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Legal positivism maintains a distinction between law as it is and law as it ought to be. In other words, for positivists, a law can be legally valid even if it is immoral. H. L. A. Hart hoped to defend legal positivism against natural law. This paper analyses Hart’s criticism of Gustav Radbruch, a natural lawyer, before suggesting that Hart’s account of legal positivism gives rise to a logical problem. It is concluded that this problem leaves logical space for a theory of natural law based on moral authority rather than legal validity.

Osteopontin (OPN) is a multifunctional cytokine involved in long bone remodeling and immune system signaling. Additionally, OPN is critical for interferon-alpha (IFN-alpha) production in murine plasmacytoid dendritic cells. We have previously shown that IFN-alpha is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variants of OPN have been associated with SLE susceptibility, and one study suggests that this association is particular to men. In this study, the 3' UTR SLE-risk variant of OPN (rs9138C) was associated with higher serum OPN and IFN-alpha in men (P=0.0062 and P=0.0087, respectively). In women, the association between rs9138 C and higher serum OPN and IFN-alpha was restricted to younger subjects, and risk allele carriers showed a strong age-related genetic effect of rs9138 genotype on both serum OPN and IFN-alpha (P0.0001). In African-American subjects, the 5' region single nucleotide polymorphisms, rs11730582 and rs28357094, were associated with anti-RNP antibodies (odds ratio (OR)=2.9, P=0.0038 and OR=3.9, P=0.021, respectively). Thus, we demonstrate two distinct genetic influences of OPN on serum protein traits in SLE patients, which correspond to previously reported SLE-risk variants. This study provides a biologic relevance for OPN variants at the protein level, and suggests an influence of this gene on the IFN-alpha pathway in SLE.

The effects of identical morning (08.05 hours) and evening (20.05 hours) meals on intragastric pH were compared in 12 healthy volunteers receiving gastric antisecretory medication. Dosing included continuous intravenous infusion ranitidine (50 mg bolus followed by 12.5 mg/h) or a matching placebo which were randomly administered prior to and following 7 days of treatment with oral omeprazole (40 mg mane). Intragastric pH was monitored continuously using a tethered indwelling pH probe. Subjects were divided into groups, one of which began the pH monitoring session in the morning, the other in the evening. The median 24-h intragastric pH was significantly increased by all active dosing regimens (P less than 0.05). Combined omeprazole and ranitidine produced the highest median pH, 5.92. However, a breakthrough drop in intragastric pH occurred during the evening after all active dosing. Intragastric pH fell prior to and after consumption of the evening meal with median pH values less than 4 during all sessions. The evening meal led to significantly lower intragastric pH compared to the morning meal for omeprazole and the combined omeprazole and ranitidine dosing periods (P less than 0.05). There was no difference between morning and evening pH during the placebo or ranitidine periods. Ranitidine and omeprazole, either alone or in combination, were unable to prevent the meal-stimulated decline in intragastric pH during the evening time period.

SUMMARY H2-receptor antagonist drug therapy is the mainstay of peptic ulcer treatment in the USA. About 75 % of patients in intensive care units receive parenteral H2-antagonists. The rationale for their use is that parenteral H2-antagonists offer about a four-fold protective effect compared with placebo against significant upper gastrointestinal haemorrhage. Parenteral administration of H2-receptor antagonists appears to be preferred to oral antacid or sucralfate regimens because of ease of administration and, perhaps, lower treatment costs. Recommended dosage schedules for intravenously administered H2-receptor antagonists are at fixed intervals, 6- to 8-h intervals for cimetidine and ranitidine and 12-h intervals for famotidine. These dosage schedules assume a fixed dose-response relationship (i.e. a given dose of H2-antagonist results in equivalent acid suppression throughout the circadian, or 24-h, period). However, human basal gastric acid secretion exhibits circadian variation, with peak rates occurring during the evening hours. Recent evidence from 24-h continuous intragastric pH studies in fasting patients with healed duodenal ulcer suggests that larger doses of intravenous H2-antagonists are required in the evening than in the morning to achieve equivalent acid suppression. These findings are consistent with a changing H2-antagonist dose/acid-inhibiting response over the circadian period. Continuous infusion has the advantage of providing consistent and sustained suppression of gastric acid secretion in patients at risk for stress ulceration. Results of a double-blind, randomized, crossover study indicated that equally effective suppression of acidity and time-to-onset of pharmacological effect can be achieved with and without priming bolus doses of ranitidine, and presumably other H2-receptor antagonists as well. Furthermore, continuous intravenous H2-antagonist therapy, compared with intravenous bolus administration, appears to offer more effective control of 24-h pH at a reduced cost. These cost savings may be augmented by administration of the H2-antagonist with the patient's total parenteral nutrition.

Antimicrobial compounds are widespread, emerging contaminants in the aquatic environment and may threaten ecosystem and human health. This study characterized effects of antimicrobial compounds common to human and veterinary medicine, aquaculture, and consumer personal care products [erythromycin (ERY), sulfamethoxazole (SMX), oxytetracycline (OTC), and triclosan (TCS)] in the grass shrimp Palaemonetes pugio. The effects of antimicrobial treatments on grass shrimp mortality and lipid peroxidation activity were measured. The effects of antimicrobial treatments on the bacterial community of the shrimp were then assessed by measuring Vibrio density and testing bacterial isolates for antibiotic resistance. TCS (0.33 mg/L) increased shrimp mortality by 37% and increased lipid peroxidation activity by 63%. A mixture of 0.33 mg/L TCS and 60 mg/L SMX caused a 47% increase in shrimp mortality and an 88% increase in lipid peroxidation activity. Exposure to SMX (30 mg/L or 60 mg/L) alone and to a mixture of SMX/ERY/OTC did not significantly affect shrimp survival or lipid peroxidation activity. Shrimp exposure to 0.33 mg/L TCS increased Vibrio density 350% as compared to the control whereas SMX, the SMX/TCS mixture, and the mixture of SMX/ERY/OTC decreased Vibrio density 78-94%. Increased Vibrio antibiotic resistance was observed for all shrimp antimicrobial treatments except for the mixture of SMX/ERY/OTC. Approximately 87% of grass shrimp Vibrio isolates displayed resistance to TCS in the control treatment suggesting a high level of TCS resistance in environmental Vibrio populations. The presence of TCS in coastal waters may preferentially increase the resistance and abundance of pathogenic bacteria. These results indicate the need for further study into the potential interactions between antimicrobials, aquatic organisms, and associated bacterial communities.

The dramatically higher surface area of mesoporous silica in comparison to commercially available Chromatographie grade silica enhances resolution of molecules by increasing capacity factors to allow effective separations of analytes. In this report, we illustrate the use of these types of silica in normal phase HPLC, reverse phase HPLC, and chiral HPLC.

Retroviral gene transfer of dominant selectable markers into hematopoietic cells can be used to select genetically modified cells in vivo or to attenuate the toxic effects of chemotherapeutic agents. We show that retroviral gene transfer of thymidylate synthase (TS) confers resistance to TS directed anticancer agents and that co-expression of TS and dihydrofolate reductase (DHFR) confers resistance to TS and DHFR cytotoxic agents. Retroviral vectors encoding Escherichia coli TS, human TS, and the Tyr-to-His at residue 33 variant of human TS (Y33HhTS) were constructed and fibroblasts transfected with these vectors conferred comparable resistance to the TS-directed agent fluorodeoxyuridine (FdUrd, approximately 4-fold). Retroviral vectors that encode dual expression of Y33HhTS and the human L22Y DHFR (L22YhDHFR) variants conferred resistance to FdUrd (3- to 5-fold) and trimetrexate (30- to 140-fold). A L22YhDHFR-Y33HhTS chimeric retroviral vector was also constructed and transduced cells were resistant to FdUrd (3-fold), AG337 (3-fold), trimetrexate (100-fold) and methotrexate (5-fold). These results show that recombinant retroviruses can be used to transfer the cDNA that encodes both TS and DHFR and dual expression in transduced cells is sufficiently high to confer resistance to TS and DHFR directed anticancer agents.

A fluke egg was identified in a probably human coprolite recovered from a Glen Canyon Utah site of prehistoric inhabitation. True parasitism with the fluke could have resulted from eating snails or fish. False parasitism could have resulted from eating a wide variety of mammals known to have lived in the region. This finding identifies another potential medical hazard in the life of man in prehistoric North America.

Cytotoxic anti-cancer drugs are meant to interact with tumor cells to impair the replicative and/or transcriptional functions of DNA in order to reduce proliferative rate and cause cell death. These drugs also affect rapidly proliferating healthy tissues such as the bone marrow and the gastrointestinal tract, thereby resulting in toxicity-related dose reductions and/or delays in treatment. We previously demonstrated a circadian rhythm in DNA synthesis (S-phase) of total bone marrow (BM) nucleated cells in 16 healthy, diurnally active men sampled every 4 h for 24 h (19 series). Highest values de- termined by flow cytometry were found near midday. We also reported a circadian rhythm in DNA synthesis of the rectal mucosa (RM) in 16 healthy men sampled every 2-3 h for 24 h under fed and fasting conditions (24 series). Highest proliferative activity as reflected by in vitro (3H)Tdr uptake, was found near the time of awakening. Circannual (about yearly) rhythmicity in cell division Characteristics of circadian amplitudes and acrophases were also compared between seasons. In addition to a significant circadian rhythm, a significant circannual rhythm in cell proliferation in healthy BM (P = 0.008) and RM (P < 0.001) could be established on the basis of these serially independent data. The range between the lowest and highest points of the fitted 1 year cosine (cir- cannual double amplitude) was comparable to the circa- dian range for BM (25%); it was at least doubled for RM (70%). Highest values occurred in the late summer for BM and mid-fall for RM. Based on limited data in some seasons, the circadian patterns were more prominent in the fall and winter, with larger amplitudes and later acrophases, when compared with summer for BM and spring and summer for RM. Thus, in addition to time of day, time of year may influence chemo- and immunother- apeutic strategies and should be considered in the design of preclinical and clinical treatment regimens and other procedures.- Sothern, R. B., Smaaland, R., Moore, J. G. Circannual rhythm in DNA synthesis (S-phase) in health human bone marrow and rectal mucosa. FASEBJ. 9, 397-403 (1995)

Fault lengths, distributions and orientations were determined at six post-Jurassic horizons in the Porcupine Basin, offshore Ireland. Three rifting periods occurred in the Porcupine Basin with fault orientations and lengths measured for the second and third of these. Dominant fault directions changed through time, while remaining broadly parallel to the basin margins, particularly in the southern part of the basin and especially for the larger faults. Observed changes in activity suggest that strain was evenly distributed throughout the basin during the periods of extension. Length population curves for the faults throughout the basin show an approximate straight line log-log relationship between cumulative number and fault length, indicating that the fracture length populations are self-similar over a range of scales. The fault patterns reflect the response to the transition from a syn-rift dominant phase of basin evolution to one where the development was primarily influenced by thermal subsidence with subsidiary rifting.

About 6,000 specific-gravity (SG) measurements of samples collected from nearly 200 granitic plutons comprising the central Sierra Nevada batholith yield a SG contour map across the batholith from 36.25° to 38° north latitude. With notable exceptions, SG decreases from values generally greater than 2.7 in the west to less than 2.6 over a few small areas of high-silica, high-potassium granites near the east edge. A good correlation between measured SG and analyzed weight percent SiO2 enables estimation of average silica variations across the batholith. The average SG is 2.69 corresponding to an average of 68 wt. % SiO2 for the 18,000 km² central part of the batholith. A 1-km gridded version of the SG measurements has been used to generate a series of synthetic gravity maps, assuming that the SG of rocks at the surface extends unchanged to various depths. The synthetic map computed for a depth of 10 km shows the best correspondence with the isostatic residual gravity map indicating that variations in the observed gravity residuals are largely caused by SG variations of the plutonic rocks exposed at the surface that apparently extend downward to an average depth of about 10 km. Although the 10-km synthetic gravity map gives the best overall fit to the observed gravity data, comparison of individual anomalies indicates that the bottoms of the plutons as defined by SG variations at the surface are generally shallower along the west edge of the Sierra Nevada (7±2 km) and deeper in the younger and more felsic eastern part (12±3 km). These depths do not necessarily represent a distinct base of the Sierra Nevada batholith. They may indicate the depth below which density homogenization occurs, either by igneous, or possibly, structural processes.

The Porcupine, Rockall and Hatton–Rockall basins lie on the continental seaboard west of Ireland. Up to 9 km of Cretaceous and Tertiary strata are preserved in the Porcupine Basin, in contrast to 2–3 km in the Rockall and Hatton–Rockall basins. Differences in seismic stratigraphic sequences through the region are attributed to an interplay between the developing North Atlantic Ocean, post-rift thermal subsidence and sea-level changes. Localized Ryazanian fault-controlled alluvial fan clastic rocks in the Porcupine Basin are succeeded by Valanginian to Barremian marine deposits. Sea-level lowstands in Albian and Paleocene–Eocene times, interpreted as rift and ridge-push effects respectively, resulted in delta and submarine fan progradation. Rapid thermal subsidence in Early Oligocene times led to marine deposits and to the onset of geostrophic currents. Miocene slumping triggered shale-dominant turbidite development, followed by tranquil deep marine sediments as subsidence outstripped sedimentation. The Cretaceous sequence in the Rockall Trough is thought to contain extensive igneous bodies overlain by an Upper Cretaceous muddy chalk sequence which is cut by abundant Tertiary sills and dykes. A number of shale-prone Upper Tertiary sequences occur. The Upper Cretaceous to Lower Tertiary succession is thin and frequently absent in the Hatton–Rockall Basin.

Fluorescence in situ hybridization (FISH) is a validated method for detection of HER-2/neu gene amplification and was recently approved by the FDA for diagnostic use in paraffin-embedded tissue. Its use in cytologic specimens, however, has not been investigated. To see whether HER-2/neu gene amplification is detectable in cytologic specimens, we examined touch imprints and corresponding tissue sections of 27 breast carcinomas (20 invasive and 7 in situ) and 3 atypical epithelial hyperplastic lesions, using the FISH technique with the HER-2/neu DNA probe kit (Vysis, Inc., Downers Grove, IL). HER-2/neu gene amplification was determined, using the ratio of HER-2/neu:CEP 17 signal counts; a ratio of 2.0 or greater was considered amplified. Successful hybridization occurred in 55/60 (92%) slides. In all cases, at least one of the paired slides was adequate for evaluation. Whole-cell imprint and tissue section slides yielded comparable HER-2/neu:CEP 17 signal counts and ratios, including one case of low-level HER-2/neu gene copy numbers where the ratio was 2.0. Our findings indicate that whole-cell imprint cytology preparations are a reliable medium for HER-2/neu gene quantification by FISH, and may substitute for or complement tissue section analysis.

Binding of multivalent glycoconjugates by lectins often leads to the formation of cross-linked complexes. Type I cross-links, which are one-dimensional, are formed by a divalent lectin and a divalent glycoconjugate. Type II cross-links, which are two or three-dimensional, occur when a lectin or glycoconjugate has a valence greater than two. Type II complexes are a source of additional specificity, since homogeneous type II complexes are formed in the presence of mixtures of lectins and glycoconjugates. This additional specificity is thought to become important when a lectin interacts with clusters of glycoconjugates, e.g. as is present on the cell surface. The cryst1al structure of the Glc/Man binding legume lectin FRIL in complex with a trisaccharide provides a molecular snapshot of how weak protein-protein interactions, which are not observed in solution, can become important when a cross-linked complex is formed. In solution, FRIL is a divalent dimer, but in the crystal FRIL forms a tetramer, which allows for the formation of an intricate type II cross-linked complex with the divalent trisaccharide. The dependence on weak protein-protein interactions can ensure that a specific type II cross-linked complex and its associated specificity can occur only under stringent conditions, which explains why lectins are often found forming higher-order oligomers.

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor TS affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and TS was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.

Primary undifferentiated carcinoma of the salivary glands is a rare, high-grade neoplasm which accounts for a very small number (1-5.5%) of malignant salivary gland tumors. The large-cell variant (LCU) is less well-characterized than the small-cell form. We report on the fine-needle aspiration (FNA) biopsy findings of 2 cases of LCU, one arising in the parotid gland, and the other in a buccal mucosa accessory salivary gland. The 2 cases were similar in composition: isolated and loosely cohesive large cells with abundant cytoplasm, and variability pleomorphic nuclei with prominent nucleoli. One case also featured multinucleated tumor giant cells and macrophage polykaryons; the latter has not previously been described in FNA biopsies of LCU. There was no evidence of squamous, myoepithelial, or widespread mucinous differentiation by morphological, cytochemical, or immunohistochemical analyses (focal rare mucin production identified on special stains in one case). The differential diagnosis is lengthy and consists of other high-grade primary salivary gland malignancies as well as metastatic lesions, including melanoma. The pattern of immunohistochemical reactivity (positive keratin, negative S-100, and HMB-45 antigens), and lack of conspicuous mucin production of significant lymphoidinfiltrate, were useful in establishing the correct diagnosis.

The total unsteadiness downstream of an axial compressor rotor was studied computationally using a 3-D Navier-Stokes solver. In the mean flow direction, the total unsteadiness was calculated and comparisons were made at the rotor exit with the experimental data. Based on a more general definition of total unsteadiness in any direction the total unsteadiness in the direction normal to the mean flow and in other directions is also discussed. The calculation results show that both the turbulence kinetic energy and the wake velocity deficit make important contributions to the total unsteadiness downstream of the rotor. The good agreement at the rotor exit between the calculated and the measured total unsteadiness suggests that steady flow NavierStokes codes with two-equation turbulence models can be useful tools for studying the flow unsteadiness in axial-flow turbomachinery.

Elevated aluminum concentrations have been implicated in several disease states in the elderly. We examined the effects of sucralfate, a basic aluminum salt of sucrose sulfate, and ranitidine, administered individually and in combination, on plasma and urine aluminum concentrations in the elderly in a prospective, randomized, three-arm crossover study. Subjects were 20 healthy volunteers over age 65 years, with no clinically significant comorbidities or recent use of aluminum-containing drugs or histamine (H)2-antagonists. The three regimens were ranitidine 300 mg at bedtime, sucralfate 1 g 4 times/day, and ranitidine 300 mg at bedtime plus sucralfate 1 g 4 times/day, administered for 4 weeks, with a washout period of at least 1 week between regimens. Plasma and urine aluminum concentrations were measured on days 0, 1, 7, 14, and 28 of each regimen. After 28 days, mean plasma aluminum concentrations were significantly higher in subjects receiving sucralfate alone (8.5 +/- 1.8 micrograms/L) and sucralfate plus ranitidine (5.1 +/- 1.3 micrograms/L) compared with those receiving ranitidine alone (2.4 +/- 0.7 micrograms/L). Urine aluminum concentrations were significantly higher in subjects receiving sucralfate alone (133.2 +/- 32.8 micrograms/g creatinine) and sucralfate plus ranitidine (148.1 +/- 51.9 micrograms/g creatinine) compared with those receiving ranitidine alone (11.0 +/- 3.7 micrograms/g creatinine). There was no significant difference in plasma or urine aluminum concentrations between subjects who received sucralfate alone versus those who received sucralfate plus ranitidine. Sucralfate 4 g/day in elderly subjects produces a significant increase in both plasma and urine aluminum concentrations, compared with ranitidine 300 mg/day. This increase most likely is secondary to gastrointestinal absorption of aluminum in the sucralfate formulation. The clinical relevance of this increase requires further evaluation.

Extensional tectonism is clearly a major factor in the formation of sedimentary basins. Tectonism influences many of the factors which control sediment deposition and preservation including: rates and styles of basin subsidence, accommodation space, drainage area size and topography, and rates of sediment input. These tectonically-influenced factors are interrelated and their local interplay determines, to a great extent, the formation, composition and structural style of sedimentary sequences.

An automated method of running a tandem sequence of oligonucleotide affinity columns was used to purify factors that interact specifically with cis-regulatory sites of the CyIIIa cytoskeletal actin gene of the sea urchin embryo (Strongylocentrotus purpuratus). The method allows quantitative enrichment in a single chromatographic run of up to 12 different sequence-specific DNA binding proteins, each of which may then be readily purified to homogeneity by methods such as preparative gel electrophoresis. The affinity chromatography and identification of six different CyIIIa-regulatory factors is described, and the general utility of the method is discussed.

Rhythmicity characterizes many functions of the human organism, including those of the gastrointestinal (GI) system. Important and significant time-dependent changes have been documented in GI motility patterns [1, 2], drug intestinal absorption rates [3, 4], small bowel mucosal enzyme activities [5], mucosal DNA synthesis rates [6], and gastric acid secretion [7], among others [8]. The literature on chronobiologically oriented investigations in humans and animals, at both the organ and cellular level, is vast and beyond the scope of this discussion. This review will focus only on large amplitude rhythms of human GI motor, absorptive, and secretory function with real or potential influence on disease expression and/or treatment. Circadian rhythms will be emphasized although important ultradian rhythms of GI function will also be mentioned.

Reports on the existence of a lag phase before solid-food gastric emptying are conflicting. We studied solid-phase gastric emptying in ten normal-weight male subjects using two opposed cameras and continuous monitoring. Each ingested a 300-g meal containing 99mTc-labeled liver pate. Identical computer-interfaced cameras continuously monitored gastric activity from anterior and posterior projections. Lag phase was determined by three techniques: (1) inspection of the emptying curve; (2) time to a 2% decrease in stomach activity; and (3) the time of visual appearance of duodenal activity. A short lag phase time was found using all methods, averaging 8.6 min. We concluded that a short solid meal lag phase exists that can be missed with conventional radionuclide gastric emptying methods not employing continuous measurements.

Radionuclide studies are widely used to estimate the gastric emptying rate of solids and liquids. Unfortunately, these methods carry the risk of radiation exposure and require expensive and complex equipment. Carbon-13, a stable, nonradioactive isotope, has been used successfully as a marker in the gastrointestinal tract for other purposes. A preliminary study using ingested NaH13CO3 and measuring 13CO2 breath excretion suggested that this test might be a simple, noninvasive, and inexpensive method for determining gastric emptying. To determine the efficacy of NaH13CO3 as a noninvasive marker for gastric emptying, the resulting 13CO2 breath excretion was determined simultaneously with standard radiolabeled meal measurements of gastric emptying of liquids and solids in 15 patients. 13CO2 breath excretion did not correlate with the gastric emptying of either solids or liquids, as determined by radionuclide techniques. These results suggest that NaH13CO3 is not a reliable indicator of gastric emptying. Factors other than gastric emptying may affect the rate of 13CO2 absorption and exhalation, rendering it unreliable as a measure of gastric emptying.

Stress-related gastric mucosal damage is a common occurrence in intensive care unit (ICU) patients. Because of the significant morbidity and mortality associated with this mucosal damage, many ICU patients routinely receive prophylactic therapy, usually with histamine H2-receptor antagonists (H2RAs). Gastric acid secretion occurs in a circadian pattern, with late afternoon and evening surges. H2RAs by continuous infusion may control this uneven pattern of secretion more effectively than H2RAs given by bolus injection. More studies are needed to identify the target ICU population for prophylactic treatment.

Circadian rhythmic variation has been documented in gastric, small bowel and colonic motility. Morning and evening studies of esophageal motility were performed to assess whether similar rhythmicity exists in esophageal function. Fifteen healthy male subjects were studied twice on separate study days. Esophageal manometry was performed either at 10 AM or 10 PM after a standardized meal given 10 h prior to each study. Lower esophageal sphincter pressures, distal esophageal contractile amplitudes, distal esophageal contractile durations, and the velocity of propagation of peristaltic waves in the proximal and distal esophagus were measured. No significant differences were detected in esophageal function between day and night studies. These findings suggest either 1) nocturnal slowing of gastrointestinal motility is not a generalized characteristic of the entire GI tract, or 2) a two time-point study is not adequate to detect a true circadian rhythm in esophageal motor function.

The effects of Reynolds number on flow through a tip gap are investigated by performing laminar flow calculations for an idealized two-dimensional tip gap geometry. The results of the calculations aid in understanding and reconciliation of low Much number turbine tip gap measurements, which range in tip gap Reynolds number from 100 to 10,000. For the higher Reynolds numbers, both the calculations and the measurements show a large separation off the sharp edge of the blade tip corner. For a high Reynolds number, fully turbulent flow calculations were also made. These also show a large separation and the results are compared with heat transfer measurements. At high Mach numbers, there are complex shock structures in the tip gap. These are modeled experimentally using a water table.

Anti-thymocyte globulin (ATG) provides effective therapy for many patients with aplastic anemia, and its mechanism of action has been presumed to be secondary to lymphocytotoxicity. However, our studies of lymphocyte function in aplastic anemia show marked abnormalities of lymphokine production, which ATG may modulate. In 12 of 17 patients with aplastic anemia, interleukin 2 (IL2) production was markedly elevated in vitro (P less than .01 by paired statistical analysis). Expression of the IL2 receptor, or Tac antigen, on peripheral lymphocytes assessed by flow microfluorometry was also increased above the normal range in 11 of 15 cases. Studies of ATG suggested that it might act to stimulate lymphocyte function. In vitro, ATG is a mitogen, as measured by incorporation of 3H-thymidine into blood mononuclear cells; the response of cells to ATG from patients with aplastic anemia was exaggerated in comparison with normals. Cell proliferation was accompanied by production of IL2 to levels that were, in some cases, similar to those obtained with lectin stimulation. Finally, supernatants from lymphocytes cultured in the presence of ATG were able to replace adherent cells in providing growth factors for the support of nonadherent cells in methylcellulose hematopoietic colony assays. These results provide a mechanism for an “immunostimulatory” action of ATG in effecting hematopoietic response in some patients with aplastic anemia.

Radio wave and optical experiments were conducted onboard a U.S. Air Force research aircraft in March 1977 and March 1978 at low magnetic latitudes to investigate the effects of F region electron density irregularities on transionospheric communications links. Imaging photometer, ionosonde, and satellite amplitude scintillation measurements were used to monitor the development and motion of F region 6300-A O I airglow depletions, spread F, and scintillation producing irregularities that are all associated with low-density bubbles in the postsunset equatorial ionosphere. The 6300-A airglow depletions are the bottomside signature of low plasma density within the bubbles. Examples of multiple airglow depletions and their relation to variations in the F layer virtual height (h′F) and to the occurrence of amplitude scintillations on 250-MHz satellite signals are described. Estimates of the average bottomside electron density, from simultaneous ionosonde measurements and 6300-A airglow intensities, show electron density decreases of ∼66% within the bubbles. These decreases are approximately the same for bubbles observed at the magnetic equator and near Ascension Island (18°S magnetic latitude). The measurements at Ascension Island show that airglow depletions extend away from the magnetic equator into the southern 6300-A intertropical arc. Variations in the maximum poleward extent of airglow depletions and of associated ionospheric irregularities that give rise to amplitude scintillations were observed. These latitudinal variations are interpreted, using field line mapping considerations, as variations in the maximum altitude of plasma bubbles over the magnetic equator. A north-south flight confirms that the overall pattern of airglow depletions and associated ionospheric irregularities extends continuously across the magnetic equator to ±15° magnetic latitude.

Calculations of three-dimensional viscous flow in the impeller of a centrifugal compressor are used as the basis of a study of the thermodynamics of the compression process. Flow in a high hub-tip ratio low specific speed impeller of approximately 3.4:1 pressure ratio is considered. Results are presented showing the work and loss production processes in the impeller. A strong influence of tip-leakage flow on the performance of this unshrouded wheel is found.

First results are reported of a comprehensive campaign to measure ionospheric structure and dynamics of nighttime polar cap F‐layer or F‐region arcs. Airborne optical and digital ionosonde data were collected simultaneously with ground based incoherent scatter radar data, continuously over many hours in time and 500 to 1000 km in space. Polar cap F‐region sub‐visual auroral arcs, which are commonly observed during quiet magnetic conditions, are found to represent boundaries (or shears) in the polar cap plasma circulation pattern. F‐region electron concentration enhancements are found in these features and can be of significance to polar thermospheric circulation, composition, and thermal structure. The quiet polar ionosphere is so structured that high time resolution intensified optical images of thermospheric emmissions can make a major contribution to interpretation of incoherent scatter radar data.

A partially-parabolic calculation procedure is used to calculate flow in a centrifugal impeller. This general-geometry, cascade-flow method is an extension of a duct-flow calculation procedure. The three-dimensional pressure field within the impeller is obtained by first performing a three-dimensional inviscid flow calculation and then adding a viscosity model and a viscous-wall boundary condition to allow calculation of the three-dimensional viscous flow. Wake flow, resulting from boundary layer accumulation in an adverse reduced-pressure gradient, causes blockage of the impeller passage and results in significant modifications of the pressure field. Calculated wake development and pressure distributions are compared with measurements.

Initial alterations in fetal hemoglobin (HbF) production among eight sickle cell anemia subjects treated with hydroxyurea (Hu) are summarized. Four of these subjects had been previously treated with 5- azacytidine (5-aza). All subjects treated with Hu (50 mg/kg/d for three to five days) had suppression of their total reticulocyte counts by seven days, whereas the four subjects previously treated with 5-aza (2 mg/kg/d for three to five days) had increased reticulocyte counts at day 7. The effect of Hu on increasing the number of HbF-containing reticulocytes (F reticulocytes) is extremely variable, ranging from ten- to less than onefold differences in maximal posttherapy v pretherapy levels. Recovery from marrow suppression did not result in greater than twofold increases in F reticulocyte counts. Mean day 7 F reticulocyte levels in the four subjects treated with both Hu and 5-aza were 4.1 X 10/microL and 15.4 X 10(4)/microL, respectively. Among Hu-treated subjects, increased F reticulocyte production was correlated with low serum creatinine levels and rapid removal of Hu from the plasma. Furthermore, suppression of CFU-E colony formation on day 2 of therapy with Hu was inversely correlated with maximal F reticulocyte response. We conclude that where Hu treatment results in marrow toxicity (decreased reticulocyte counts, decreased CFU-E colony formation) HbF production is less likely to increase. Those sickle cell anemia subjects with minimal renal dysfunction (serum creatinine level, greater than 1.0 mg/dL) exhibit the most cytotoxicity and least F reticulocyte response to Hu.