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Background/objectives: Prenatal exposure to ambient air pollution is associated with adverse cardiometabolic outcomes in childhood. We previously observed that prenatal black carbon (BC) was inversely associated with adiponectin, a hormone secreted by adipocytes, in early childhood. Changes to DNA methylation have been proposed as a potential mediator linking in utero exposures to lasting health impacts., Methods: Among 532 mother-child pairs enrolled in the Colorado-based Healthy Start study, we performed an epigenome-wide association study of the relationship between prenatal exposure to a component of air pollution, BC, and DNA methylation in cord blood. Average pregnancy ambient BC was estimated at the mother's residence using a spatiotemporal prediction model. DNA methylation was measured using the Illumina 450K array. We used multiple linear regression to estimate associations between prenatal ambient BC and 429,246 cysteine-phosphate-guanine sites (CpGs), adjusting for potential confounders. We identified differentially methylated regions (DMRs) using DMRff and ENmix-combp. In a subset of participants (n = 243), we investigated DNA methylation as a potential mediator of the association between prenatal ambient BC and lower adiponectin in childhood., Results: We identified 44 CpGs associated with average prenatal ambient BC after correcting for multiple testing. Several genes annotated to the top CpGs had reported functions in the immune system. There were 24 DMRs identified by both DMRff and ENmix-combp. One CpG (cg01123250), located on chromosome 2 and annotated to the UNC80 gene, was found to mediate approximately 20% of the effect of prenatal BC on childhood adiponectin, though the confidence interval was wide (95% CI: 3, 84)., Conclusions: Prenatal BC was associated with DNA methylation in cord blood at several sites and regions in the genome. DNA methylation may partially mediate associations between prenatal BC and childhood cardiometabolic outcomes., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

This nested case-control study identified broad dysregulation of the circulating proteome in neonates receiving postoperative extracorporeal membrane oxygenation support after congenital heart disease surgery, including differential responses in those not surviving to hospital discharge. Tissue hypoxia and mitochondrial-associated proteins may represent novel candidate biomarkers for poor extracorporeal membrane oxygenation outcomes., Competing Interests: Declaration of Competing Interest This project was funded by National Institutes of HealthR01HL156936 (Davidson) and R38HL14351 StARR Award (Thomson). The funders had no role in study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication. The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes., Methods: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia., Results: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05)., Conclusion: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD., Impact: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Fetal exposures may impact offspring epigenetic signatures and adiposity. The authors hypothesized that maternal metabolic traits associate with cord blood DNA methylation, which, in turn, associates with child adiposity., Methods: Fasting serum was obtained in 588 pregnant women (27-34 weeks' gestation), and insulin, glucose, high-density lipoprotein cholesterol, triglycerides, and free fatty acids were measured. Cord blood DNA methylation and child adiposity were measured at birth, 4-6 months, and 4-6 years. The association of maternal metabolic traits with DNA methylation (429,246 CpGs) for differentially methylated probes (DMPs) and regions (DMRs) was tested. The association of the first principal component of each DMR with child adiposity was tested, and mediation analysis was performed., Results: Maternal triglycerides were associated with the most DMPs and DMRs of all traits tested (261 and 198, respectively, false discovery rate < 0.05). DMRs were near genes involved in immune function and lipid metabolism. Triglyceride-associated CpGs were associated with child adiposity at 4-6 months (32 CpGs) and 4-6 years (2 CpGs). One, near CD226, was observed at both timepoints, mediating 10% and 22% of the relationship between maternal triglycerides and child adiposity at 4-6 months and 4-6 years, respectively., Conclusions: DNA methylation may play a role in the association of maternal triglycerides and child adiposity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Introduction: Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time, with 70% of patients experiencing acute kidney injury, 33% neurodevelopmental impairment, 14% growth failure, and 5.5% of patients suffering necrotizing enterocolitis. Proteomics is a method to identify new biomarkers and mechanisms of injury in complex physiologic states., Methods: Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80°C, and run on a panel of 1,500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR <0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape., Results: PLS-DA readily discriminated between SVHD cases ( n  = 33) and controls ( n  = 24) based on their proteomic pattern alone (Accuracy = 0.96, R 2  = 0.97, Q 2  = 0.80). 568 proteins differed between groups (FDR <0.05). We identified 25 up-regulated functional clusters and 13 down-regulated. Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neural development, gastrointestinal system, and cardiac physiology and development., Conclusions: We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. These proteomic data identify widespread protein dysregulation across multiple biologic systems with promising biological plausibility as drivers of SVHD morbidity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Thomson, Mancuso, Wolfe, Khailova, Niemiec, Ali, DiMaria, Mitchell, Twite, Morgan, Frank and Davidson.)

The placenta undergoes many changes throughout gestation to support the evolving needs of the foetus. There is also a growing appreciation that male and female foetuses develop differently in utero , with unique epigenetic changes in placental tissue. Here, we report meta-analysed sex-specific associations between gestational age and placental DNA methylation from four cohorts in the National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) Programme (355 females/419 males, gestational ages 23-42 weeks). We identified 407 cytosine-guanine dinucleotides (CpGs) in females and 794 in males where placental methylation levels were associated with gestational age. After cell-type adjustment, 55 CpGs in females and 826 in males were significant. These were enriched for biological processes critical to the immune system in females and transmembrane transport in males. Our findings are distinct between the sexes: in females, associations with gestational age are largely explained by differences in placental cellular composition, whereas in males, gestational age is directly associated with numerous alterations in methylation levels.

Acute respiratory distress syndrome (ARDS) has high mortality (~40 %) and requires the lifesaving intervention of mechanical ventilation. A variety of systemic inflammatory insults can progress to ARDS, and the inflamed and injured lung is susceptible to ventilator-induced lung injury (VILI). Strategies to mitigate the inflammatory response while restoring pulmonary function are limited, thus we sought to determine if treatment with CNP-miR146a, a conjugate of novel free radical scavenging cerium oxide nanoparticles (CNP) to the anti-inflammatory microRNA (miR)-146a, would protect murine lungs from acute lung injury (ALI) induced with intratracheal endotoxin and subsequent VILI. Lung injury severity and treatment efficacy were evaluated via lung mechanical function, relative gene expression of inflammatory biomarkers, and lung morphometry (stereology). CNP-miR146a reduced the severity of ALI and slowed the progression of VILI, evidenced by improvements in inflammatory biomarkers, atelectasis, gas volumes in the parenchymal airspaces, and the stiffness of the pulmonary system., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting., Aim: To determine the incidence of grade 3 and 4 neutropenia and identify risk factors for neutropenia among CLL patients treated with the VenG regimen., Methods: We conducted a retrospective, single-center study of all adult patients with a diagnosis of CLL treated with VenG at the University of Colorado Hospital. Demographic information, laboratory data, clinical data, and medication prescriptions were collected from the patients' electronic medical record., Results: A total of 14 patients (73%) developed neutropenia during the course of therapy. The mean time to neutropenia from the start of treatment was 42 days (range 1-131). Our cohort harbored more high risk disease features and more comorbidities (CIRS score of 12). Four patients (28.6%) in the neutropenic group developed infectious complications during therapy and 6 (31%) patients were unable to be dose escalated to the final FDA approved dose of 400 mg., Conclusion: Our study cohort had higher incidence of grade 3 and 4 neutropenia occurring in 73% of patients. This could be attributed to a higher rate of comorbidities, high risk features, concomitant interacting medications, and prior chemotherapy. Further studies are warranted to determine if growth factor support is efficacious to achieve dose escalation with this therapy., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

In the United States, $87 billion per year is spent on the care of diabetic ulcers alone. Although the pathophysiology of diabetic wound healing is multifaceted, high systemic levels of inflammation and increased reactive oxygen species are often implicated in the wound healing impairment. Zwitterionic materials have been demonstrated to reduce inflammation and increase extracellular matrix deposition in wound beds, and here, we demonstrate a fabrication method for photopolymerized zwitterionic hydrogels that also enables sustained drug delivery over time. A therapeutic molecule of interest that is examined in this work is cerium oxide nanoparticle tagged with microRNA-146a (CNP-miR146a) to combat both oxidative stress and inflammation. The hydrogels are composed of zwitterionic and nonzwitterionic monomers, and the hydrogel formation occurs in the absence of a crosslinker. The hydrogels exhibit a wide range of stiffness and mechanical properties depending on their monomer content. Additionally, these hydrogels exhibit sustained release of nanoparticles and proteins. Finally, when employed in an in vivo diabetic mouse wound healing model, the zwitterionic hydrogels alone and laden with the CNP-miR146a conjugate significantly improved the rate of diabetic wound healing. Overall, these materials have excellent potential to be used as a topical treatment for chronic diabetic wounds.

Background: Skin aging is an inevitable process with one of the key features of aging being dryness or flakiness of the skin. Previous in vivo and in vitro testing has highlighted that a silk-based product may be effective in improving moisture retention in skin., Methods: We evaluated the safety and efficacy of our silk-based product through a combination of objective- including scanning electron microscopy (SEM) and EpiDerm Skin Irritation tests - and subjective tests - including direct evaluation of patient's own perception of their skin., Results: In alignment with previous studies, patients reported significant concerns about aging, wrinkling, or saggy skin. We found that our silk-based product was safe and effective in improving hydration and resilience of facial skin and a majority of participants stated they would continue to use this product, when commercially available., Conclusion: Our novel silk-based product, NanoSilk Cosmo, is safe for use on human facial skin and it improves skin resiliency and hydration., (© 2021 Wiley Periodicals LLC.)

Context: Psychological distress is common in patients with cancer, and oncology providers are often tasked with utilizing psychotropic medications to treat such symptoms., Objective: This study aims to characterize how oncology providers prescribe psychotropic medications and to assess their comfort level with prescribing these medications., Methods: A cross-sectional survey was sent to oncology medical doctors, nurse practitioners, and physician assistants who prescribe psychotropic medications to patients with cancer at a large academic medical center in the Mountain West. The survey included questions regarding provider subspecialty, degree, comfort with prescribing psychotropic medications, and factors that informed their prescribing., Results: Oncology providers (n = 65) reported equal proportions of comfort and discomfort with prescribing psychotropic medications. The medication class with the most prescribers was benzodiazepines, with 89.2% (n = 58) of the respondents prescribing those medications. The least prescribed category was mood stabilizers, with 4.6% (n = 3) prescribing this category. Prescribers identified that barriers to their comfort included difficulty connecting patients to follow-up care with mental health professionals and inadequate mental health education for providers. Providers responded that continuing mental health education and increasing patient access to mental health resources would increase their prescribing comfort., Conclusion: Providers reported equal parts comfort and discomfort with prescribing psychotropic medications; avenues to increase comfort should involve focused mental health education during formal training and continued education throughout their oncology careers. A clinical pathway for prescribing psychotropic medications with resources to connect patients to long-term mental health care may also increase prescribing comfort., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: In congenital diaphragmatic hernia (CDH), ultrasound (U/S) measurements of the contralateral lung commonly provide the observed-to-expected lung-to-head ratio (O/E LHR) and are used to determine the severity of pulmonary hypoplasia. Fetal magnetic resonance imaging (MRI) measurement of the observed-to-expected total lung volume (O/E TLV) has been used as an adjunct to O/E LHR in predicting outcomes. Since O/E LHR only measures the contralateral lung, we sought to investigate if MRI measurements of the contralateral lung volume (O/E CLV) can accurately predict outcomes in CDH. We hypothesize that O/E CLV is a better predictor of CDH outcomes than O/E LHR., Methods: We identified all infants with a prenatal diagnosis of CDH at our fetal center who had both MRI and U/S measurements. Using lung volume ratios of right-left 55:45, we calculated O/E CLV from O/E TLV. We used receiver-operating characteristic (ROC) curves to calculate the area under the curve (AUC) to compare the predictive accuracy of O/E CLV to O/E LHR for ECMO support, as well as survival to both discharge and 1 year., Results: Seventy-four patients had complete prenatal imaging with 39% requiring ECMO support. The median O/E CLV was 48.0% and the median O/E LHR was 42.3%. O/E CLV was a better predictor of the need for ECMO support (AUC 0.81 vs. 0.74). O/E CLV was a better predictor of survival to discharge (AUC 0.84 vs. 0.64) and 1-year survival (AUC 0.83 vs. 0.63) than O/E LHR., Conclusion: O/E LHR is a well-validated standard for predicting outcomes and guiding prenatal counseling in CDH. We provide evidence that fetal MRI measurements of the contralateral lung volume corrected for gestational age were more accurate in predicting the need for ECMO and survival. Future prospective studies validating O/E CLV regarding outcomes and ECMO utilization are warranted., Level of Evidence: Level III, retrospective comparative study., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To examine how self-reported pain- and fatigue-related activity interference relates to symptoms and physical activity (PA) in daily life among people with knee or hip osteoarthritis., Design: Cross-sectional study with a 7-day repeated-measures assessment period., Setting: General community., Participants: Participants (N=154; mean age, 65y; 60% women [n=92]) with knee or hip osteoarthritis and pain lasting ≥3 months., Interventions: Not applicable., Main Outcome Measures: Pain- or fatigue-related activity interference items on the Brief Pain Inventory or Brief Fatigue Inventory, respectively, from baseline survey, momentary pain and fatigue severity (measured 5times/d for 7d), and PA measured with a wrist-worn accelerometer over 7 days. We hypothesized that perception of pain- and fatigue-related activity interference would moderate the association between symptoms (pain or fatigue) and PA. People with higher pain- or fatigue-related activity interference were thought to have stronger negative associations between momentary ratings of pain and fatigue and PA than did those with lower activity interference., Results: Pain-related activity interference moderated the association between momentary pain and PA, but only in the first part of the day. Contrary to expectation, during early to midday (from wake-up time through 3 pm), low pain-related interference was associated with stronger positive associations between pain and PA but high pain-related interference was associated with a small negative association between pain and PA. Fatigue-related activity interference did not moderate the relation between fatigue and activity over the course of a day., Conclusions: Depending on a person's reported level of pain-related activity interference, associations between pain and PA were different earlier in the day. Only those with high pain-related activity interference had lower levels of PA as pain increased and only in the morning. High pain-related activity interference may be important to address, particularly to maintain PA early in the day despite pain., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Duodenal carcinoma is a rare tumor of the gastrointestinal tract of an insidious and secretive course, often diagnosed during the advanced stage of the disease. The study presented a case of a female patient diagnosed with duodenal carcinoma, subjected to two-staged surgery. The initial surgical intervention consisted in the implementation of a gastrointestinal anastomosis, followed by radical surgery by means of Whipple's method performed after three years.

Calcifying fibrous tumor is a rare disease entity, usually concerning the soft tissues of the limbs, neck, trunk, or scrotum. Cases of the above-mentioned pathology have also been reported considering the pleural and peritoneal cavity, and small bowel mesentery. The essence of the disease, whose etiology and pathogenesis remains unclear, is the fibrous tissue infiltration and diffuse inflammation with focal calcifications. The study presented a case of a 27-year old male patient subjected to surgical intervention, due to an abdominal cavity tumor. The tumor was radically removed, and its character and definitive diagnosis were established postoperatively. After a seven-year follow-up period, recurrence was not observed.

Individuals with cystinosis exhibit specific cognitive deficits in visual spatial function. The purpose of the current study was to examine if obligate heterozygotes of the CTNS mutation have the same pattern of cognitive functioning seen in homozygotes, namely aberrant visual-spatial functioning against a background of relatively intact visual-perceptual functioning and overall cognitive ability. Study participants were 254 adults (100 heterozygotes and 154 controls), ages 17 years 10 months through 74 years 9 months. Tests of intelligence, visual perceptual, and visual spatial functioning were administered. Our results showed that cystinosis heterozygotes demonstrated intelligence within the normal range, and performed similarly to controls on tests of visual-perceptual ability. In contrast, the heterozygotes performed significantly more poorly on each of the visual-spatial tests when compared to controls. Obligate heterozygotes for the CTNS mutation display a similar pattern of visual processing decrements as do individuals with cystinosis. Namely, carriers demonstrate relative weaknesses in visual-spatial processing, while maintaining normal visual perceptual ability and intelligence in the normal range. The visual spatial decrements in heterozygotes were not as marked as those found in individuals with cystinosis, suggesting a gene dosing effect. This study provides an impetus for other studies of gene-behavior relationships in recessive disorders, and may stimulate further interest in the role of aberrant genes on "individual differences" in behavior., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: Based on adherence to intestinal mucosa, intralumenally administered liposomal formulations of 5-aminosalicylate (5-ASA) and 6-mercaptopurine (6-MP) were studied for their potential to enhance local drug delivery to intestinal tissue for the treatment of inflammatory bowel disease., Methods: 5-ASA was encapsulated in standard phospholipid liposomes while 6-MP required encapsulation in nonphospholipid liposomes to obtain equivalent drug loading. Encapsulation efficiency was measured by size-exclusion chromatography/high-performance liquid chromatogtaphy (HPLC). Liposomal formulations or solution of the drugs were injected into unligated jejunum to compare pharmacokinetics and into ligated loops of rat ileum and colon to evaluate local delivery. Dextran sulfate and acetic acid induced colitis were used as models of lower intestinal inflammation. Plasma, tissue and luminal drug and metabolite levels were measured by liquid scintillation counting or HPLC., Results: Encapsulation efficiency of 6-MP was dependent on lipid content and composition. While liposomal encapsulation significantly reduced systemic absorption of 5-ASA this was not the case for 6-MP. Liposomal adherence to intestinal tissue resulted in increased tissue levels for 5-ASA; however, 6-MP local tissue levels were not improved compared to solution drug., Conclusions: Nonphospholipid liposomes optimize encapsulation of 6-MP. While liposomal formulations show potential for local drug delivery to diseased bowel, drug physicochemical properties, absorption, and metabolic profiles dictate tissue-targeting potential. Liposomes reduce systemic availability from paracellular absorption of hydrophilic 5-ASA, but fail to improve local tissue delivery of 6-MP, a molecule absorbed by passive membrane permeation that undergoes extensive first- pass metabolism.

Expression plasmid DNA for the human interleukin-1 receptor antagonist (IL-1ra) protein was formulated with nonionic:cationic (NC) liposomes or phosphatidylcholine:cationic (PC) liposomes and applied to the auricular skin of hamsters in single- and multiple-dose protocols. Confocal microscopy identified delivery of plasmid DNA proximal to perifollicular cells, and successful transfection of perifollicular cells was identified by immunohistochemistry and ELISA. Skin treated for 3 days with the NC liposomes had statistically significant levels of transgenic IL-1ra present for 5 days post-treatment. Expression of transgenic IL-1ra was specific to areas of skin treated with NC liposomes but not PC liposomes. The results indicate that the NC liposomes can deliver expression plasmid DNA to perifollicular cells and mediate transient transfection in vivo.

Purpose: The purpose of this study was to test the hypothesis that nonionic liposomes facilitate the topical delivery of peptide drugs into pilosebaceous units., Methods: The hamster ear was used as a model for human pilosebaceous units. The deposition of a hydrophilic protein, alpha-interferon (alpha-IFN), into pilosebaceous units and other strata of the hamster ear 12 hours after topical in vivo application of three nonionic liposomal formulations, one composed of glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether (Non-1), the second composed of glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether (Non-2) and the third composed of polyoxyethylene-10-stearyl ether/cholesterol (Non-3), a phospholipid-based liposomal formulation (PC) and an aqueous control solution (AQ) was determined. We also determined the deposition of a hydrophobic peptide, cyclosporin-A (CsA), into pilosebaceous units and other strata of the hamster ear after topical in vivo application of these liposomal formulations and a hydroalcoholic control solution (HA)., Results: The deposition of alpha-IFN into the pilosebaceous units was in the order: Non-1 >> PC > Non-2 > Non-3 = AQ. The deposition of CsA into the pilosebaceous units was in the order: Non-1 >> HA > PC > Non-2 = Non-3., Conclusions: Despite differences in the hydrophobicities and size of the drug molecules, deposition into the various ear strata was significantly enhanced by the Non-1 liposomal system.

The results of this study clearly demonstrates the utility of novel non-ionic liposomal systems in facilitating transfer of GHRP-6 into and across deeper strata of skin following topical application. These findings indicate that it may be possible to deliver therapeutic doses of a wide variety of peptides to local skin tissue via topical application. The results also suggest the possibility of controlled enhancement of skin penetration or metered polypeptide deposition through appropriate choice of liposomal lipid components. The pronounced enhancement of GHRP-6 and mannitol transport from emulsions containing the nonionic lipids suggests a promising delivery system for hydrophilic drugs in general.

A 74-year-old man is reported in whom hormonally inactive gastric carcinoid coexisted with leiomyoma. The patient was operated on with the preoperative diagnosis of gastric cancer. Microscopic postoperative examination made possible correct diagnosis.

Three patients were treated for far advanced facial carcinoma. In all cases one-time reconstruction was done using arterialized temporofrontal flap, and full healing-in of the flap was achieved. The high usefulness of this operation is stressed in reconstructive procedures on the face. Far advances facial carcinoma should be treated surgically, and not disqualified for surgery, as this is frequently the case.

The synthesis of juvenile hormone I (JH I) and juvenile hormone III (JH III) in vitro by isolated corpora allata (CA) and brain-corpora cardiaca-corpora allata complexes (BR-CC-CA) from fourth and fifth instar larvae and pupae of Manduca sexta was assessed by JH I and JH III radioimmunoassays of incubation medium. Fluctuations in synthesis occurred at specific stages during larval-pupal development. These fluctuations temporally approximated those of previously determined hemolymph titers of JH I and III for this developmental period, except for the synthesis of JH III during the prepupal period, when the JH III hemolymph titer was negligible but JH III synthesis in vitro increased to the highest rate observed. The overall agreement between CA activity and the JH hemolymph titers suggests that the in vitro system supports physiological gland activity and that changes in biosynthesis contribute significantly to changes in the titers. A comparison of JH I and JH III synthesis by isolated CA with that by BR-CC-CA suggests that the BR-CC can differentially modulate the synthesis of these two homologs. The significance of these findings with regard to the possible endocrine function of JH III and the proposed neuroendocrine control of the CA is discussed.