A modular computational framework for medical digital twins.

This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams. They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data-driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories. Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.

Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

Single-Slice XRF Mapping of Light Elements in Frozen-Hydrated Allium schoenoprasum via a Self-Absorption-Corrected Hyperspectral Tomographic Reconstruction Approach.

3D and 2D-cross-sectional X-ray fluorescence analysis of biological material is a powerful tool to image the distribution of elements and to understand and quantify metal homeostasis and the distribution of anthropogenic metals and nanoparticles with minimal preparation artifacts. Using tomograms recorded on cryogenically prepared leaves of Allium schoenoprasum, the cross-sectional distribution of physiologically relevant elements like calcium, potassium, manganese, and zinc could be tomographically reconstructed by peak fitting followed by a conventional maximum-likelihood algorithm with self-absorption correction to reveal the quantitative cross-sectional element distribution. If light elements such as S and P are located deep in the sample compared to the escape depth of their characteristic X-ray fluorescence lines, the quantitative reconstruction becomes inaccurate. As a consequence, noise is amplified to a magnitude where it might be misinterpreted as actual concentration. We show that a tomographic MCA hyperspectral reconstruction in combination with a self-absorption correction allows for fitting of the XRF spectra directly in real space, which significantly improves the qualitative and quantitative analysis of the light elements compared to the conventional method as noise and artifacts in the tomographic reconstruction are reduced. This reconstruction approach can substantially improve the quantitative analysis of trace elements as it allows the fitting of summed voxel spectra in anatomical regions of interest. The presented method can be applied to XRF 2D single-slice tomography data and 3D tomograms and is particularly relevant for, but not limited to, biological material in order to help retrieve self-absorption corrected quantitative reconstructions of the spatial distribution of light elements and ultra-trace-elements.

Improved Tissue Processing in Esophageal Adenocarcinoma After Ivor Lewis Esophagectomy Allows Histological Analysis of All Surgically Removed Lymph Nodes with Significant Effects on Nodal UICC Stages.

BACKGROUND: In esophageal carcinoma, the numbers of metastatic and total removed lymph nodes (LN) are well-established variables of long-term prognosis. The overall rate of retrieved LN depends on neoadjuvant treatment, the extent of surgical lymphadenectomy, and the modality of the pathological workup. The question in this study is whether technically extended histopathological preparation can increase the number of detected (metastatic) LN with an impact on nodal UICC staging. PATIENTS AND METHODS: A cohort of 77 patients with esophageal adenocarcinoma was treated with Ivor Lewis esophagectomy including standardized two-field lymphadenectomy. The specimens were grossed, and all manually detectable LN were retrieved. The remaining tissue was completely embedded by the advanced "acetone compression" retrieval technique. The primary outcome parameter was the total number of detected lymph nodes before and after acetone workup. RESULTS: A mean number of 23,1 LN was diagnosed after standard manual LN preparation. With complete embedding of the fatty tissue using acetone compression, the number increased to 40.5 lymph nodes (p < 0.0001). The mean number of metastatic LN increased from 3.2 to 4.2 nodal metastases following acetone compression (p < 0.0001). Additional LN metastases which caused a change in the primary (y)pN stage were found in ten patients (13.0%). CONCLUSIONS: Advanced lymph node retrieval by acetone compression allows a reliable statement on the real number of removed LN. Results demonstrate an impact on the nodal UICC stage. A future multicenter study will examine the prognostic impact of improved lymph node retrieval on long-term oncologic outcome.

X-ray fluorescence analysis of metal distributions in cryogenic biological samples using large-acceptance-angle SDD detection and continuous scanning at the Hard X-ray Micro/Nano-Probe beamline P06 at PETRA III.

A new Rococo 2 X-ray fluorescence detector was implemented into the cryogenic sample environment at the Hard X-ray Micro/Nano-Probe beamline P06 at PETRA III, DESY, Hamburg, Germany. A four sensor-field cloverleaf design is optimized for the investigation of planar samples and operates in a backscattering geometry resulting in a large solid angle of up to 1.1 steradian. The detector, coupled with the Xspress 3 pulse processor, enables measurements at high count rates of up to 106 counts per second per sensor. The measured energy resolution of ∼129 eV (Mn Kα at 10000 counts s-1) is only minimally impaired at the highest count rates. The resulting high detection sensitivity allows for an accurate determination of trace element distributions such as in thin frozen hydrated biological specimens. First proof-of-principle measurements using continuous-movement 2D scans of frozen hydrated HeLa cells as a model system are reported to demonstrate the potential of the new detection system.

Ultracold Electrons via Near-Threshold Photoemission from Single-Crystal Cu(100).

Achieving a low mean transverse energy or temperature of electrons emitted from the photocathode-based electron sources is critical to the development of next-generation and compact x-ray free electron lasers and ultrafast electron diffraction, spectroscopy, and microscopy experiments. In this Letter, we demonstrate a record low mean transverse energy of 5 meV from the cryo-cooled (100) surface of copper using near-threshold photoemission. Further, we also show that the electron energy spread obtained from such a surface is less than 11.5 meV, making it the smallest energy spread electron source known to date: more than an order of magnitude smaller than any existing photoemission, field emission, or thermionic emission based electron source. Our measurements also shed light on the physics of electron emission and show how the energy spread at few meV scale energies is limited by both the temperature and the vacuum density of states.

Stenosis of the celiac trunk is associated with anastomotic leak after Ivor-Lewis esophagectomy.

Transthoracic esophagectomy with gastric tube formation is the surgical treatment of choice for esophageal cancer. The surgical reconstruction induces changes of gastric microcirculation, which are recognized as potential risk factors of anastomotic leak. This prospective observational study investigates the association of celiac trunk (TC) stenosis with postoperative anastomotic leak. One hundred fifty-four consecutive patients with esophageal cancer scheduled for Ivor-Lewis esophagectomy were included. Preoperative staging computed tomography (CT) was used to identify TC stenosis. Any narrowing of the lumen due to atherosclerotic changes was classified as stenosis. Percentage of stenotic changes was calculated using the North American Symptomatic Carotid Endarterectomy Trial formula. Multivariable analysis was used to identify possible risk factors for leak. The overall incidence of TC stenosis was 40.9%. Anastomotic leak was identified in 15 patients (9.7%). Incidence of anastomotic leak in patients with stenosis was 19.4% compared to 2.3% in patients without stenosis. Incidence of stenosis in patients with leak was 86.7% (13 of 15 patients) and significantly higher than 38.8% (54 of 139 patients) in patients without leak (P < 0.001). There was a significant difference in median degree of TC stenosis (50.0% vs 39.4%; P = 0.032) in patients with and without leak. In the multivariable model, TC stenosis was an independent risk factor for anastomotic leak (odds ratio: 5.98, 95% CI: 1.58-22.61). TC stenosis is associated with postoperative anastomotic leak after Ivor-Lewis esophagectomy. Routine assessment of TC for possible stenosis is recommended to identify patients at risk.

Surgical management of esophageal sarcoma: a multicenter European experience.

Esophageal sarcomas are rare and evidence in literature is scarce making their management difficult. The objective is to report surgical and oncological outcomes of esophageal sarcoma in a large multicenter European cohort. This is a retrospective multicenter study including all patients who underwent en-bloc esophagectomy for esophageal sarcoma in seven European tertiary referral centers between 1987 and 2016. The main outcomes and measures are pathological results, early and long-term outcomes. Among 10,936 esophageal resections for cancer, 21 (0.2%) patients with esophageal sarcoma were identified. The majority of tumors was located in the middle (n = 7) and distal (n = 9) third of the esophagus. Neoadjuvant chemoradiotherapy was performed in five patients. All the patients underwent en-bloc transthoracic esophagectomy (19 open, 2 minimally invasive). Postoperative mortality occurred in 1 patient (5%). One patient received adjuvant chemotherapy. Definitive pathological results were carcinosarcoma (n = 7), leiomyosarcoma (n = 5), and other types of sarcoma (n = 9). Microscopic R1 resection was present in one patient (5%) and seven patients (33%) had positive lymph nodes. Median follow-up was 16 (3-79) months in 20 of 21 patients (95%). One-, 3-, and 5-year overall survival rates were 74%, 43%, and 35%, respectively. One-, 3- and 5-years disease-free survival rates were 58%, 40%, and 33%, respectively. Median overall survival was 6 months in N+ patients vs. 37 months for N0 patients (p = 0.06). At the end of the follow-up period, nine patients had died from cancer recurrences (43%), three patients died from other reasons (14%), one patient was still alive with recurrence (5%) and the seven remaining patients were free of disease (33%). Recurrence was local (n = 3), metastatic (n = 3), or both (n = 4). In conclusion, carcinosarcoma and leiomyosarcoma were the most common esophageal sarcoma histological subtypes. Lymph node involvement was seen in one third of cases. A transthoracic en-bloc esophagectomy with radical lymphadenectomy should be the best surgical option to achieve complete resection. Long-term survival remained poor with a high local and distant recurrence rate.

Controlling the generation of bilayer and multilayer vesicles in block copolymer/epoxy blends by a slow photopolymerization process.

Vesicles are a highly attractive morphology to achieve in micellar dispersions of block copolymers (BCP) in epoxy thermosets due to the fact that small amounts can affect a large volume fraction of the matrix, a fact that is important for toughening purposes. However, generating vesicles in epoxy matrices requires operating in a narrow range of formulations and processing conditions. In this report, we show that block-copolymer vesicles dispersed in an epoxy matrix could be obtained through a sphere-to-cylinder-to-vesicle micellar transition induced by visible-light photopolymerization at room temperature. A 10 wt% colloidal solution of poly(ethylene-co-butene)-block-poly(ethylene oxide) (PEB-b-PEO) block copolymer (BCP) in an epoxy monomer (DGEBA) self-assembled into spherical micelles as shown by small-angle X-ray scattering (SAXS). During a slow photopolymerization of the epoxy monomer carried out at room temperature, a sphere-to-cylinder-to-vesicle transition took place as revealed by in situ SAXS and TEM images. This was driven by the tendency of the system to reduce the local interfacial curvature as a response to a decrease in the miscibility of PEO blocks in the polymerizing epoxy matrix. When the BCP concentration was increased from 10 to 20 and 40 wt%, the final structure evolved from bilayer vesicles to multilayer vesicles and to lamellae, respectively. In particular, for 20 wt% PEB-b-PEO, transient structures such as partially fused multilayered vesicles were observed by TEM, giving insight into the growth mechanism of multilayer vesicles. On the contrary, when a relatively fast thermal polymerization was performed at 80 °C, the final morphology consisted of kinetically trapped spherical and cylindrical micelles. Hopefully, this study will lead to new protocols for the preparation of vesicles dispersed in epoxy matrices in a controlled way.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

Intrinsic electron beam emittance from metal photocathodes: the effect of the electron effective mass.

A theoretical development of prior analyses, together with our solenoid scan measurements on eight planar metal photocathodes (Ag, Be, Cr, Cu, Mo, Sn, Ta, and W) and previous data on Mg [X. J. Wang, M. Babzien, R. Malone, and Z. Wu, in Proceedings of LINAC2002, Gyeongju, Korea, 2002 (Pohang Accelerator Laboratory, Pohang, Korea, 2002), pp. 142-144.] indicate that the transverse momentum (and hence intrinsic emittance) of an electron beam is fundamentally dependent on the electron effective mass in the metal.

Factor X deficiency and intracranial bleeding: who is at risk?

Very few mutations of the gene encoding for coagulation factor X (FX) have been found associated with intracranial haemorrhage (ICH) due to FX deficiency (FXD). No guidelines exist as to when prophylaxis in FXD should be started and how patients at risk for ICH can be identified. We report on a novel mutation causative for ICH in a family of Iranian origin and provide a summary of all published mutations in the FX gene related to ICH. The index patient is an infant with umbilical bleeding requiring blood transfusion in the postnatal period. The international normalized ratio (6.01) and activated partial thromboplastin time (117 s) were prolonged. Coagulation factor analysis was normal except for FX activity (<1%). At 4 months, the child suffered a spontaneous severe intracranial haemorrhage. The child was the product of a consanguineous union. Four of five available family members from three generations displayed minor bleeding symptoms and mildly reduced FX. Sequencing of FX gene demonstrated homozygosity for a novel duplication A (c.1402_1403dupA)* in exon 8 and heterozygosity in four family members. We compare this case to all 15 patients with FXD and ICH and their 11 known mutations described so far. This case illustrates a pattern of FXD (a male neonate with umbilical or gastrointestinal bleeding, very low FX:C (<1%) and an underlying homozygous genotype) who may be at high risk for ICH. In these cases, we recommend to start early prophylactic substitution of FX to prevent a possible life-threatening haemorrhage.

Novel Ultrabright and Air-Stable Photocathodes Discovered from Machine Learning and Density Functional Theory Driven Screening.

The high brightness, low emittance electron beams achieved in modern X-ray free-electron lasers (XFELs) have enabled powerful X-ray imaging tools, allowing molecular systems to be imaged at picosecond time scales and sub-nanometer length scales. One of the most promising directions for increasing the brightness of XFELs is through the development of novel photocathode materials. Whereas past efforts aimed at discovering photocathode materials have typically employed trial-and-error-based iterative approaches, this work represents the first data-driven screening for high brightness photocathode materials. Through screening over 74 000 semiconducting materials, a vast photocathode dataset is generated, resulting in statistically meaningful insights into the nature of high brightness photocathode materials. This screening results in a diverse list of photocathode materials that exhibit intrinsic emittances that are up to 4x lower than currently used photocathodes. In a second effort, multiobjective screening is employed to identify the family of M2 O (M = Na, K, Rb) that exhibits photoemission properties that are comparable to the current state-of-the-art photocathode materials, but with superior air stability. This family represents perhaps the first intrinsically bright, visible light photocathode materials that are resistant to reactions with oxygen, allowing for their transport and storage in dry air environments.

Surgery for recurrent ovarian cancer: role of peritoneal carcinomatosis: exploratory analysis of the DESKTOP I Trial about risk factors, surgical implications, and prognostic value of peritoneal carcinomatosis.

BACKGROUND: Almost all retrospective trials pointed out that a benefit of surgery for recurrent ovarian cancer may be limited to patients in whom a macroscopic complete resection could be achieved. Peritoneal carcinomatosis has been reported to be either a negative predictor for resectability or a negative prognostic factor, or both. The role of peritoneal carcinomatosis in a multicenter trial was investigated. METHODS: Exploratory analysis of the DESKTOP I trial (multicenter trial of patients undergoing surgery for recurrent ovarian cancer, 2000 to 2003). RESULTS: A total of 125 patients (50%) who underwent surgery for recurrent ovarian cancer had peritoneal carcinomatosis. Univariate analyses showed worse overall survival for patients with peritoneal carcinomatosis compared with patients without carcinomatosis (P < .0001). Patients with and without peritoneal carcinomatosis had a complete resection rate of 26% and 74%, respectively (P < .0001). This corresponded with the observation that patients with complete resection had a better prognosis than those with minimal residual disease of 1 to 5 mm, which commonly reflects peritoneal carcinomatosis (P = .0002). However, patients who underwent complete resection, despite peritoneal carcinomatosis, had a 2-year survival rate of 77%, which was similar to the 2-year survival rate of patients with completely debulked disease who did not have peritoneal carcinomatosis (81%) (P = .96). Analysis of prognostic factors did not show any independent effect of peritoneal carcinomatosis on survival in patients who underwent complete resection. CONCLUSIONS: Peritoneal carcinomatosis was a negative predictor for complete resection but had no effect on prognosis if complete resection could be achieved. Improving surgical skills might be one step to increase the proportion of patients who might benefit from surgery for recurrent disease.

AsH3 ultraviolet photochemistry.

High-n Rydberg time-of-flight spectroscopy has been used to study the 193.3 nm photolysis of AsH(3). The center-of-mass translational energy distribution for the 1-photon process, AsH(3) + h nu --> AsH(2) + H, P(E(c.m.)), indicates that AsH(2) internal excitation accounts for approximately 64% of the available energy [i.e., h nu - D(0)(H(2)As - H)]. Secondary AsH(2) photodissociation also takes place. Analyses of superimposed structure atop the broad P(E(c.m.)) distribution suggest that AsH(2) is formed with significant a-axis rotation as well as bending excitation. Comparison of the results obtained with AsH(3) versus those of the lighter group-V hydrides (NH(3), PH(3)) lends support to the proposed mechanisms. Of the group-V hydrides, AsH(3) lies intermediate between the nonrelativistic and relativistic regimes, requiring high-level electronic structure theory.

DC photoelectron gun parameters for ultrafast electron microscopy.

We present a characterization of the performance of an ultrashort laser pulse driven DC photoelectron gun based on the thermionic emission gun design of Togawa et al. [Togawa, K., Shintake, T., Inagaki, T., Onoe, K. & Tanaka, T. (2007). Phys Rev Spec Top-AC 10, 020703]. The gun design intrinsically provides adequate optical access and accommodates the generation of approximately 1 mm2 electron beams while contributing negligible divergent effects at the anode aperture. Both single-photon (with up to 20,000 electrons/pulse) and two-photon photoemission are observed from Ta and Cu(100) photocathodes driven by the harmonics (approximately 4 ps pulses at 261 nm and approximately 200 fs pulses at 532 nm, respectively) of a high-power femtosecond Yb:KGW laser. The results, including the dependence of the photoemission efficiency on the polarization state of the drive laser radiation, are consistent with expectations. The implications of these observations and other physical limitations for the development of a dynamic transmission electron microscope with sub-1 nm.ps space-time resolution are discussed.

High-power, femtosecond, thermal-lens-shaped Yb:KGW oscillator.

Thermal lens shaping for astigmatism compensation is extended to a high-power, diode-pumped, Yb:KGW laser by employing a gain crystal geometry designed for efficient polarized pumping. The 63MHz oscillator is soliton mode-locked with the aid of a saturable Bragg reflector to yield 250fs (347fs) pulses at an output power of 3.5W (5W). Frequency doubling of the 250fs pulses with an intrinsic efficiency >60% provides 1.65W of average green power.

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive O2 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate O2-metabolite-induced pulmonary vasoconstriction. We found that O2 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27 +/- 4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels of thromboxane B2 (the stable metabolite of thromboxane A2) compared with only twofold increases in 6-keto-PGF1a (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4 +/- 1.5 mmHg). Furthermore, imidazole, a thromboxane synthetase inhibitor, also decreased O2-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in O2-metabolite-induced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree of vasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to O2 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.

Nature of fetal hemoglobin in the Greek type of hereditary persistence of fetal hemoglobin with and without concurrent beta-thalassemia.

The fetal hemoglobin in the affected members of three Greek families with the hereditary persistence of fetal hemoglobin has only gamma-chains of the type with alanine in position 136. Although certain Negro families had been considered to have only this type of gamma-chains in their fetal hemoglobin, further studies required that they be reclassified. Consequently, the Greek cases are the sole examples of this class among the heterozygotes for the hereditary persistence of fetal hemoglobin. In Greek double heterozygotes for beta-thalassemia and the hereditary persistence of fetal hemoglobin, fetal hemoglobin is increased above the level of hemoglobin F in simple heterozygotes and gamma-chains with glycine in position 136 become apparent. In these individuals, gamma-chains with alanine in position 136 apparently derive from the chromosome for the hereditary persistence of fetal hemoglobin and are present in the hemoglobin F with gamma-chains of both types from the chromosome for beta-thalassemia. When these data are correlated with earlier knowledge of the genetic state of the Greek individuals, modifications of our previous ideas about deletions as the genetic basis of the hereditary persistence of fetal hemoglobin must be considered.