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This study reports the first case of an innovative drop-on-powder (DoP) three-dimensional (3D) printing technology to produce oral tablets (diameters of 10 mm and 13 mm) loaded with an anticancer model drug, 5-fluorouracil (FLU). For this study, a composition of the powder carrier containing CaSO4 hydrates, vinyl polymer, and carbohydrate was used as the matrix former, whereas 2-pyrrolidone with a viscosity like water was used as a binding liquid or inkjet ink. All tablets were printed using a commercial ZCorp 3D printer with modification. The resultant tablets were subject to coating with various polymeric solutions containing the drug. The composition of the polymeric solutions was adjusted at drug: polymer(s) 1:1 (w/w) ratio. Either Soluplus® (SOL) alone or in combination with polyethylene glycol (PEG) was used to develop the coating solution of 2.5% (w/v) concentration. The particle size analysis, flow test, and particle morphology studies revealed mono-modal narrow size distribution, good flow properties, and porous loosely bound texture (of the tablets), respectively. Moreover, the advanced application of the fluorescence microscopy showed a homogenous distribution of the drug throughout the surface of the 3D printed tablets. The in vitro dissolution studies showed that the tablet compositions, dimensions, and the coating solution compositions influenced the release of the drug from the tablets. It can be concluded that our innovative DoP 3D printing technology can be used to fabricate personalized dosage forms containing optimized drug content with high accuracy and shape fidelity. This is particularly suitable for those drugs that are highly unstable in thermal processing and cannot withstand the heat treatment, such as in fused deposition modeling (FDM) 3D printing.

We present the results of a search through the photometric database of Kepler eclipsing binaries looking for evidence of hierarchical triple-star systems. The presence of a third star orbiting the binary can be inferred from eclipse timing variations. We apply a simple algorithm in an automated determination of the eclipse times for all 2157 binaries. The "calculated" eclipse times, based on a constant period model, are subtracted from those observed. The resulting O-C (observed minus calculated times) curves are then visually inspected for periodicities in order to find triple-star candidates. After eliminating false positives due to the beat frequency between the ~1/2 hr Kepler cadence and the binary period, 39 candidate triple systems were identified. The periodic O-C curves for these candidates were then fit for contributions from both the classical Roemer delay and so-called physical delay, in an attempt to extract a number of the system parameters of the triple. We discuss the limitations of the information that can be inferred from these O-C curves without further supplemental input, e.g., ground-based spectroscopy. Based on the limited range of orbital periods for the triple-star systems to which this search is sensitive, we can extrapolate to estimate that at least 20% of all close binaries have tertiary companions. [ABSTRACT FROM AUTHOR]

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E–binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.

This study reports the first case of an innovative drop-on-powder (DoP) three-dimensional (3D) printing technology to produce oral tablets (diameters of 10 mm and 13 mm) loaded with an anticancer model drug, 5-fluorouracil (FLU). For this study, a composition of the powder carrier containing CaSO4 hydrates, vinyl polymer, and carbohydrate was used as the matrix former, whereas 2-pyrrolidone with a viscosity like water was used as a binding liquid or inkjet ink. All tablets were printed using a commercial ZCorp 3D printer with modification. The resultant tablets were subject to coating with various polymeric solutions containing the drug. The composition of the polymeric solutions was adjusted at drug: polymer(s) 1:1 (w/w) ratio. Either Soluplus® (SOL) alone or in combination with polyethylene glycol (PEG) was used to develop the coating solution of 2.5% (w/v) concentration. The particle size analysis, flow test, and particle morphology studies revealed mono-modal narrow size distribution, good flow properties, and porous loosely bound texture (of the tablets), respectively. Moreover, the advanced application of the fluorescence microscopy showed a homogenous distribution of the drug throughout the surface of the 3D printed tablets. The in vitro dissolution studies showed that the tablet compositions, dimensions, and the coating solution compositions influenced the release of the drug from the tablets. It can be concluded that our innovative DoP 3D printing technology can be used to fabricate personalized dosage forms containing optimized drug content with high accuracy and shape fidelity. This is particularly suitable for those drugs that are highly unstable in thermal processing and cannot withstand the heat treatment, such as in fused deposition modeling (FDM) 3D printing. [ABSTRACT FROM AUTHOR]

We introduce an approach for analyzing the responses of dynamical systems to external perturbations that combines score-based generative modeling with the generalized fluctuation-dissipation theorem. The methodology enables accurate estimation of system responses, including those with non-Gaussian statistics. We numerically validate our approach using time-series data from three different stochastic partial differential equations of increasing complexity: an Ornstein-Uhlenbeck process with spatially correlated noise, a modified stochastic Allen-Cahn equation, and the 2D Navier-Stokes equations. We demonstrate the improved accuracy of the methodology over conventional methods and discuss its potential as a versatile tool for predicting the statistical behavior of complex dynamical systems.

Hypertension is the primary cause of cardiovascular disease, which is a leading killer worldwide. Despite the prevalence of this non-communicable disease, still between 90% and 95% of cases are of unknown or multivariate cause ("essential hypertension"). Current therapeutic options focus primarily on lowering blood pressure through decreasing peripheral resistance or reducing fluid volume, but fewer than half of hypertensive patients can reach blood pressure control. Hence, identifying unknown mechanisms causing essential hypertension and designing new treatment accordingly are critically needed for improving public health. In recent years, the immune system has been increasingly implicated in contributing to a plethora of cardiovascular diseases. Many studies have demonstrated the critical role of the immune system in the pathogenesis of hypertension, particularly through pro-inflammatory mechanisms within the kidney and heart, which, eventually, drive a myriad of renal and cardiovascular diseases. However, the precise mechanisms and potential therapeutic targets remain largely unknown. Therefore, identifying which immune players are contributing to local inflammation and characterizing pro-inflammatory molecules and mechanisms involved will provide promising new therapeutic targets that could lower blood pressure and prevent progression from hypertension into renal or cardiac dysfunction., 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 Benson, Guo, Deck, Mora, Liu and Mu.)

Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For more than half a century, researchers have demonstrated that immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that proinflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFN- γ ), in particular, as an important cytokine that modulates immune responses, has been recently identified as a critical regulator of blood pressure by several groups, including us. In this review, we focus on exploring the role of IFN- γ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFN- γ in hypertension through global knockout studies and related downstream signaling pathways that IFN- γ production from CD8 + T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation., Competing Interests: All authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Crystallization of supercooled liquid water in most natural environments starts with heterogeneous nucleation of ice induced by a nucleation site. Mineral surfaces, which form the majority of aqueous interfaces in Earth's ecosystem, possess a plethora of surface morphological and chemical features that can serve as ice nucleation sites. The nature of surface sites responsible for ice nucleation from supersaturated water vapor have been recently identified for alkali feldspar, a family of rock-building minerals constituting 60% of the Earth's crust. It was demonstrated that ice preferentially forms upon the patches of crystalline surface with (100) orientation, exposed in the surface defects such as cracks, pores, and pits arising due to chemically induced stress and further enhanced by hydrothermal alterations of natural feldspars. However, whether the same sites were responsible for nucleation from liquid water, remained to be shown. Here, we investigate the mechanism of heterogeneous ice nucleation in a layer of aqueous sucrose solution on top of thin sections of feldspar prepared along the (010) crystalline plane. We observe a preferential orientation of ice crystals defined by an epitaxial relationship between feldspar and ice, with ice crystals growing on the crystalline surfaces of feldspar with (100) orientation. We thus conclude that the ice nucleating sites active in deposition freezing mode are also active in the immersion freezing regime. This conclusion is further supported by the enhancement of ice nucleation active site density observed for the thin sections of feldspar prepared sub-parallel to the (100) plane as compared to sections prepared along (010) and (001) crystallographic orientations.

Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.5 µg twice daily (BID), 15 µg BID, 30 µg once daily (QD), 30 µg BID) for four consecutive days. Primary outcome measure was average patient-reported Numeric Pain Rating Scale (NPRS) score during Days 21-28 post-treatment. Changes in mean NPRS score were not statistically different between cohorts, due to small trial size and influence of a few robust placebo responders. Cumulative responder analysis showed significant difference from placebo with 30 µg BID cohort using the maximum response at any timepoint ( p = 0.072), 5-day ( p = 0.059), 10-day ( p = 0.027), and 20-day ( p = 0.071) rolling averages. In secondary quality of life (QOL) outcomes, 30 µg BID cohort also differed significantly from placebo in a number of SF-36 and CIPN20 subscales. Most adverse events (AE) were mild or moderate with oral paresthesia (29.6%) and oral hypoesthesia (24.8%) as most common.

The unfolded protein response (UPR) is a signaling network that maintains homeostasis of the endoplasmic reticulum (ER). In the human-pathogenic fungus Aspergillus fumigatus , the UPR is initiated by activation of an endoribonuclease (RNase) domain in the ER transmembrane stress sensor IreA, which splices the downstream mRNA hacA u into its active form, hacA i , encoding the master transcriptional regulator of the pathway. Small-molecule inhibitors against IRE1, the human ortholog of IreA, have been developed for anticancer therapy, but their effects on the fungal UPR are unexplored. Here, we demonstrate that the IRE1 RNase inhibitor 4μ8C prevented A. fumigatus from increasing the levels of hacA i mRNA, thereby blocking induction of downstream UPR target gene expression. Treatment with 4μ8C had minimal effects on growth in minimal medium but severely impaired growth on a collagen substrate that requires high levels of hydrolytic enzyme secretion, mirroring the phenotype of other fungal UPR mutants. 4μ8C also increased sensitivity to carvacrol, a natural compound that disrupts ER integrity in fungi, and hygromycin B, which correlated with reduced expression of glycosylation-related genes. Interestingly, treatment with 4μ8C was unable to induce all of the phenotypes attributed to the loss of the canonical UPR in a Δ hacA mutant but showed remarkable similarity to the phenotype of an RNase-deficient IreA mutant that is also unable to generate the hacA i mRNA. These results establish proof of principle that pharmacological inhibition of the canonical UPR pathway is feasible in A. fumigatus and support a noncanonical role for the hacA u mRNA in ER stress response. IMPORTANCE The unfolded protein response (UPR) is a signaling pathway that maintains endoplasmic reticulum (ER) homeostasis, with functions that overlap virulence mechanisms in the human-pathogenic mold Aspergillus fumigatus The canonical pathway centers on HacA, its master transcriptional regulator. Translation of this protein requires the removal of an unconventional intron from the cytoplasmic mRNA of the hacA gene, which is achieved by an RNase domain located in the ER-transmembrane stress sensor IreA. Here, we show that targeting this RNase activity with a small-molecule inhibitor effectively blocked UPR activation, resulting in effects that mirror the consequences of genetic deletion of the RNase domain. However, these phenotypes were surprisingly narrow in scope relative to those associated with a complete deletion of the hacA gene. These findings expand the understanding of UPR signaling in this species by supporting the existence of noncanonical functions for the unspliced hacA mRNA in ER stress response., (Copyright © 2020 Guirao-Abad et al.)

Background: There is much current as well as long-standing concern that nurses need to be more involved in and also more adept at politics and political action for the advancement of the profession, and for the health and wellbeing of the public., Objectives: An historical scoping literature review was carried out to identify if, as well as why, when, and how nurses become involved in government or meso-level political action or politics, and what is or has been gained through this involvement., Design: Scoping literature review., Settings (including Geographical Location): Worldwide published literature., Participant: Nil., Methods: Research and non-research articles on the topic were identified in a decade-by-decade search of the CINAHL database, all relevant ones were retained, and the per-decade findings in them were compared over time., Results: Only 25 research reports, published 1988-2019, were identified. These studies were conducted in a few, mostly developed, countries. They provide a varied picture of nurse or nursing association involvement in political action and policy circles. In contrast, the opinion and theory articles demonstrate increased nurse and nursing association involvement in, as well as rising skill in political action and public policy engagement, although primarily in the United States and Canada., Conclusions: Research and case reports are needed now in all countries to correct the view that nurses and nursing associations are apolitical, and to gain information on how and why nurses and nursing associations become politically active and also determine what is gained through this activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Surgical site infiltration with bupivacaine results in short-lived analgesia. The MATRIX-1 and MATRIX-2 studies examined the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair. INL-001, designed to provide early and extended delivery of bupivacaine, provides prolonged duration of perioperative analgesia., Methods: In two phase 3 double-blind studies [MATRIX-1 (ClinicalTrials.gov identifier, NCT02523599) and MATRIX-2 (ClinicalTrials.gov identifier, NCT02525133)], patients undergoing open tension-free mesh inguinal hernia repair were randomized to receive 300-mg bupivacaine (three INL-001 100-mg bupivacaine HCl collagen-matrix implants) (MATRIX-1 n = 204; MATRIX-2 n = 213) or three placebo collagen-matrix implants (MATRIX-1 n = 101; MATRIX-2 n = 106) during surgery. Postsurgical medication included scheduled acetaminophen and as-needed opioids., Results: Patients who received INL-001 in both studies reported statistically significantly lower pain intensity (P ≤ 0.004; primary end point) and opioid analgesic use (P < 0.0001) through 24-h post-surgery versus those who received a placebo collagen-matrix. Patients who received INL-001 reported lower pain intensity through 72 h (P = 0.0441) for the two pooled studies. In both studies, more of the patients (28-42%) who received INL-001 used no opioid medication 0-24, 0-48, and 0-72 h post-surgery versus those who received a placebo collagen-matrix (12-22%). Among patients who needed opioid medication, patients receiving INL-001 used fewer opioids than those who received a placebo collagen-matrix through 24 h in both studies (P < 0.0001) and through 48 h in MATRIX-2 (P = 0.0003). Most adverse events were mild or moderate, without evidence of bupivacaine toxicity or deleterious effects on wound healing., Conclusion: These findings indicate that INL-001 results in post-inguinal hernia repair analgesia that is temporally aligned with the period of maximal postsurgical pain and may reduce the need for opioids while offering a favorable safety profile., Trial Registration: ClinicalTrials.gov identifiers, NCT02523599; NCT02525133., Funding: Innocoll Pharmaceuticals. Plain language summary available for this article.

Background: Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection., Methods: We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935., Findings: Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1-39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation., Interpretation: Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted., Funding: Wellcome Trust and Summit Therapeutics., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance., Methods: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept., Results: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept., Conclusion: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

Purpose: To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)., Methods: BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples., Results: The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2., Conclusions: The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.

Background: When sentinel node dissection reveals breast cancer metastasis, completion axillary lymph node dissection is ideally performed during the same operation. Intraoperative histologic techniques have low and variable sensitivity. A new intraoperative molecular assay (GeneSearch BLN Assay; Veridex, LLC, Warren, NJ) was evaluated to determine its efficiency in identifying significant sentinel lymph node metastases (>.2 mm)., Methods: Positive or negative BLN Assay results generated from fresh 2-mm node slabs were compared with results from conventional histologic evaluation of adjacent fixed tissue slabs., Results: In a prospective study of 416 patients at 11 clinical sites, the assay detected 98% of metastases >2 mm and 88% of metastasis greater >.2 mm, results superior to frozen section. Micrometastases were less frequently detected (57%) and assay positive results in nodes found negative by histology were rare (4%)., Conclusions: The BLN Assay is properly calibrated for use as a stand alone intraoperative molecular test.

We applied a new haplotype sharing method to the simulated Genetic Analysis Workshop 12 data for both isolated and general populations without knowledge of the disease model, using affection status as phenotype and three different sample sizes. The highest peak for the mean sharing of the haplotypes was found in the isolated population for the markers D06G034 and D06G035, which flank the candidate genes located on chromosome 6, with -log10(p) values of 2.9 and 7.0 in the moderate and large study samples, respectively. The whole genome screen detected three further loci with -log10(p) values of 3.0, which turned out to be false positives. None of the true gene loci were detected in the general population even in the largest sample. The test of linkage disequilibrium based on excess haplotype sharing over the linkage equilibrium expectation revealed z-values one order of magnitude higher in the isolated than in the general population. This approach appears to be promising for mapping genes of complex diseases depending on population characteristics.

A propsective study of 60 children with appendicitis suggested a correlation between the length of symptoms prior to perforation and the level of appendiceal obstruction. These observations support the concept that obstruction of the appendiceal lumen near its tip leads to early perforation, while obstruction near the base leads to late perforation.

Pathologic and surgical aspects of 1,027 breast cancer cases treated between 1961 and 1972 were reviewed. Sixty-eight (7%) of the cases recurred locally. This low rate of recurrence is associated with the small average diameter of 2.7 cm of all carcinomas and the correspondingly low rate of axillary lymph node metastasis of 40%. Subsequently recurring tumors had a higher incidence of axillary lymph node metastasis (68%). Eight hundred eighty-eight infiltrating duct carcinomas represented the largest group of cases and had a recurrence rate of 5.7%. Comedo, infiltrating papillary, and infiltrating lobular carcinomas recurred locally more frequently, but none of 26 mucinous carcinomas recurred. In eight cases, the recurrent tumor was of a more malignant histologic type than the primary lesion. The average width of the excised segments of skin decreased from 9.8 cm during the first three-year period (1961 to 1963) to 8.4 cm during the last period (1970 to 1972). The average width for the entire period was 9.1 cm, identical for locally recurring and nonrecurring tumors.

More than 1,700 patients with essential or renal hypertension were treated with nitrendipine; data from 967 of these were included in a data pool, and safety data were evaluated. Treatment duration was between 7 days and 2 years. The most frequent side-effects were headache, flush, oedema, dizziness, and palpitations due to the pharmacodynamic effect of the drug. All other side-effects had an incidence below 2%. Eighty-two of the 967 patients stopped therapy before the end of the trial. In 33 of these patients, this was probably due to the side-effects of nitrendipine. Hematological and clinical chemistry data did not indicate any systemic or organ damage. When nitrendipine was combined with thiazides, a lowering of plasma potassium levels could be found, which, however, did not necessitate any therapy.

Plasma cortisol levels in 2 normal persons, 2 obese persons, 2 uraemic patients, and 2 patients with cirrhosis of the liver were raised in 4 steps by a combination of iv priming doses and continuous infusions of cortisol. Plasma cortisol levels and transcortin binding were measured as well as plasma clearance rates of labelled and unlabelled cortisol during each of the 5 experimental periods. Plasma cortisol levels increased less and plasma clearance rates of labelled and unlabelled cortisol increased more in obese persons than in normal persons; in patients with disturbed metabolism of cortisol (uraemia, cirrhosis of the liver) the reverse is true. Plasma clearance rates of free cortisol were calculated and differed from an estimated hepatic plasma flow of 0.7 1/min under certain conditions. Since free cortisol is metabolized faster than transcortin-bound cortisol, increasing plasma clearance rates of cortisol are probably due to increasing ratios free/bound cortisol when total plasma cortisol levels are raised. Low plasma clearance rates of cortisol in uraemia and cirrhosis of the liver are thought to be due to endproduct inhibition, respectively reduced liver cell mass.

About one third of leiomyosarcomas of the gastrointestinal tract do develop metastasis; and nearly 90% of the metastasis are intra-abdominal. It is said that leiomyosarcoma rarely involves regional nodes, although two series reported 8% of leiomyosarcomas of the stomach and 7% of the small intestines had nodal metastasis at initial operations (mostly of limited resections). It is suggested that wider resection of primary tumor with adjacent mesentery may reveal higher frequency of occult nodal metastasis and might prevent some of the loco-regional relapse and sarcomatosis.