Surgical site infection: the "Achilles Heel" of all types of abdominal wall hernia reconstruction.

PURPOSE: Surgical site infection is the most common hospital-acquired infection in surgical patients. Recently, public health organizations have updated prevention guidelines. This review discusses surgical site infections as a complication of abdominal wall reconstruction. METHODS: The authors reviewed guidelines on prevention of surgical site infections from the Center for Disease Control and Prevention, World Health Organization, and National Institute for Health and Care Excellence and put them into context with the relevant abdominal wall reconstruction literature. This was the subject of the Nyhus-Wantz lecture given at The International Hernia Congress on March 14, 2018 in Miami, FL and is summarized here. RESULTS: Routine use of preoperative antibiotics in prosthetic groin hernia repair is not supported by the available literature. High-quality data on antibiotic prophylaxis in ventral (both primary and incisional) hernia repair is lacking, but it is widely utilized and may reduce SSIs. Recommended preventative strategies discussed in this manuscript include: treatment of remote site infections, perioperative normothermia and normoglycemia, avoidance of hypoxemia, antiseptic preparation of surgical team hands and patient skin, treatment of obesity, smoking cessation, correction of malnutrition, and physical conditioning. CONCLUSION: Surgical site infections lead to significant morbidity and mortality, hernia recurrences, prolonged hospital stay, and increased hospital costs. This makes surgical site infections the "Achilles Heel" of abdominal wall reconstruction. Strict adherence to standardized guidelines and preoperative optimization of patients' risk profiles are crucial to decrease the incidence of surgical site infections.

IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques.

Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal Th17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4(+) T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as Th17 cells, had limited recovery. Here, we sought to promote Th17 cell recovery by administering interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected individuals.

Dysbiotic bacteria translocate in progressive SIV infection.

Infection of gut-resident CD4(+) memory T cells during acute human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection is associated with rapid loss of these cells and damage to the epithelial barrier. Damage to the epithelial barrier allows translocation of microbial products from the intestinal lumen into the body. Immune activation caused by these microbial products has been associated with disease progression. Although microbial translocation has been demonstrated in SIV-infected nonhuman primates, the identity of translocating bacteria has not been determined. In this study we examined the communities of bacteria both within the gastrointestinal (GI) tract and systemic tissues of both healthy and experimentally SIV-infected Asian macaques. Although there were only modest changes in the GI tract-associated microbiome resulting from infection, there is substantial dysbiosis after administration of antiretrovirals. Analysis of bacterial DNA isolated from tissues of infected animals revealed a preference for the phylum Proteobacteria, suggesting that they preferentially translocate. Consistent with this finding, we observed increased metabolic activity of Proteobacterial species within the colonic lumen of SIV-infected animals. Overall, these data provide insights into disease progression and suggest that therapies aimed at altering the composition and metabolic activity of the GI tract microbiome could benefit chronically HIV-infected individuals, particularly those on antiretroviral therapies.

Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection.

Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV) disease progression is associated with multifocal damage to the gastrointestinal tract epithelial barrier that correlates with microbial translocation and persistent pathological immune activation, but the underlying mechanisms remain unclear. Investigating alterations in mucosal immunity during SIV infection, we found that damage to the colonic epithelial barrier was associated with loss of multiple lineages of interleukin (IL)-17-producing lymphocytes, cells that microarray analysis showed expressed genes important for enterocyte homeostasis, including IL-22. IL-22-producing lymphocytes were also lost after SIV infection. Potentially explaining coordinate loss of these distinct populations, we also observed loss of CD103+ dendritic cells (DCs) after SIV infection, which associated with the loss of IL-17- and IL-22-producing lymphocytes. CD103+ DCs expressed genes associated with promotion of IL-17/IL-22+ cells, and coculture of CD103+ DCs and naïve T cells led to increased IL17A and RORc expression in differentiating T cells. These results reveal complex interactions between mucosal immune cell subsets providing potential mechanistic insights into mechanisms of mucosal immune dysregulation during HIV/SIV infection, and offer hints for development of novel therapeutic strategies to address this aspect of AIDS virus pathogenesis.

Altered distribution of mucosal NK cells during HIV infection.

The human gut mucosa is a major site of human immunodeficiency virus (HIV) infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells have an important role in control of HIV infection, but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here, we show that two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (intraepithelial lymphocytes, IELs) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective killer immunoglobulin-like receptor/human leukocyte antigen genotypes. Both IEL and LP NK cells were significantly expanded in immunological non-responsive patients, who incompletely recovered CD4+ T cells on highly active antiretroviral therapy (HAART). These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T-cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut.

Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection.

Pigtail macaques (PTMs) rapidly progress to AIDS after simian immunodeficiency virus (SIV) infection. Given the strong association between human immunodeficiency virus (HIV) and SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTMs. We found that before SIV infection, PTMs had high levels of microbial translocation that correlated with significant damage to the structural barrier of the gastrointestinal tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of interleukin-17-producing T cells. These data highlight the relationship among mucosal damage, microbial translocation and systemic immune activation in the absence of SIV replication, and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTMs. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation.

Causes and consequences of marine mammal population declines in southwest Alaska: a food-web perspective.

Populations of sea otters, seals and sea lions have collapsed across much of southwest Alaska over the past several decades. The sea otter decline set off a trophic cascade in which the coastal marine ecosystem underwent a phase shift from kelp forests to deforested sea urchin barrens. This interaction in turn affected the distribution, abundance and productivity of numerous other species. Ecological consequences of the pinniped declines are largely unknown. Increased predation by transient (marine mammal-eating) killer whales probably caused the sea otter declines and may have caused the pinniped declines as well. Springer et al. proposed that killer whales, which purportedly fed extensively on great whales, expanded their diets to include a higher percentage of sea otters and pinnipeds following a sharp reduction in great whale numbers from post World War II industrial whaling. Critics of this hypothesis claim that great whales are not now and probably never were an important nutritional resource for killer whales. We used demographic/energetic analyses to evaluate whether or not a predator-prey system involving killer whales and the smaller marine mammals would be sustainable without some nutritional contribution from the great whales. Our results indicate that while such a system is possible, it could only exist under a narrow range of extreme conditions and is therefore highly unlikely.

Functional and phenotypic characterization of the humanized BLT mouse model.

T cells play a central role in the development of immune responses. Patients lacking T cells because of genetic defects such as DiGeorge or Nezelof syndromes and patients infected with the human immunodeficiency virus are highly susceptible to infections and cancers. The lack of adequate in vivo models of T cell neogenesis have hindered the development and clinical implementation of effective therapeutic modalities aimed at treating these and other clinically important maladies. Transplantation of severe combined immunodeficient (SCID) mice with human hematopoietic stem cells results in long-term engraftment and systemic reconstitution with human progenitor, B, and myeloid cells, but curiously, human T cells are rarely present in any tissue. While the implantation of SCID mice with human fetal thymus and liver (SCID-hu thy/liv mice) allows the development of abundant thymocytes that are localized in the human organoid implant, there is minimal systemic repopulation with human T cells. However, we have recently shown that transplantation of autologous human hematopoietic fetal liver CD34+ cells into the nonobese diabetic (NOD)/SCID mouse background previously implanted with fetal thymic and liver tissues results in long-term, systemic human T cell homeostasis. In addition to human T cells, these mice have systemic repopulation with human B cells, monocytes/macrophages, and dendritic cells (DC). Importantly, in these mice the T cells developed in the human thymic implant are capable of being activated by human antigen-presenting cells and mount potent human MHC-restricted T cell immune responses.

Patterns of growth and body condition in sea otters from the Aleutian archipelago before and after the recent population decline.

1. Growth models for body mass and length were fitted to data collected from 1842 sea otters Enhydra lutris shot or live-captured throughout south-west Alaska between 1967 and 2004. Growth curves were constructed for each of two main year groups: 1967-71 when the population was at or near carrying capacity and 1992-97 when the population was in steep decline. Analyses of data collected from animals caught during 2004, when the population density was very low, were precluded by a small sample size and consequently only examined incidentally to the main growth curves. 2. Growth curves demonstrated a significant increase in body mass and body length at age in the 1990s. Asymptotic values of body mass were 12-18% higher in the 1990s than in the 1960s/70s, and asymptotic values for body length were 10-11% higher between the same periods. Data collected in 2004 suggest a continued increase in body size, with nearly all data points for mass and length falling significantly above the 1990s growth curves. 3. In addition to larger asymptotic values for mass and length, the rate of growth towards asymptotic values was more rapid in the 1990s than in the 1960s/70s: sea otters reached 95% of asymptotic body mass and body length 1-2 years earlier in the 1990s. 4. Body condition (as measured by the log mass/log length ratio) was significantly greater in males than in females. There was also an increasing trend from the 1960s/70s through 2004 despite much year-to-year variation. 5. Population age structures differed significantly between the 1960s/70s and the 1990s with the latter distribution skewed toward younger age classes (indicating an altered lx function) suggesting almost complete relaxation of age-dependent mortality patterns (i.e. those typical of food-limited populations). 6. This study spanned a period of time over which the population status of sea otters in the Aleutian archipelago declined precipitously from levels at or near equilibrium densities at some islands in the 1960s/70s to < 5% of estimated carrying capacity by the late 1990s. The results of this study indicate an improved overall health of sea otters over the period of decline and suggest that limited nutritional resources were not the cause of the observed reduced population abundance. Our findings are consistent with the hypothesis that the decline was caused by increased killer whale predation.

Introduced predators transform subarctic islands from grassland to tundra.

Top predators often have powerful direct effects on prey populations, but whether these direct effects propagate to the base of terrestrial food webs is debated. There are few examples of trophic cascades strong enough to alter the abundance and composition of entire plant communities. We show that the introduction of arctic foxes (Alopex lagopus) to the Aleutian archipelago induced strong shifts in plant productivity and community structure via a previously unknown pathway. By preying on seabirds, foxes reduced nutrient transport from ocean to land, affecting soil fertility and transforming grasslands to dwarf shrub/forb-dominated ecosystems.

Sequential megafaunal collapse in the North Pacific Ocean: an ongoing legacy of industrial whaling?

Populations of seals, sea lions, and sea otters have sequentially collapsed over large areas of the northern North Pacific Ocean and southern Bering Sea during the last several decades. A bottom-up nutritional limitation mechanism induced by physical oceanographic change or competition with fisheries was long thought to be largely responsible for these declines. The current weight of evidence is more consistent with top-down forcing. Increased predation by killer whales probably drove the sea otter collapse and may have been responsible for the earlier pinniped declines as well. We propose that decimation of the great whales by post-World War II industrial whaling caused the great whales' foremost natural predators, killer whales, to begin feeding more intensively on the smaller marine mammals, thus "fishing-down" this element of the marine food web. The timing of these events, information on the abundance, diet, and foraging behavior of both predators and prey, and feasibility analyses based on demographic and energetic modeling are all consistent with this hypothesis.

Evaluation of an indirect fluorescent antibody test (IFAT) for demonstration of antibodies to Toxoplasma gondii in the sea otter (Enhydra lutris).

An indirect fluorescent antibody test (IFAT) for detection of Toxoplasma gondii infection was validated using serum from 77 necropsied southern sea otters (Enhydra lutris nereis) whose T. gondii infection status was determined through immunohistochemistry and parasite isolation in cell culture. Twenty-eight otters (36%) were positive for T. gondii by immunohistochemistry or parasite isolation or both, whereas 49 (64%) were negative by both tests. At a cutoff of 1:320, combined values for IFAT sensitivity and specificity were maximized at 96.4 and 67.3%, respectively. The area under the receiver-operating characteristic curve for the IFAT was 0.84. A titer of 1:320 was used as cutoff when screening serum collected from live-sampled sea otters from California (n = 80), Washington (n = 21), and Alaska (n = 65) for T. gondii infection. Thirty-six percent (29 out of 80) of California sea otters (E. lutris nereis) and 38% (8 out of 21) of Washington sea otters (E. lutris kenyoni) were seropositive for T. gondii, compared with 0% (0 out of 65) of Alaskan sea otters (E. lutris kenyoni).

Historical overfishing and the recent collapse of coastal ecosystems.

Ecological extinction caused by overfishing precedes all other pervasive human disturbance to coastal ecosystems, including pollution, degradation of water quality, and anthropogenic climate change. Historical abundances of large consumer species were fantastically large in comparison with recent observations. Paleoecological, archaeological, and historical data show that time lags of decades to centuries occurred between the onset of overfishing and consequent changes in ecological communities, because unfished species of similar trophic level assumed the ecological roles of overfished species until they too were overfished or died of epidemic diseases related to overcrowding. Retrospective data not only help to clarify underlying causes and rates of ecological change, but they also demonstrate achievable goals for restoration and management of coastal ecosystems that could not even be contemplated based on the limited perspective of recent observations alone.

Outcome after combined carotid endarterectomy and coronary artery bypass is related to patient selection.

OBJECTIVE: The optimal management of patients with significant coronary and carotid artery disease remains controversial. Since reporting on a series of 100 patients undergoing combined carotid endarterectomy and coronary artery bypass (CEA/CAB) 4 years ago, we have liberalized our selection criteria for combined operation. We sought to compare outcomes of the recent cohort of 74 patients and the previous group. METHODS: All patients who underwent CEA/CAB since 1984 have been tracked in a database containing identifying information, demographic factors, anatomic information, details of surgery, and short- and long-term follow-up data. We compared the 74 patients (Group 2) undergoing CEA/CAB since 1994 with the previously reported group of 100 patients (Group 1) who underwent CEA/CAB between 1984 and 1994. We examined demographic and comorbidity factors, presence of cerebrovascular symptoms, degree of contralateral carotid stenosis, and perioperative stroke and death. Statistical comparisons were made with the chi(2) test. RESULTS: The groups had similar age and sex distributions and similar incidences of hypertension, diabetes, congestive heart failure, prior myocardial infarction, and hypercholesterolemia. More patients in Group 1 had preoperative transient cerebral ischemia or monocular blindness (55% vs 31%, P <.002) and preoperative stroke (18% vs 7%, P <.03). More patients in Group 2 had unilateral asymptomatic carotid artery stenosis (55% vs 18%, P <.001). The incidence of all perioperative strokes was higher in Group 1 (9% vs 1.4%, P <.035). There were fewer deaths (3% vs 8%) and ipsilateral strokes (0 vs 4%) in Group 2, though these were not statistically significant. CONCLUSION: We have liberalized our criteria for performing combined CEA/CAB, such that more than 50% of our recent patients have asymptomatic unilateral carotid stenosis. This practice is associated with a lower incidence of all perioperative strokes and a trend toward lower ipsilateral stroke and death. These observations suggest that perioperative stroke after CEA/CAB is related to patient selection and that low-risk patients can undergo CEA/CAB with the benefits of low morbidity, patient convenience, and cost savings from avoiding a second hospitalization and operation.

The carotid artery as alternative access for endoluminal aortic aneurysm repair.

Endograft treatment of aortic aneurysms has become a common procedure in many centers. However, not all patients are candidates for this new technology, because of their vascular anatomy and device limitations. One common problem is iliofemoral occlusive disease, which when present, even in a moderate degree, may preclude introduction of the large-diameter delivery devices currently in use. We present a case of a high-risk male patient with a thoracic aortic aneurysm and severe occlusive disease of the iliac arteries. An alternative approach for device delivery through the carotid artery was used and the procedure was successful with no neurologic complications. We recommend this technique for highly selected patients with an aneurysm who can undergo tube endograft repair without feasible access through the iliac or femoral arteries.

Interdependence of profilin, cation, and nucleotide binding to vertebrate non-muscle actin.

The interaction of profilin and non-muscle beta,gamma-actin prepared from bovine spleen has been investigated under physiologic ionic conditions. Profilin binding to actin decreases the affinity of actin for MgADP and MgATP by about 65- and 13-fold, respectively. Kinetic measurements indicate that profilin binding to actin weakens the affinity of actin for nucleotides primarily due to an increased nucleotide dissociation rate constant, but the nucleotide association rate constant is also increased about 2-fold. Removal of the actin-bound nucleotide and divalent cation produces the labile intermediate species in the nucleotide exchange reaction, nucleotide free actin (NF-actin), and increases the affinity of actin for profilin about 10-fold. Profilin binds NF-actin with high affinity, K(D) = 0.013 microM, and slows the observed denaturation rate of NF-actin. Addition of ATP to NF-actin weakens the affinity for profilin and addition of Mg(2+) to ATP-actin further weakens the affinity for profilin. The high-affinity Mg(2+) of actin regulates binding of both nucleotide and profilin to actin and is important for actin interdomain coupling. The data suggest that profilin binding to actin weakens nucleotide binding to actin by disrupting Mg(2+) coordination in the actin central cleft.

7-alkylcarbonyl and 7-alkyloxycarbonyl prodrugs of theophylline.

Five members (6-10) of an homologous series of 7-alkyloxycarbonyltheophylline (7-AOC-Th) and four members (2-5) of a homologous series of 7-alkylcarbonyltheophylline (7-AC-Th) prodrugs have been synthesized by known methods and characterized. All of the members in both series were much more soluble in isopropyl myristate (S(IMP)) (10-200 times) and in each series, at least one member was more soluble in pH 4.0 buffer (S(AQ)) than Th. However, in the 7-AC-Th series, only the acetyl member, 2, which exhibited about 90% of the S(AQ) of Th, was sufficiently stable to be evaluated - it gave four times the flux of Th/IPM (isopropyl myristate). In the 7-AOC-Th series, all the members were sufficiently stable to be evaluated but the member which exhibited the greatest S(AQ), 6 (methyloxycarbonyl), did not exhibit the greatest flux. Instead, 8 (propyloxycarbonyl), which exhibited the second greatest S(AQ) (about 80% of the S(AQ) of Th), but exhibited over ten times the S(IPM) of 6 gave the greatest flux - two times the flux of Th/IPM. Thus, good biphasic solubility was the best predictor of increased flux. All of the prodrugs delivered only Th through the mouse skin. Only 2/IPM actually delivered more Th into the skin than Th/IPM which correlated with its ability to increase the flux of Th through the skin.

Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience.

CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine (131)I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P =.005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine (131)I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL. (Blood. 2000;96:1259-1266)

Factors predicting prolonged length of stay after carotid endarterectomy.

BACKGROUND: Over the last several years, implementation of critical pathways in patients undergoing carotid endarterectomy has decreased postoperative length of stay significantly. Discharge the day after surgery has become commonplace in many centers, including our own. Unfortunately, managed care may interpret this refinement as a standard of care and limit reimbursement or even disallow admissions extending beyond 1 day. We therefore examined our carotid registry to identify risk factors associated with postoperative length of stay exceeding 1 day. METHODS: We retrospectively reviewed all patients undergoing carotid endarterectomy at our academic center from May 1996 through April 1999. Combined procedures and patients undergoing subsequent noncarotid-related procedures on those admissions were excluded. The charts were inspected for atherosclerosis risk factors, including sex and age, specific attending surgeon, side of the surgery, use of intravenous vasoactive drugs, actual preoperative blood pressure, and presence of neurologic symptoms or postoperative complications. Multiple regression analysis was performed on all collected variables. Statistical significance was inferred for P less than.05. RESULTS: A total of 188 patients met the study criteria and had complete, retrievable medical records. A mean postoperative length of stay of 1.65 +/- 0.08 days and a mean total length of stay of 2.17 +/- 0.14 days were observed. Fifty-seven percent of patients went home the day after surgery. There was a 1.6% stroke-mortality rate. Significant predictors of a prolonged stay, listed in order of decreasing importance on the basis of their calculated contribution to prolonging the postoperative length of stay, are as follows (P value; beta coefficient): postoperative complications (<.0001; 1.03), age > 79 years (.008; 0.547), diabetes mellitus (.011; 0.407), female sex (.007; 0.398), and intravenous vasodilator requirement (. 035; 0.382). Other atherosclerosis risk factors, prior neurologic symptoms, the postoperative use of vasopressors, and reoperative surgery did not contribute to extended length of stay. CONCLUSIONS: Discharge on the first postoperative day is feasible in many, but not all, patients undergoing carotid endarterectomy. Our data help define subsets of patients at risk for prolonged postoperative stay. Targeting these subsets for preoperative medical and social interventions may allow safe early discharge more frequently.