Histologic characterization of the post-radiation urethral stenosis in men treated for prostate cancer.

PURPOSE: To evaluate histological changes in stenotic urethral tissue post-radiation therapy. Treatment of prostate cancer by radiation therapy carries a risk of off-target injury to the membranous urethra causing urethral stenosis. Limited characterization of post-radiation urethral stenosis exists in the literature. We hypothesize that specific histopathologic parameters distinguish this stricture etiology. METHODS: Eighty-two consecutive patients with membranous urethral stenosis underwent urethroplasty between 2013 and 2018. Seventy specimens (86.4%) were available for evaluation: 51 from patients without radiation exposure and 19 from patients with history of radiation therapy for prostate cancer. All specimens were reviewed by a pathologist blinded to patient/stricture information. Histological scoring system was used for the quantification of collagen density, collagen organization, hyalinized fibrosis, vascular density, spindle-cell change, necrosis, hemorrhage, fat entrapment, vacuolation, acute and chronic inflammation, and foreign-body giant cells. Differences in histologic outcomes between groups were statistically analyzed. RESULTS: Post-radiation specimens had a higher collagen density (p = 0.01), higher collagen organization (p = 0.001), increased hyalinized fibrosis (p = 0.03), fat entrapment (p = 0.005) and spindle cell change (p = 0.005) when compared to membranous specimens without prior exposure to radiation. Post-radiation specimens also had a significantly decreased vascularity compared to specimens of non-radiated etiology (p = 0.0005). Fibrous connective tissue degenerative change with vacuolation was pronounced in post-radiation specimens and seldom seen in those without radiation (p = 0.0001). CONCLUSIONS: Membranous urethral stenosis following radiation demonstrates specific histologic characteristics including vascular loss and increased scarring (collagen density, organization). This histologic grading system may be used in grading severity of radiation damage, and conceivably adopted for correlation with clinical outcomes.

Data-driven simulations for training AI-based segmentation of neutron images.

Neutron interferometry uniquely combines neutron imaging and scattering methods to enable characterization of multiple length scales from 1 nm to 10 µm. However, building, operating, and using such neutron imaging instruments poses constraints on the acquisition time and on the number of measured images per sample. Experiment time-constraints yield small quantities of measured images that are insufficient for automating image analyses using supervised artificial intelligence (AI) models. One approach alleviates this problem by supplementing annotated measured images with synthetic images. To this end, we create a data-driven simulation framework that supplements training data beyond typical data-driven augmentations by leveraging statistical intensity models, such as the Johnson family of probability density functions (PDFs). We follow the simulation framework steps for an image segmentation task including Estimate PDFs → Validate PDFs → Design Image Masks → Generate Intensities → Train AI Model for Segmentation. Our goal is to minimize the manual labor needed to execute the steps and maximize our confidence in simulations and segmentation accuracy. We report results for a set of nine known materials (calibration phantoms) that were imaged using a neutron interferometer acquiring four-dimensional images and segmented by AI models trained with synthetic and measured images and their masks.

Impact of Insecticide Treatments for Phyllocnistis citrella (Lepidoptera: Gracillariidae) on Growth and Yield of Young Citrus reticulata Mandarins.

The citrus leafminer, Phyllocnistis citrella Stainton, is an invasive pest of citrus whose larvae damage developing leaves, which can impact tree photosynthetic capacity and may ultimately reduce tree growth and yield. Damage is most pronounced in young trees due to their greater propensity for production of new foliage, which supports P. citrella oviposition and larval development. We studied P. citrella damage and tree growth and yield among different insecticide treatment regimes to gauge their effectiveness at protecting young citrus trees. Three levels of insecticide treatments were applied over 3 yr to 'Tango' mandarin (Citrus reticulata Blanco) citrus trees planted in the prior summer, which were inspected regularly along with untreated trees. Leaves suitable for oviposition by P. citrella were available during all census dates, though their numbers fluctuated in the summer months. Phyllocnistis citrella were suppressed for 2-3 wk by systemic or foliar treatments of insecticides. The higher number of treatments provided more sustained suppression of larvae. Trunk diameter was unchanged and canopy volume affected by only the most aggressive treatment regime. However, citrus yield was 2-2.5 times higher following the second year of treatments and 1.2- to 1.8-fold times following the third year of treatments for trees in the treatment regimes that included systemic imidacloprid plus 2-3 or 4-5 foliar applications, respectively, relative to untreated controls. Suitable leaf flush and larval densities declined over the 3 yr of the study. These data support the use of insecticidal control of P. citrella to protect young 'Tango' mandarin trees, but demonstrated that frequent applications are necessary to suppress populations.

Mating Disruption of the California Red Scale, Aonidiella aurantii (Hemiptera: Diaspididae) in Central California Citrus.

A warmer climate and the development of pesticide resistance have led to an increase in the number of generations and higher population densities of California red scale, Aonidella aurantii (Maskell) in central California. Commercial citrus orchard studies were conducted to determine how effective mating disruption using CheckMate CRS was at reducing A. aurantii. In 2016-2017, two replicated trials were conducted in 15.0-15.5 ha orchards and in 2018 and 2019, one half of each of 10 orchards 8-16.2 ha in size were treated with CheckMate CRS. Mating disruption significantly suppressed male captures for up to 8 mo. Average reductions of 90% in cumulative male flight trap catches were recorded, twig and leaf infestations were reduced by 95%, and highly scale-infested fruit were reduced by 75% in the CheckMate CRS plots for the 2018 and 2019 trials. In seven of 12 sites the percentage of highly infested fruit was reduced below 0.5%. Leaf and twig infestations in August and reductions in male captures during the 4th flight were strongly related to the percentage of highly infested fruit at the end of the season and could be used as predictors of the success of mating disruption. The results of the study indicated mating disruption using CheckMate CRS can be an effective method to reduce California red scale populations throughout the 4+ generations that occur in central California. Mating disruption has the potential to reduce or eliminate pesticide applications, especially in low scale density situations.

Molecular code for cooperativity in hemoglobin.

Although tetrameric hemoglobin has been studied extensively as a prototype for understanding mechanisms of allosteric regulation, the functional and structural properties of its eight intermediate ligation forms have remained elusive. Recent experiments on the energetics of cooperativity of these intermediates, along with assignments of their quaternary structures, have revealed that the allosteric mechanism is controlled by a previously unrecognized symmetry feature: quaternary switching from form T to form R occurs whenever heme-site binding creates a tetramer with at least one ligated subunit on each dimeric half-molecule. This "symmetry rule" translates the configurational isomers of heme-site ligation into six observed switchpoints of quaternary transition. Cooperativity arises from both "concerted" quaternary switching and "sequential" modulation of binding within each quaternary form, T and R. Binding affinity is regulated through a hierarchical code of tertiary-quaternary coupling that includes the classical allosteric models as limiting cases.

Safety and efficacy of oral low-volume sodium phosphate bowel preparation for colonoscopy in dogs.

BACKGROUND: Sodium phosphate (NaP) is a low-volume, hyperosmolar laxative that is an effective bowel-cleansing agent in humans. HYPOTHESIS: NaP will be as safe and efficacious as polyethylene glycol (PEG) bowel preparation for colonoscopy in dogs. ANIMALS: Eight purpose-bred healthy dogs. METHODS: In phase I, standard (NaP and enemas; NaP(1)) and control preparations (PEG and enemas) were compared in a crossover design to determine the safety and efficacy of NaP. Serial clinical and serum analytical evaluations were used to determine the safety of NaP. In phase II, the efficacy of the standard NaP preparation was compared with 3 other NaP variations, which excluded enema or included bisacodyl, with or without enemas in a crossover design. An observer blinded to the bowel preparation assigned a score of 1-4 (1=clean colon; 4=unacceptable colon cleansing preventing adequate endoscopic evaluation) to each of 5 regions of the colon. RESULTS: The mean total colon cleansing score (TCS), defined as the sum of scores from each region, of the control (9.4) was less than NaP(1) (13.6) (P < 0.05). There were no significant differences in regional or TCS for the remaining 4 NaP protocols. NaP(1) resulted in moderate, but clinically occult, hyperphosphatemia and hypocalcemia, which resolved within 24 hours. CONCLUSIONS AND CLINICAL IMPORTANCE: Despite the safety and ease of administration of the NaP preparations, the NaP bowel-cleansing preparations used in this study cannot be recommended for use because of the inadequate quality of bowel preparation compared with the protocol using PEG-containing fluids.

Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily.

BACKGROUND: Homoserine kinase (HSK) catalyzes an important step in the threonine biosynthesis pathway. It belongs to a large yet unique class of small metabolite kinases, the GHMP kinase superfamily. Members in the GHMP superfamily participate in several essential metabolic pathways, such as amino acid biosynthesis, galactose metabolism, and the mevalonate pathway. RESULTS: The crystal structure of HSK and its complex with ADP reveal a novel nucleotide binding fold. The N-terminal domain contains an unusual left-handed betaalphabeta unit, while the C-terminal domain has a central alpha-beta plait fold with an insertion of four helices. The phosphate binding loop in HSK is distinct from the classical P loops found in many ATP/GTP binding proteins. The bound ADP molecule adopts a rare syn conformation and is in the opposite orientation from those bound to the P loop-containing proteins. Inspection of the substrate binding cavity indicates several amino acid residues that are likely to be involved in substrate binding and catalysis. CONCLUSIONS: The crystal structure of HSK is the first representative in the GHMP superfamily to have determined structure. It provides insight into the structure and nucleotide binding mechanism of not only the HSK family but also a variety of enzymes in the GHMP superfamily. Such enzymes include galactokinases, mevalonate kinases, phosphomevalonate kinases, mevalonate pyrophosphate decarboxylases, and several proteins of yet unknown functions.

The TATA-binding protein from Saccharomyces cerevisiae oligomerizes in solution at micromolar concentrations to form tetramers and octamers.

Equilibrium analytical ultracentrifugation has been used to determine the stoichiometry and energetics of the self-assembly of the TATA-binding protein of Saccharomyces cerevisiae at 30 degreesC, in buffers ranging in salt concentration from 60 mM KCl to 1 M KCl. The data are consistent with a sequential association model in which monomers are in equilibrium with tetramers and octamers at protein concentrations above 2.6 microM. Association is highly cooperative, with octamer formation favored by approximately 7 kcal/mol over tetramers. At high [KCl], the concentration of tetramers becomes negligible and the data are best described by a monomer-octamer reaction mechanism. The equilibrium association constants for both monomer <--> tetramer and tetramer <--> octamer reactions change with [KCl] in a biphasic manner, decreasing with increasing [KCl] from 60 mM to 300 mM, and increasing with increasing [KCl] from 300 mM to 1 M. At low [KCl], approximately 3 mole equivalents of ions are released at each association step, while at high [KCl], approximately 3 mole equivalents of ions are taken up at each association step. These results suggest that there is a salt concentration-dependent change in the assembly mechanism, and that the mechanistic switch takes place near 300 mM KCl. The possibility that this self-association reaction may play a role in the activity of the TATA-binding protein in vivo is discussed.

Microsecond protein folding through a compact transition state.

Dynamic NMR methods have been employed to measure the folding and unfolding rate constants of two extremely fast-folding proteins. lambda 6-85, a truncated, monomeric form of the N-terminal domain of lambda repressor, refolds with a lifetime of approximately 250 microseconds. These methods have also been applied to a thermostable lambda 6-85 variant with alanine substituted for glycine residues 46 and 48 in the third helix (G46A/G48A). Both proteins exhibit linear ln (kf,u) versus [urea] plots, consistent with two-state folding for both proteins. When extrapolated to 0M urea, the data indicate that G46A/G48A folds with a lifetime of less than 20 microseconds. The slopes of the ln (kf,u) versus [urea] curves (mu and mf) indicate that the modest Gly-->Ala double mutation dramatically changes the transition state solvent accessibility. The transition state for lambda 6-85 has a fractional accessibility (mu/(mu-mf)) of 0.61, whereas the transition state for G46A/G48A is much more native-like, with a fractional accessibility of 0.16. The extraordinary change in the folding pathway that these mutations induce suggests that the intrinsic stability of helix 3 is an important determinant of the folding mechanism.

Is Vector Control Sufficient to Limit Pathogen Spread in Vineyards?

Vector control is widely viewed as an integral part of disease management. Yet epidemiological theory suggests that the effectiveness of control programs at limiting pathogen spread depends on a variety of intrinsic and extrinsic aspects of a pathosystem. Moreover, control programs rarely evaluate whether reductions in vector density or activity translate into reduced disease prevalence. In areas of California invaded by the glassy-winged sharpshooter (Homalodisca vitripennis Germar), Pierce's disease management relies heavily on chemical control of this vector, primarily via systemic conventional insecticides (i.e., imidacloprid). But, data are lacking that attribute reduced vector pressure and pathogen spread to sharpshooter control. We surveyed 34 vineyards over successive years to assess the epidemiological value of within-vineyard chemical control. The results showed that imidacloprid reduced vector pressure without clear nontarget effects or secondary pest outbreaks. Effects on disease prevalence were more nuanced. Treatment history over the preceding 5 yr affected disease prevalence, with significantly more diseased vines in untreated compared with regularly or intermittently treated vineyards. Yet, the change in disease prevalence between years was low, with no significant effects of insecticide treatment or vector abundance. Collectively, the results suggest that within-vineyard applications of imidacloprid can reduce pathogen spread, but with benefits that may take multiple seasons to become apparent. The relatively modest effect of vector control on disease prevalence in this system may be attributable in part to the currently low regional sharpshooter population densities stemming from area-wide control, without which the need for within-vineyard vector control would be more pronounced.

Primary aortoduodenal fistula: extra-anatomic vascular reconstruction not required for successful management.

Eleven patients reported in the literature and three patients presented herein have survived treatment of primary aortoduodenal fistula by standard aortic reconstruction with prosthesis placement and duodenal repair. Follow-up of these patients documents that 93% (13 of 14) have had no graft-related complications. Standard aortic reconstruction appears to be justified in the treatment of primary aortoduodenal fistula.

Relationship between collateral development and renin in experimental renal arterial stenosis.

Lateralizing renal venous plasma renin activity (RVPRA) ratios offer a predictive index of success of revascularization procedures for renovascular hypertension. Reliance upon nonlateralizing renin ratios to reject functional significance of renal arterial stenosis may deny some patients benefit of successful operations. To test the hypothesis that RVPRA ratios revert toward unity coincident with development of collateral circulation to an ischemic kidney, the relationship between development of collaterals and RVPRA was studied in nine dogs after gradual unilateral renal arterial occlusion with a constrictor. Arterial blood pressure and arteriographic measurement of collateral channels, RVPRA, and renal surface index (RSI) were measured before and during the 10-week interval after constrictor placement. RSI measurements, documenting changes in volume of the renal parenchyma, reflected changes in renal blood flow. Arterial pressure increased in each animal (p less than 0.0009). The number of collateral vessels to the constricted kidney increased with time (p less than 0.01). During the 4 weeks following placement of the constrictors, RSI ratios (constricted: nonconstricted) decreased (p less than 0.003) and RVPRA ratios (constricted: nonconstricted) increased (p less than 0.005). Subsequently, coincident with development of collateral vessels, RSI ratios increased and RVPRA ratios decreased toward control values. These data suggest that absence of lateralizing RVPRA ratios in the presence of collateral vessels does not mean lack of functional significance of stenotic renal arterial lesions.

Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs.

We localized the sites of vasodilation of inhaled nitric oxide (NO), a selective pulmonary vasodilator, and sodium nitroprusside (SNP) in isolated rat lungs. The sites were determined by analyzing the arterial, venous, and double-occlusion data with a two-resistor (small arteries and veins) three-capacitor (large arteries, large veins, and capillaries) model of the pulmonary vascular bed. Inhaled NO (170 and 670 ppm) and SNP (22.5 and 45.0 micrograms) decreased the small-artery resistance by 7.4 +/- 1.6, 17.2 +/- 2.2, 14.2 +/- 2.8, and 21.4 +/- 3.4% and the small-vein resistance by 13.5 +/- 3.2, 20.3 +/- 3.4 (SNP of 22.5 micrograms not significant), and 9.3 +/- 3.3%, respectively, in blood-perfused lungs (n = 12). Similar results were observed in Krebs-perfused lungs (n = 12). Capillary compliance was unaffected by inhaled NO and SNP. SNP increased the large-artery capacitance by 40.0 +/- 8.6 and 69.3 +/- 9.7%, whereas inhaled NO had no effect. SNP increased the large-vein capacitance by 31.0 +/- 8.7 and 48.0 +/- 10.7%, whereas inhaled NO had no effect in blood-perfused lungs. However, in Krebs-perfused lungs inhaled NO and SNP (45.0 micrograms only) increased the large-vein capacitance by 43.3 +/- 11.9, 41.4 +/- 14.2, and 44.2 +/- 11.0%. In conclusion, in blood-perfused isolated rat lungs inhaled NO and SNP dilate small-resistance arteries and veins, whereas SNP but not inhaled NO dilates larger capacitance arteries and veins. Furthermore, blood appears to prevent the downstream vasodilation by inhaled NO on larger capacitance pulmonary veins.

Inhaled nitric oxide: dose response and the effects of blood in the isolated rat lung.

Inhaled nitric oxide (NO) is a vasodilator selective to the pulmonary circulation. Using isolated rat lungs, we determined the dose-response relationship of NO and the role of blood in mediating pulmonary vasodilation and selectivity. Inhaled 20, 50, 100, and 1,000 ppm NO attenuated (P < 0.001) hypoxic pulmonary vasoconstriction by 16.1 +/- 4.9, 22.6 +/- 6.8, 28.4 +/- 3.5, and 69.3 +/- 4.2%, respectively. Inhaled 13, 34, 67, and 670 ppm NO attenuated the increase in pulmonary arterial pressure secondary to angiotensin II more (P < 0.001) in Greenberg-Bohr buffer- (GB) than in blood-perfused lungs (51.7 +/- 9.9, 71.9 +/- 8.9, 78.2 +/- 5.3, and 91.9 +/- 2.1% vs. 14.3 +/- 4.1, 23.8 +/- 4.6, 28.4 +/- 3.8, and 55.5 +/- 5.9%, respectively). Samples from GB- but not blood-perfused lungs contained NO (93.0 +/- 26.3 nM). Intravascular NO attenuated the response to angiotensin II more (P < 0.001) in GB- (with and without plasma) than in blood- (hematocrit = 41 and 5%) perfused lungs (75.6 +/- 6.4 and 70.9 +/- 4.8% vs. 22.2 +/- 2.4 and 39.4 +/- 7.6%). In conclusion, inhaled NO produces reversible dose-dependent pulmonary vasodilation over a large range of concentrations. Inhaled NO enters the circulation, but red blood cells prevent systemic vasodilation and also a significant amount of pulmonary vasodilation.

Removal of a thrombotic plug from an occluded limb of an aortofemoral graft.

We describe a technique for removal of a thrombotic plug from an occluded aortofemoral bypass limb that only requires operative exposure of the involved graft limb and that utilizes a balloon-tipped catheter and a Cannon endarterectomy loop. This method assures pulsatile inflow and avoids extended reconstructive procedures.

Proximal hepatic duct reconstruction. Repair using sutureless mucosal graft hepaticojejunostomy.

Six patients who had hepatic duct lesions, five who had strictures, and one who had a right hepatic duct transection underwent repair by sutureless mucosal graft hepaticojejunostomy. All patients had initial improvement, and five have maintained excellent biliary-intestinal continuity after an average 25-month follow-up. In one patient, recurrent symptoms developed and she died of cholangiocarcinoma. This technique is simple and fulfills the criteria for successful high hepatic duct reconstruction. The promising early results in these patients suggest that this procedure may provide a superior approach to this difficult problem.

Improved treatment of popliteal arterial injuries using anticoagulation and extra-anatomic reconstruction.

Management of popliteal arterial injuries remains a challenging problem. Early recognition and treatment, arteriography, fasciotomy, and repair of concomitant popliteal venous injuries are modalities that have contributed to improved results. Systemic heparin sodium anticoagulation and selected extra-anatomic vein graft bypass of the popliteal area are two additional measures that have contributed to a 91% success rate in treatment of popliteal arterial injuries and five of six blunt injuries were treated successfully in this time period. A limb salvage rate of only 46% was attained in the previous five-year period. There were no operative deaths. No complications attributable to systemic anticoagulation or extra-anatomic bypass graft occurred. These adjuncts are recommended to all who manage vascular injuries.

Supraceliac pseudoaneurysm of abdominal aorta. Staged repair employing preliminary axillary-femoral bypass.

The fifth successfully treated pseudoaneurysm of the visceral branch segment of abdominal aorta emphasizes individualized management of such complex lesions. Staged operative management of a supraceliac pseudoaneurysm by preliminary axillary-femoral bypass minimized potential intraoperative hazards. Visceral protection during aortic occlusion was simplified by axillary-femoral perfusion.

Invertebrate carcasses as a resource for competing Aedes albopictus and Aedes aegypti (Diptera: Culicidae).

Terrestrial invertebrate carcasses are an important resource for insects developing in pitcher plants. However, little is known of the role of these carcasses in other containers, which also receive leaf fall and stemflow inputs. This experiment investigated effects of accumulated invertebrate carcasses as a resource for two competing mosquitoes, Aedes albopictus (Skuse) and Aedes aegypti (L.), whether either species differentially benefited from accumulated carcasses, and if such a benefit affected interspecific competition. First, we measured accumulation of invertebrate carcasses in standard containers at a field site. We then used a replacement series with five different species ratios at the same total density, and varied the input of invertebrate carcasses [dead Drosophila melanogaster (Meigen) ] in three levels: none, the average input from our field site, or the maximum input recorded at our field site. Survivorship, development time, and mass were measured for each mosquito species as correlates of population growth, and were used to calculate a population performance index, lambda'. There were strong positive effects of invertebrate carcass additions on all growth correlates and lambda'. Differences in performance between species were pronounced in small or no carcass additions and absent in large inputs of invertebrate carcasses, but there was little evidence that inputs of invertebrate carcasses altered the competitive advantage in this system. These results suggest that terrestrial invertebrate carcasses may be an important resource for many types of container communities, and large accumulations of dead invertebrates may reduce resource competition between these mosquitoes, thus favoring coexistence. We propose that the total amount of resource, including accumulated invertebrate carcasses, may explain observed patterns of replacement involving these mosquitoes.

Renal transplant arterial stenosis: amelioration of hypertension and improvement of transplant function after revascularization.

Two of 70 patients treated for a minimum of six months after renal transplantation developed main arterial stenosis to the allograft. Both underwent transplant revascularization and had follow-up at least six months to document lasting benefit. Amelioration of hypertension and improvement of transplant function proved statistically significant. Collateral vessels were not identified on pre-revascularization arteriographic studies. It is suggested that loss of the potential to develop protective collateral channels to transplanted kidneys mandates aggressive evaluation when hypertension and deteriorating renal function occur in the late follow-up period after renal transplantation. In such instances, arteriography and renin determinations may identify salvagable renal allografts, obviating necessity of subsequent retransplantation.