 0.19 degrees C, 6. CONCLUSIONS: Despite obviously different distances to the vagina of the uterine and the low rectal probes (<9 cm) the temperature decrease occurred at the same time. Cold transfer from vagina to the uterus and rectum is probably not the result of simple diffusion but of a vascular counter-current transfer. Differential cooling of corpus and tubal angles suggests a different arterial supply; while uterine corpus is supplied from the uterine artery, the tubal angles seem to be mainly supplied from the ovarian artery via the tubal arcade.     

Transvaginal colour Doppler in patients with ovarian endometriomas and pelvic pain

BACKGROUND: The aim of this investigation was to correlate ovarian endometrioma vascularization with the presence of pelvic pain. METHODS: The presence of blood flow, peak systolic velocity (PSV, cm/s) and lowest pulsatility index (PI), assessed by transvaginal colour Doppler ultrasonography and CA-125 plasma concentrations, were retrospectively analysed in 74 patients who had undergone operations for cystic ovarian endometriosis. Fifty-two patients were asymptomatic (group A) and 22 presented with pelvic pain (group B). There were 56 endometriomas in group A and 26 in group B. RESULTS: Blood flow was found in 66.1 and 88.5% of endometriomas in groups A and B respectively (P = 0.036). PI was significantly lower (P = 0.009) and CA-125 concentration higher (P = 0.0004) in group B. There were no differences in PSV. CONCLUSIONS: We conclude that vascularization of ovarian endometriomas in patients presenting with pelvic pain is higher than in asymptomatic patients. This could be an indicator of endometriosis activity.     

3D in vitro tissue models and their potential for drug screening

Introduction: The development of one standard, simplified in vitro three-dimensional tissue model suitable to biological and pathological investigation and drug-discovery may not yet be feasible, but standardized models for individual tissues or organs are a possibility. Tissue bioengineering, while concerned with finding methods of restoring functionality in disease, is developing technology that can be miniaturized for high throughput screening (HTS) of putative drugs. Through collaboration between biologists, physicists and engineers, cell-based assays are expanding into the realm of tissue analysis. Accordingly, three-dimensional (3D) micro-organoid systems will play an increasing role in drug testing and therapeutics over the next decade. Nevertheless, important hurdles remain before these models are fully developed for HTS.

Areas covered: We highlight advances in the field of tissue bioengineering aimed at enhancing the success of drug candidates through pre-clinical optimization. We discuss models that are most amenable to high throughput screening with emphasis on detection platforms and data modeling.

Expert opinion: Modeling 3D tissues to mimic in-vivo architecture remains a major challenge. As technology advances to provide novel methods of HTS analysis, so do potential pitfalls associated with such models and methods. We remain hopeful that integration of biofabrication with HTS will significantly reduce attrition rates in drug development.     

Using miniature brain implants in rodents for novel drug discovery

Introduction: There continues to be a need to create an artificial human blood-brain barrier for pharmacological testing and modeling of diseases. Our group has recently vascularized human brain organoids with human iPSC-derived endothelial cells. Other groups have achieved brain organoid perfusion after vascularization with murine endothelial cells.

Areas covered: This review article discusses the remaining hurdles, advantages, and limitations of creating a human organoid blood-brain barrier in rodents for novel drug discovery.

Expert opinion: The creation of a human organoid blood-brain barrier in rodents will be feasible with appropriate molecular and cellular cues. An artificial human blood-brain barrier model may be used for pharmacological testing or for the study of the human blood-brain barrier in development or disease. Potential limitations of the model include an inferior competence of the blood-brain organoid barrier, the immunodeficient environment and low reproducibility due to variations in organoid morphology and vascularization. Despite its limitations, an artificial human blood-brain barrier model in rodents will further our understanding of blood-brain barrier pharmacology, and the field is expected to see significant advances in the next years.     

Signature of the vascular tumor microenvironment as a marker of the therapeutic response to doxorubicin in a preclinical model of osteosarcoma

Predicting a response of osteosarcoma patients to chemotherapy, such as doxorubicin or high-dose methotrexate cocktail, remains a challenge in the clinic. Moreover, the prognostic value of currently used necrosis analysis is debatable. New markers of the therapeutic response or the prognostic response are urgently needed. The microenvironment plays a key role in the vascularization of highly heterogeneous tumors. Using the syngeneic MOS-J mouse model of osteosarcoma, we focused our study on the immunohistochemistry of tumor vascularization in order to identify new vessel markers, and to search for potential markers of the therapeutic response. Endomucin+, CD31+, and α-SMA+-positive elements were quantified in control (n=6) and doxorubicin-treated (n=6) mice in three different intra-tumor locations. We also used co-labeling to assess CD31+/Endomucin+ and CD31+/α-SMA+ co-expression. We identified a central tumor zone with a low vascularization profile for all of these markers. We identified two distinct types of vessels: CD31+/Endomucin+ vessels with a sprouting, neo-angiogenic, interlaced appearance, and CD31+/α-SMA+ vessel with a well-defined, mature structure. Doxorubicin appeared to reduce CD31+ expression in the tumor invasion front. In the doxorubicin-sensitive model, there were four times more CD31+/α-SMA+ elements than in the poorly responsive model. Therefore, we propose a methodology based on immunohistochemistry and multiplexed immunofluorescence to use endomucin as a promising new vascular marker in the osteosarcoma model. Moreover, our results suggest that CD31+/α-SMA+ vessels could be considered to be indicators of vasculature normalization and they may be used as specific markers of a good therapeutic response.     

乳腺癌血管生成拟态及其与基质金属蛋白酶-2表达的相关性研究

目的 探讨乳腺癌中是否存在血管生成拟态(VM),并通过研究其与基质金属蛋白酶-2(MMP-2)表达的相关性,初步探讨VM形成的机制.方法 选取女性乳腺癌的石蜡标本共146例作为试验组,再选取20例女性乳腺的良性病变作为对照组,进行过碘酸雪夫氏反应以及CD34的双重染色,观察VM是否存在,再对VM阳性者和阴性者均进行MMP-2染色,比较二者相互关系.结果 VM的阳性表达与肿瘤大小、病理分级和淋巴结转移有关(P＜0.05).高分化和中低分化乳腺癌组织中VM的阳性率比较,差异有统计学意义(P＜0.05).在有淋巴结转移的乳腺癌组织中及无淋巴结转移的乳腺癌组织中VM的阳性率比较,差异有统计学意义(P＜0.05).MMP-2在乳腺癌组织中表达阳性率与乳腺良性病变比较,差异有统计学意义(P＜0.05).MMP-2在乳腺癌组织中的阳性表达率与病理学分级、淋巴结转移有关.高分化的乳腺癌组织MMP-2阳性率和中低分化乳腺癌组织比较,差异有统计学意义(P＜0.05).有淋巴结转移的乳腺癌组织MMP-2阳性率和无淋巴结转移的乳腺癌组织比较,差异有统计学意义(P＜0.05).MMP-2在VM阳性组中阳性表达率显著高于阴性组,二者在乳腺癌组织中的表达呈正相关性(r=0.550,P＜0.05).结论 乳腺癌是中存在VM的,MMP-2表达同VM具有相关性.     

Influence of polymorphisms in VEGF, ACE, TNF and GST genes on the susceptibility to retinopathy of prematurity among Chinese infants

AIM: To investigate common polymorphisms in VEGF, ACE, TNF and GST genes with retinopathy of prematurity (ROP) risk among Chinese infants. METHODS: Nine polymorphisms in the above genes were genotyped on 724 advanced cases of ROP and 878 prematurely-born infants of low birth weight who were without any ophthalmologic disease. The frequencies of the polymorphisms were compared between cases and controls to identify the association present, if any. RESULTS: Of the nine polymorphisms, only two showed significant associations: ACE insertion deletion (ID) polymorphism (P=0.031) and TNF -308G/A polymorphism (P<0.001). The former was associated with a reduced ROP risk [ID genotype, adjusted OR (aOR): 0.603, 95%CI: 0.427-0.893, P=0.034; DD genotype, aOR: 0.468, 95%CI: 0.229-0.626, P=0.002], while the latter showed an increased risk (GA genotype, aOR: 1.956, 95%CI: 1.396-2.465, P<0.001; AA genotype, aOR: 2.809, 95%CI: 1.802-4.484, P<0.001). The association was also noted at the allele level (ACE D allele aOR: 0.698, 95%CI: 0.294-0.883, P<0.001; TNF -308A allele aOR: 1.776, 95%CI: 1.446-2.561, P<0.001). CONCLUSION: The ACE ID polymorphism can protect against ROP development while the TNF -308G/A can increase the risk of the disease among Chinese infants.