Cross‐linking of porcine acellular dermal matrices negatively affects induced neovessel formation using platelet‐rich plasma in a rat model of hernia repair

The degree of cross‐linking within acellular dermal matrices (ADM) seems to correlate to neovascularization when used in ventral hernia repair (VHR). Platelet‐rich plasma (PRP) enhances wound healing through several mechanisms including neovascularization, but research regarding its effect on soft tissue healing in VHR is lacking. We sought to study the effect of cross‐linking on PRP‐induced neovascularization in a rodent model of bridging VHR. We hypothesized that ADM cross‐linking would negatively affect PRP‐induced neovessel formation. PRP was extracted and characterized from pooled whole blood. Porcine cross‐linked (cADM) and non–cross‐linked ADMs (ncADM) were implanted in a rat model of chronic VHR after treatment with saline (control) or PRP. Neovascularization of samples at 2, 4, and 6 weeks was assessed by hematoxylin and eosin and immunohistochemical staining of CD 31. Adhesion severity at necropsy was compared using a previously validated scale. Addition of PRP increased neovascularization in both cADM and ncADM at 2‐ and 4‐week time points but appeared to do so in a dependent fashion, with significantly greater neovascularization in the PRP‐treated ncADMs compared to cADMs. Omental adhesions were increased in all PRP‐treated groups. Results indicate that, for 2‐week measurements when compared with the cADM group without PRP therapy, the mean change in neovascularization due to ncADM was 3.27 (Z = 2.75, p = 0.006), PRP was 17.56 (Z = 14.77, p < 0.001), and the combined effect of ncADM and PRP was 9.41 (Z = 5.6, p < 0.001). The 4‐week data indicate that the average neovascularization change due to ncADM was 0.676 (Z = 0.7, p = 0.484), PRP was 7.69 (Z = 7.95, p < 0.001), and combined effect of ncADM and PRP was 5.28 (Z = 3.86, p < 0.001). These findings validate PRP as a clinical adjunct to enhance the native tissue response to implantable biomaterials and suggest that ncADM is more amenable than cADM to induced neovascularization. PRP use could be advantageous in patients undergoing VHR where poor incorporation is anticipated and early‐enhanced neovascularization is desired.     

Subchronic Toxicity of Orally Administered (Gavage and Dosed-Feed) Theophylline in Fischer 344 Rats and B6C3F2 13 Mice

Subchronic Toxicity of Orally Administered (Gavage and Dosed-Feed)Theophylline in Fischer 344 Rats and B6C3F, Mice.COLLINS, J.J., ELWELL, M. R., LAMP, J. C, IV, MANUS, A. C, HEATH, J. E.,and MAKOVEC, G. T. (1988). Fundam Appl Toxicol. 11, 472—484.Theophylline, a methylated xanthine closely resembling caffeineand theobromine, is a widely used pharmaceutical agent for thetreatment of respiratory disorders and certain acute cardiovascularconditions. The National Toxicology Program has conducted 13-weeksubchronic toxicity studies in F344 rats and B6C3F₁ mice (10animals/group) following administration of theophylline viathe diet or by gavage. Administration of theophylline in thefeed (0, 1000, 2000, and 4000 ppm) resulted in no mortalityor body weight effects in F344 rats, but did induce periarteritisof the arteries adjacent to mesenteric lymph nodes and the pancreas,particularly arterioles in the latter. Also observed in ratsdosed with theophylline via the diet was an increased severityof chronic nephropathy in males, especially at the high dose.Administration of theophylline at the same concentrations inthe feed to B6C3Fi 2 mice resulted in no mortality, but terminalbody weights were significantly decreased in all dosed groups.An increased incidence of hepatocellular glycogen depletionwas observed in male and female mice, and this change is believedto represent a physiological alteration exacerbated by the administrationof theophylline. Administration of theophylline by gavage toF344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the earlydeath of one high-dose male and female and significantly decreasedor increased terminal body weights of high-dose males and females,respectively. Similar to the results of the dosed-feed study,male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severityof perivascular inflammation of mesen teric arteries. Gavageadministration of theophylline to B6C3F, mice (0, 75, 150, and300 mg/kg) resulted in the early death of all high-dose femalesand 3/10 high-dose males and significant depres sion of terminalbody weights in high- and mid-dose males and low-dose females.As in the dosed feed study, the primary histopathologk changein the mouse subchronic gavage study was hepatocel lular glycogendepletion, although in this case it was seen only in females.In summary, the major target organs for orally administeredtheophylline in 13-week subchronic toxicity studies appear tobe the mesenteric arteries in F344 rats and the liver in B6C3F₁mice. On the basis of organ weight changes and/or minor histopathologiceffects, many other tissues were also affected, particularlythe kidneys in dosed-feed male rats and the uterus in gavage-dosedfemale rats.     

Reproductive Effects of Theophylline in Mice and Rats

Reproductive Effects of Theophylline in Mice and Rats. MORRISSEY,R. E., COLLINS, J. J., LAMB, J. C, IV, MANUS, A. G., AND GULATI.D. K. (1988). Fundam Appl. Toxtcol. 10, 525–536. Theophyllinewas administered by gavage in 13-week studies to B6C3F, mice(0, 75, 150, 300 mg/kg/day) and F344 rats (0, 37.5, 75, 150mg/kg/day) with significant reductions in male mouse terminalbody and testicular weights. Male rats also displayed reducedtesticular weight, as well as nonsignificant but dose-relateddecreases in body weight. There was a significant but non-dose-relateddecrease in female mouse body weight. In parallel studies ofB6C3F, mice and F344 rats, theophylline administered in thediet (0, 0.1, 0.2, 0.4%) produced significantly decreased terminalbody weights in male and female mice, but not rats. In rats,cauda epididymis weight was reduced at the high dose comparedto the control group, and there was an increase in abnormalsperm. These studies were followed by continuous breeding reproductiveassays in CD-I mice in which theophylline was administered infeed (0.0, 0.075, 0.15, and 0.30% calculated doses of 0, 125,265, and 530 mg/kg/day, respectively) to breeding pairs for14 weeks. There was a dose-dependent decrease in the numberof live pups produced per litter, a significant decrease inthe number of litters produced per pair (0.30%) and in the adjustedlive pup weight (0.30%), a decrease in the percentage of pupsborn alive (0.15 and 0.30%), and an increase in the number ofdays needed to produce each litter (0.30%). After 19 weeks ofcontinuous treatment at 0.307%, a crossover mating trial indicatedthat females and males were adversely affected by theophylline,as judged by the decreased percentage of pups born alive, thedecreased live pup weight, and the decreased number of livepups per litter relative to matings within the control group,but the effects in females were more extensive. Based on otherstudies, there is a suggestion that the observed changes infertility may be partially attributed to embryotoxicity.     

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.     

Endothelial cell hyperproliferation and stratification in uteroplacental blood vessels of the black mastiff bat, Molossus rufus

Placentation was studied histologically and immunocytochemically in black mastiff bats obtained at frequent intervals throughout pregnancy. These were bred in a captive colony or collected from a reproductively-synchronized wild population. During late pregnancy, the single fetus was largely sustained by a discoidal, hemochorial placenta located at the cranial end of the right uterine horn. This invariant positioning was determined by a vascular tuft that developed there both during early pregnancy and non-pregnant cycles. This provided a scaffold for early placental morphogenesis. As development proceeded, small arterioles and venules serving the tuft were converted to large uteroplacental vessels. Within the base of the placenta, these became lined by an unusual vascular epithelium composed of intermingled patches of multilayered endothelial cells and cytotrophoblast. Initially, the endothelium became multilayered by hypertrophy, proliferation, and infolding of its basal lamina. These created endothelial bilayers usually insinuated between basal laminae. The development of temporary gaps in the laminae then permitted further enlargement of the vessels and proliferation of the endothelial cells as monolayer sheets or chains. The latter were interconnected, forming a complex, stratified, cellular network associated with a prominent meshwork of basal laminae. Throughout much of pregnancy, these endothelial cells were cuboidal to columnar and possessed an abundance of basal glycoprotein granules presumably containing basal lamina precursors. The cells also expressed vimentin and frequently von Willebrand factor, but not cytokeratins or desmin. Pronounced thickening of the endothelia and amplification of their basal laminae likely evolved to greatly strengthen the walls of the uteroplacental vessels.     

Evidence of multiple chromosomal inversions in Aedes aegypti formosus from Senegal

Chromosomal inversions are prevalent in mosquito species but polytene chromosomes are difficult to prepare and visualize in members of the tribe Aedinii and thus there exists only indirect evidence of inversions. We constructed an F₁ intercross family using a P₁ female from a laboratory strain of Aedes aegypti aegypti ( Aaa ) and a P₁ male Aedes aegypti formosus ( Aaf ) from a strain collected from south-eastern Senegal. Recombination rates in the F₂ offspring were severely reduced and genotype ratios suggested a deleterious recessive allele on chromosome 3. The F₂ linkage map was incongruent in most respects with the established map for Aaa . Furthermore, no increased recombination was detected in F₅ offspring. Recombination rates and gene order were consistent with the presence in Aaf of at least four large inversions on chromosome 1, a single small inversion on chromosome 2 and three inversions on chromosome 3.     

Multiple Primary Acral Melanomas in African-Americans: A Case Series and Review of the Literature

BACKGROUND: Although melanoma accounts for only 4% to 5% of all skin cancers in the United States, it causes most skin cancer-related deaths. We describe a unique group of African-American patients with multiple primary acral lentiginous melanomas (ALMs). OBJECTIVE: The purpose of this study was to review the case histories and management of a cohort of patients in the Mohs practice of our dermatologic surgeon with multiple primary ALM. METHODS: This is a case series of patients with multiple ALM identified by chart review from 2000 to 2005. A thorough review of the literature was performed. RESULTS: Four patients, all African-American, were identified with multiple ALM. All patients were managed with excision or Mohs micrographic surgery utilizing permanent sections. None of the patients with ALM had melanomas at nonacral sites or other types of skin cancer. Several had acral melanosis. Information in the literature on patients with multiple primary acral melanomas was insufficient. CONCLUSION: Patients with multiple acral melanomas have not, to our knowledge, been reported thus far. It can be extrapolated from current literature, however, that appropriate management of these patients, including staging work and surgical intervention, is to be determined by the individual characteristics of the melanoma and the patient's concomitant risk factors, if any.