Characteristics of US Adults Delaying Dental Care Due to the COVID-19 Pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has disrupted the delivery of health care services, including dental care. The objective of this study was to quantify and describe US adults who delayed dental care due to the COVID-19 pandemic. METHODS: We analyzed cross-sectional responses collected from a nationally representative and long-running panel survey of US adults conducted in late May and early June 2020 (response rate = 70%). The survey included questions about dental care delayed due to the COVID-19 pandemic, purpose of the delayed dental visits, timing of future dental visits, and demographic information. Pearson's chi-square tests were used to determine if rates of delayed dental care varied by subgroup. A multivariable regression model, adjusted for age, race, Hispanic ethnicity, census division, and rurality, was estimated to predict the odds of reporting delayed dental care. RESULTS: Nearly half of respondents (46.7%) reported delaying going to the dentist or receiving dental care due to the COVID-19 pandemic. Among adults who reported delaying dental care due to the pandemic, 74.7% reported delaying a checkup, 12.4% reported delaying care to address something that was bothering them, and 10.5% reported delaying care to get planned treatment. About 44.4% of adults reported that they planned to visit the dentist within the next 3 mo. In the multivariable regression model, only living in an urban (vs. rural) area was associated with significantly higher odds of delayed dental care due to the pandemic (odds ratio: 1.5; 95% confidence interval: 1.1, 2.1). CONCLUSIONS: Nearly half of US adults reported delaying dental care due to the COVID-19 pandemic during the spring of 2020. Our results offer insight into the experiences of patients seeking dental care this spring and the economic challenges faced by dental providers due to the pandemic. KNOWLEDGE TRANSFER STATEMENT: This article describes US adults who delayed dental care due to the COVID-19 pandemic. Results can be used by clinicians and policymakers to understand delayed care during the pandemic.

Do Oral Health Services in Medical Offices Replace Pediatric Dental Visits?

In the United States, state Medicaid programs pay for medical and dental care for children from low-income families and support nondental primary care providers delivering preventive oral health services (POHS) to young children in medical offices ("medical POHS"). Despite the potential of these policies to expand access to care, there is concern that they may replace dental visits with medical POHS. Using Medicaid claims from 38 states from 2006 to 2014, we conducted a repeated cross-sectional study and used linear probability regression to estimate the association between the annual proportion of children in a county receiving medical POHS and the probability that a child received 1) dental POHS and 2) a dental visit in a given year. Models included county and year fixed effects and controlled for child- and county-level factors, and standard errors were clustered at the state level. In a weighted population of 45.1 million child-years (age, 6 mo to <6 y), we found no significant nor substantively important association between the proportion of children in a county receiving medical POHS and the probability that a child received dental POHS or a dental visit. Additionally, we found an almost zero probability (<0.001) that the reduction in dental POHS was at least as large as the expansion in medical POHS (full substitution) and a 0.50 probability that increased medical POHS was associated with an increase in dental POHS of at least 6.6% of the expansion of medical POHS. Results were similar when receipt of dental visits was examined. This study failed to find evidence that medical POHS replaced dental visits for young children enrolled in Medicaid and, in fact, offers evidence that increased medical POHS was associated with increased utilization of dental care. Given lower-than-desired rates of dental visits for this population, delivery of medical POHS should be expanded.

Weekend days are not required to accurately measure oral intake in hospitalised patients.

BACKGROUND: Nutrition studies in patients admitted to hospital frequently disregard oral intake because measurement is time-intensive and logistically challenging. In free-living populations, weighed food records (WFR) are the gold-standard and are conducted on weekend and weekdays to capture variations in intake, although this may not translate during hospitalisation. The present study aimed to determine whether oral intake differs between weekends and weekdays in hospitalised patients. METHODS: For adult patients initially admitted to the intensive therapy unit with a moderate-severe head injury over a 12-month period, WFR were conducted each week on Tuesday, Thursday and Saturday throughout hospitalisation. Meal components were weighed before and after consumption, and energy and protein intakes were calculated using specialised software. Data are reported as the mean (SD). Differences were assessed using paired t-tests and agreement using Bland-Altman plots. RESULTS: Thirty-two patients had WFR collected on 220 days, 68% (n = 149) on weekdays and 32% (n = 71) on weekends. Overall, daily intakes were 5.72 (3.67) MJ [1367 (877) kcal] and 62 (40) g protein. There were no differences in intake across all days (P = 0.937 energy, P = 0.797 protein), nor between weekdays and weekends, in weeks 1-3 of oral intake (all P > 0.1). Limits of agreement between mean intakes across days were wide for energy [range -11.20 to 9.55 MJ (-2680 to 2283 kcal)] and protein (range -125 to 110 g). CONCLUSIONS: Grouped energy and protein intakes from WFR in hospitalised patients are similar on weekdays and weekends, although large intra-patient variations occur. Future quantification of oral intake during hospitalisation should include as many days as feasible, although not necessarily weekend days, to reflect true intake.

Preventive Services by Medical and Dental Providers and Treatment Outcomes.

OBJECTIVE: Nearly all state Medicaid programs reimburse nondental primary care providers (PCPs) for providing preventive oral health services to young children; yet, little is known about how treatment outcomes compare with children visiting dentists. This study compared the association between the provider of preventive services (PCP, dentist, or both) with Medicaid-enrolled children before their third birthday and subsequent dental caries-related treatment (CRT) and CRT payment. METHODS: We conducted a retrospective study of young children enrolled in North Carolina Medicaid during 2000 to 2006. The annual number of CRT and CRT payments per child between the ages of 3 and 5 yr were estimated with a zero-inflated negative binomial regression and a hurdle model, respectively. Models were adjusted for relevant child- and county-level characteristics and used propensity score weighting to address observed confounding. RESULTS: We examined 41,453 children with > 1 preventive oral health visit from a PCP, dentist, or both before their third birthday. Unadjusted annual mean CRT and payments were lowest among children who had only PCP visits (CRT = 0.87, payment = $172) and higher among children with only dentist visits (CRT = 1.48, payment = $234) and both PCP and dentist visits (CRT = 1.52, payment = $273). Adjusted results indicated that children who had dentist visits (with or without PCP visits) had significantly more CRT and higher CRT payments per year during the ages of 3 and 4 yr than children who had only PCP visits. However, these differences attenuated each year after age 3 yr. CONCLUSIONS: Because of children's increased opportunity to receive multiple visits in medical offices during well-child visits, preventive oral health services provided by PCPs may lead to a greater reduction in CRT than dentist visits alone. This study supports guidelines and reimbursement policies that allow preventive dental visits based on individual needs.

Radiation-induced morphological changes in the vagina.

BACKGROUND AND PURPOSE: Treatment-induced chronic vaginal changes after definitive radio(chemo)therapy for locally advanced cervical cancer patients are reported as one of the most distressing consequences of treatment, with major impact on quality of life. Although these vaginal changes are regularly documented during gynecological follow-up examinations, the classic radiation morbidity grading scales are not concise in their reporting. The aim of the study was therefore to identify and qualitatively describe, on the basis of vaginoscopies, morphological changes in the vagina after definitive radio(chemo)therapy and to establish a classification system for their detailed and reproducible documentation. PATIENTS AND METHODS: Vaginoscopy with photodocumentation was performed prospectively in 22 patients with locally advanced cervical cancer after definitive radio(chemo)therapy at 3-24 months after end of treatment. All patients were in complete remission and without severe grade 3/4 morbidity outside the vagina. RESULTS: Five morphological parameters, which occurred consistently after treatment, were identified: mucosal pallor, telangiectasia, fragility of the vaginal wall, ulceration, and adhesions/occlusion. The symptoms in general were observed at different time points in individual patients; their quality was independent of the time of assessment. Based on the morphological findings, a comprehensive descriptive and semiquantitative scoring system was developed, which allows for classification of vaginal changes. A photographic atlas to illustrate the morphology of the alterations is presented. CONCLUSION: Vaginoscopy is an easily applicable, informative, and well-tolerated procedure for the objective assessment of morphological vaginal changes after radio(chemo)therapy and provides comprehensive and detailed information. This allows for precise classification of the severity of individual changes.

B cell depletion for autoimmune diseases in paediatric patients.

Data on B cell depletion therapy in severe autoimmune diseases in paediatric patients are very limited. We conducted a retrospective cohort study and recruited patients who were treated with rituximab (RTX) and followed up for at least 6 months through the German societies of paediatric rheumatology and nephrology. The aim was to describe the spectrum of autoimmune disorders for which RTX was used and to describe the applied therapeutic regimens, the observed efficacy, as well as potential immunological side effects. The need to develop standard treatment guidelines for future trials should be discussed. Sixty-five patients were included. Nineteen patients suffered from systemic lupus erythematosus, 13 from vasculitic disorders, 12 from hematological autoimmune diseases, 5 from mixed connective tissue disorders, 4 from juvenile idiopathic arthritis, and 9 had other autoimmune diseases. Adverse, infusion-related events were reported in 12/65 (18%) patients. Considering laboratory and clinical parameters, 13 patients (22%) were in complete remission, 31 (52%) were in partial remission, 6 (10%) were unchanged and 10 (17%) had progressed after 6 months. In 46% of the patients, the steroid dose could be more than halved. IgG, IgM and IgA decreased from normal levels prior to RTX therapy to below normal levels at 6 months in 2/22 (9%), 10/21 (48%), and 4/22 (18%) patients, respectively. Immunoglobulin deficiency or prolonged CD20 depletion was reported in eight patients after an observation period longer than 12 months. RTX therapy led to a perceivable reduction in disease activity. However, long-term immunological alterations may occur in more than 10% of the patients. Guidelines and protocols for off-label therapy are desirable to document reasonable follow-up data. Controlled prospective studies for RTX therapies in children with standardised therapeutic and diagnostic protocols are urgently needed.

Conservation genetics and population history of the threatened European mink Mustela lutreola, with an emphasis on the west European population.

In species of great conservation concern, special attention must be paid to their phylogeography, in particular the origin of animals for captive breeding and reintroduction. The endangered European mink lives now in at least three well-separated populations in northeast, southeast and west Europe. Our aim is to assess the genetic structure of these populations to identify 'distinct population segments' (DPS) and advise captive breeding programmes. First, the mtDNA control region was completely sequenced in 176 minks and 10 polecats. The analysis revealed that the western population is characterized by a single mtDNA haplotype that is closely related to those in eastern regions but nevertheless, not found there to date. The northeast European animals are much more variable (pi = 0.012, h = 0.939), with the southeast samples intermediate (pi = 0.0012, h = 0.469). Second, 155 European mink were genotyped using six microsatellites. The latter display the same trends of genetic diversity among regions as mtDNA [gene diversity and allelic richness highest in northeast Europe (H(E) = 0.539, R(S) = 3.76), lowest in west Europe (H(E) = 0.379, R(S) = 2.12)], and provide evidences that the southeast and possibly the west populations have undergone a recent bottleneck. Our results indicate that the western population derives from a few animals which recently colonized this region, possibly after a human introduction. Microsatellite data also reveal that isolation by distance occurs in the western population, causing some inbreeding because related individuals mate. As genetic data indicate that the three populations have not undergone independent evolutionary histories for long (no phylogeographical structure), they should not be considered as distinct DPS. In conclusion, the captive breeding programme should use animals from different parts of the species' present distribution area.

Uptake of the ATP-binding cassette (ABC) transporter Ste6 into the yeast vacuole is blocked in the doa4 Mutant.

Previous experiments suggested that trafficking of the a-factor transporter Ste6 of Saccharomyces cerevisiae to the yeast vacuole is regulated by ubiquitination. To define the ubiquitination-dependent step in the trafficking pathway, we examined the intracellular localization of Ste6 in the ubiquitination-deficient doa4 mutant by immunofluorescence experiments, with a Ste6-green fluorescent protein fusion protein and by sucrose density gradient fractionation. We found that Ste6 accumulated at the vacuolar membrane in the doa4 mutant and not at the cell surface. Experiments with a doa4 pep4 double mutant showed that Ste6 uptake into the lumen of the vacuole is inhibited in the doa4 mutant. The uptake defect could be suppressed by expression of additional ubiquitin, indicating that it is primarily the result of a lowered ubiquitin level (and thus of reduced ubiquitination) and not the result of a deubiquitination defect. Based on our findings, we propose that ubiquitination of Ste6 or of a trafficking factor is required for Ste6 sorting into the multivesicular bodies pathway. In addition, we obtained evidence suggesting that Ste6 recycles between an internal compartment and the plasma membrane.

A family of small coiled-coil-forming proteins functioning at the late endosome in yeast.

The multispanning membrane protein Ste6, a member of the ABC-transporter family, is transported to the yeast vacuole for degradation. To identify functions involved in the intracellular trafficking of polytopic membrane proteins, we looked for functions that block Ste6 transport to the vacuole upon overproduction. In our screen, we identified several known vacuolar protein sorting (VPS) genes (SNF7/VPS32, VPS4, and VPS35) and a previously uncharacterized open reading frame, which we named MOS10 (more of Ste6). Sequence analysis showed that Mos10 is a member of a small family of coiled-coil-forming proteins, which includes Snf7 and Vps20. Deletion mutants of all three genes stabilize Ste6 and show a "class E vps phenotype." Maturation of the vacuolar hydrolase carboxypeptidase Y was affected in the mutants and the endocytic tracer FM4-64 and Ste6 accumulated in a dot or ring-like structure next to the vacuole. Differential centrifugation experiments demonstrated that about half of the hydrophilic proteins Mos10 and Vps20 was membrane associated. The intracellular distribution was further analyzed for Mos10. On sucrose gradients, membrane-associated Mos10 cofractionated with the endosomal t-SNARE Pep12, pointing to an endosomal localization of Mos10. The growth phenotypes of the mutants suggest that the "Snf7-family" members are involved in a cargo-specific event.

Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay. METHODS AND RESULTS: We report a chemotaxis assay using isolated monocytes from individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden chamber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%; P<0.0001). In contrast, the response of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A-inducible kinase activity of Flt-1, as assessed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiometric assay, was significantly elevated in diabetic patients. CONCLUSIONS: The cellular response of monocytes to VEGF-A is attenuated in diabetic patients because of a downstream signal transduction defect. These data suggest that monocytes are important in arteriogenesis and that their ability to migrate might be critical to the arteriogenic response. Thus, we resolved a fundamental mechanism involved in the problem of impaired collateral formation in diabetic patients.

Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system.

OBJECTIVE: The mortality of patients with liver cirrhosis admitted to an intensive care unit (ICU) has been found to be high. This study was performed to assess the physiological and laboratory parameters which are able to identify on ICU admission the cirrhotic patients who are most likely to die. DESIGN: Prospective clinical trial. METHODS: Two groups of patients were analysed. Group A consisted of 196 consecutive cirrhotic patients admitted to our medical ICU for various reasons. For the detection of independent outcome predictors, we used a multiple logistic regression model. Based on these variables, the 'intensive care cirrhosis outcome (ICCO) score' was calculated. The ability to discriminate between survivors and non-survivors was determined by receiver operating characteristic curves, and the area under the curve was calculated. Group B consisted of 70 consecutive cirrhotic patients for prospective validation of the ICCO score. RESULTS: Applying multiple logistic regression analysis, bilirubin, cholesterol, creatinine clearance and lactate were found to be independently associated with the hospital mortality. The ICCO score was 0.3707 + (0.0773 x bilirubin (mg/dl)) - (0.00849 x cholesterol (mg/dl)) -(0.0155 x creatinine clearance (ml/min)) + (0.1351 x lactate (mmol/l)), giving an area under a receiver operating characteristic curve of 0.9. Increasing score values were associated with an increase in mortality. All patients with an ICCO score > +2.6 died. CONCLUSIONS: Application of the ICCO score is rapid and available at the patient's bedside, and its application is simple and reproducible. In cirrhotic patients, the ICCO score has a high ability to discriminate between survivors and non-survivors. The ICCO score may facilitate estimation on ICU admission of the prognosis of critically ill cirrhotic patients.

Metabolic encephalopathy in critically ill patients suffering from septic or nonseptic multiple organ failure.

OBJECTIVE: Evaluation of changes in the peak latencies of sensory evoked potentials in different patient groups, to evaluate differences in metabolic encephalopathy of critically ill patients with multiple organ failure as a result of septic or nonseptic conditions. DESIGN: Prospective cohort study. SETTING: Intensive care units of the university hospital, Vienna. PATIENTS: Patients (n = 103) treated on an intensive care unit because of multiple organ failure with additional metabolic encephalopathy. Multiple organ failure was induced by sepsis (group A; n = 56), surgery (group B; n = 29), or both (group C; n = 18). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Metabolic encephalopathy was determined by measuring median nerve-stimulated short-latency and long-latency sensory evoked potentials. No differences in the peak latencies of the sensory evoked potentials were detected among the groups. Septic patients had a N70 peak latency of 131+/-21 msecs, nonseptic postsurgical patients of 132+/-17 msecs, and septic postsurgical patients of 134+/-17 msecs. The cervicomedullary N13 to cortical N20 conduction times were 6.4+/-1 msec, 6.4+/-1.4 msecs, and 6.8+/-1.2 msecs, respectively. All measured peak latencies were significantly prolonged compared with peak latencies of healthy controls. The severity of illness assessed by the Acute Physiology and Chronic Health Evaluation III score was not different between the three groups. An increase of the delay of N70 peak latencies was significantly correlated with the severity of illness (r2 = .15; p < .00005). CONCLUSION: There was no difference in sensory evoked potential measurements detectable among septic patients with multiple organ failure, nonseptic postsurgical patients with multiple organ failure, and septic postsurgical patients with multiple organ failure. The N70 peak latency was significantly correlated with the severity of illness but not with the presence or absence of sepsis. In postsurgical patients with multiple organ failure and superimposed sepsis, the N70 peak latencies were not further prolonged compared with postsurgical patients without sepsis.

Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine.

BACKGROUND: The effects of food restriction on energy metabolism have been under investigation for more than a century. Data obtained are conflicting and research has failed to provide conclusive results. OBJECTIVE: The objective of this study was to test the hypothesis that in lean subjects under normal living conditions, short-term starvation leads to an increase in serum concentrations of catecholamines and thus to an increase in resting energy expenditure. DESIGN: Resting energy expenditure, measured by indirect calorimetry, and hormone and substrate concentrations were measured in 11 healthy, lean subjects on days 1, 2, 3, and 4 of an 84-h starvation period. RESULTS: Resting energy expenditure increased significantly from 3.97 +/- 0.9 kJ/min on day 1 to 4.53 +/- 0.9 kJ/min on day 3 (P < 0.05). The increase in resting energy expenditure was associated with an increase in the norepinephrine concentration from 1716. +/- 574 pmol/L on day 1 to 3728 +/- 1636 pmol/L on day 4 (P < 0.05). Serum glucose decreased from 4.9 +/- 0.5 to 3.5 +/- 0.5 mmol/L (P < 0.05), whereas insulin did not change significantly. CONCLUSIONS: Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.

Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance.

Following the onset of acute myocardial infarction (AMI), a number of serum parameters show well-defined changes reflecting myocardial injury. During the consecutive repair phase, compensatory processes are initiated including the formation of a collateral circulation on the basis of angiogenesis and arteriogenesis. An important angiogenic factor is vascular endothelial growth factor-A (VEGF-A), shown to be upregulated in the ischemic myocardium. It is unclear, however, whether acute myocardial ischemia leads to a detectable elevation of VEGF-A serum concentrations. With the use of an immunoradiometric assay, we measured the levels of VEGF-A in the serum of patients after AMI at defined time intervals, of patients with unstable angina pectoris (UAP) and of healthy individuals. In addition, in a small group of patients with subacute myocardial infarction VEGF-A concentrations were measured in coronary sinus blood. The data are given as median followed by the 25th and 75th percentiles. In the group with AMI serum VEGF-A measured 105 [78; 176] pg/ml on day 1 and 114 pg/ml [72; 163] pg/ml on day 3 after onset of AMI. Serum levels of VEGF-A significantly increased on day 7 after AMI to 189 [119; 373] pg/ml (P=0.0103) and on day 10 to 255 [162; 371] pg/ml (P=0.0007). The VEGF-A serum level in healthy controls and in patients with UAP measured 98 [75; 137] pg/ml and 116 [57; 140] pg/ml, respectively. Serum at day 10 after AMI contained VEGF-A at a biologically relevant concentration capable of stimulating proliferation of endothelial cells. Surprisingly, VEGF-A serum levels were similar in samples taken from the coronary sinus with 61 [43; 83] pg/ml. Therefore the main source for VEGF-A in the blood stream is not the infarcted myocardium. However, the number of platelets, a rich source of VEGF-A, is significantly increased after myocardial infarction, i.e. 284 [252; 363] x 10(9)/litre v 220 [177; 250] x 10(9)/litre. In conclusion, the time course of VEGF-A elevation following AMI strongly suggests that VEGF-A plays a role as an endogenous activator of coronary collateral formation in the human heart. The most likely source of the elevated VEGF-A are platelets, rather than the infarcted myocardium.

Heavy chronic alcohol abuse has no additional adverse effect on the function of extrahepatic organs and ICU mortality in patients with liver cirrhosis.

BACKGROUND AND AIMS: We questioned whether heavy chronic alcohol abuse influences extrahepatic organ failure and ICU mortality in cirrhotic patients admitted to a medical intensive care unit. PATIENTS AND METHODS: Medical records of 208 consecutive cirrhotic critically ill patients were reviewed. Patients were classified into two groups. Group A comprised 144 patients with liver cirrhosis due to heavy chronic alcohol abuse and group B, 64 patients with liver cirrhosis due to non-alcoholic causes. The presence of extrahepatic organ failures in patients of both groups was assessed with parameters determined on the day of admission to the ICU. Furthermore, ICU mortality was determined. RESULTS: The occurrence of extrahepatic organ failure was similar in group A and group B (83% vs. 80%; p = NS). The rate of extrahepatic organ failure was 1.7 +/- 1.2 organs in group A, compared to 1.4 +/- 1 organs in group B (p = NS). ICU mortality was 53% in group A and 44% in group B (p = NS). An increase in the number of extrahepatic organ failures was associated with a concomitant increase in ICU mortality in both groups of patients. CONCLUSION: The occurrence of extrahepatic organ failure and ICU mortality was not different between patients with liver cirrhosis secondary to heavy chronic alcohol abuse and patients with liver cirrhosis due to nonalcoholic causes. Cirrhotic patients should be admitted to a medical intensive care unit for extended intensive care treatment prior to the occurrence of extrahepatic multiple organ failure, independent of the underlying aetiology.

Inhalation of nitric oxide as a life-saving therapy in a patient after pulmonary embolectomy.

We describe a 54-yr-old man with cardiogenic shock caused by acute right heart failure after pulmonary embolectomy. Inhalation of nitric oxide led to immediate improvement in respiratory and haemodynamic variables. Inhaled nitric oxide can be used to reduce acute right heart failure until conventional therapy can provide successful haemodynamic stability.

The coronary endothelium: a target for vascular endothelial growth factor. Human coronary artery endothelial cells express functional receptors for vascular endothelial growth factor in vitro and in vivo.

Vascular endothelial growth factor (VEGF) is an angiogenic peptide that can stimulate endothelial cell proliferation and migration in vitro and collateral development in ischemic organs in vivo. Although postulated, the expression of functional VEGF receptors in the heart has not been demonstrated yet. To prove this hypothesis and to extend the molecular basis of myocardial angiogenesis, we have characterized the expression and function of VEGF receptors in human coronary artery endothelial cells (HCAEC) and in human heart tissue. VEGF strongly induces proliferation and migration of HCAEC. These cells express transcripts of the two VEGF receptors KDR and Flt-1. Their expression levels are higher in HCAEC as compared with human umbilical vein endothelial cells. In HCAEC, VEGF stimulates phosphorylation of KDR in a concentration-dependent manner proving that KDDR is a functional receptor tyrosine kinase. Scatchard analysis demonstrated the presence of the high affinity receptor Flt-1 in HCAEC with a kd of 8 pM. Flt-1 protein could be visualized as a single band corresponding to a size of 210 kd. In addition mature KDR protein could be detected in adult human heart. Taken together, HCAEC and human heart tissue express high levels of functional VEGF receptors. These results broaden the molecular basis for understanding and manipulating VEGF-induced endothelial function and angiogenesis in the coronary circulation.

Molecular mediators of tumor angiogenesis: enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer.

The progression of breast cancer growth and its ability to metastasize are associated with the process of angiogenesis. In this study, we examined the protein expression of vascular endothelial growth factor (VEGF) and its specific and functional receptor KDR in human breast tissue. We investigated a total of 13 mammary carcinomas, 3 fibroadenomas, 5 specimens with fibrocystic breast disease as well as normal (adjacent to malignant) breast tissue using immunohistochemistry and Western blot analysis. In all carcinomas examined, functional KDR protein was present independent of tumor type, tumor stage and histological grade as demonstrated by tyrosine phosphorylation analysis of KDR. When malignant tissues were compared with their neighboring non-neoplastic regions, activated KDR was found to be expressed to a much higher extent within the malignant tissue samples. In fibroadenomas, KDR was barely detectable, whereas in fibrocystic breast disease KDR expression was variable. Immunostaining of KDR was localized to endothelium and epithelium of mammary ducts in malignant and benign breast tissue, while VEGF immunoreactivity was primarily found in the endothelium and also in tumor cells and macrophages. Our data demonstrate that KDR activation is enhanced in breast cancer in vivo and emphasize the functional role of VEGF and KDR in the development of malignant breast disease.

Transient left ventricular failure following bilateral lung transplantation for pulmonary hypertension.

BACKGROUND: Bilateral lung transplantation is an established therapy for end-stage pulmonary hypertension. Its early postoperative outcome may be biased by various complications resulting in unexpected deterioration of the patient in terms of hemodynamics and blood gases. METHODS: We have reviewed the early postoperative course of patients who underwent bilateral lung transplantation for pulmonary hypertension at our institution and analyzed all available data, especially hemodynamic measurements, echocardiographic documentation and therapeutical strategies, in those cases where cardiac dysfunction was found to be responsible for clinical deterioration. RESULTS: Three out of 20 lung transplant recipients operated for pulmonary hypertension experienced severe respiratory insufficiency accompanied by hemodynamic decompensation during the first days after surgery. Clinical and laboratory findings together with results of echocardiography and pulmonary artery catheterism helped establish the diagnosis of left ventricular failure. This proved to be transitory, but the response to therapy (inotropic drugs, afterload reduction and eventually prostaglandins) was very variable. Adequately treated, this complication did not preclude the outcome of transplantation by itself. CONCLUSION: Left ventricular failure is a possible complication after lung transplantation for pulmonary hypertension. Echocardiography and pulmonary artery catheterism may be useful adjuvant diagnostic tools, beside routine physical examination, chest X-ray, and laboratory analysis. Therapy of this complication must be adapted individually and may be complex.