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Pediatric oral health care in North Carolina has taken a unique path to its current form and will require similar innovation to counter headwinds to its continued success. This commentary describes that path and attempts to set a vision and strategy for the future that leverages Community Care of North Carolina's infrastructure and continues to promote the expansion of clinical guidelines for pediatric preventive oral health care for vulnerable populations.

Novel strategies are required to combat pox virus infections, whether caused by escape of viruses such as monkeypox from indigenous areas or intentional release of smallpox. Anti-smallpox drugs with a unique mode of antiviral action, inhibition of transcription termination, were known but not therapeutically useful. Using a combinatorial method, variants of the basic isatin-β-thiosemicarbazone structure were prepared and examined for cytotoxicity and antiviral activity in vaccinia virus- and cowpox virus-infected human cells. Potent and much more selective N-aminomethyl-isatin-β-thiosemicarbazones were discovered.

Phenylmethylphosphor-L-alaninate pronucleotides 7a, 7b, 8a, and 8b, cyclic phosphates 10a and 10b, and phosphates 11a and 11b derived from 2,2-bis(hydroxymethyl)methylenecyclopropane analogues 1a, 1b, 2a, and 2b were synthesized and evaluated for their antiviral activity. An improved protocol for the synthesis of analogues 1a, 1b, 2a, and 2b is also described. Phosphate 11a was the most effective agent against human and murine cytomegalovirus (EC50 0.25−1.1 μM). The Z-pronucleotides 7a and 7b had EC50 3.6−25.2 and 3−18.4 μM, respectively. The EC50 of cyclic phosphate 10a was 6.0−20 μM. The activity against Epstein−Barr (EBV) was assay-dependent. Pronucleotides 7a and 7b and phosphate 11a had EC50 2.3−3.4 μM against EBV/H-1, but 7b was cytotoxic (CC50 3.8 μM). Cyclic phosphate 10a was the only compound effective against EBV/Daudi (EC50 0.96 μM), but it was inactive in H-1 cells. Pronucleotide 7a was active against varicella zoster virus with EC50 6.3 and 7.3 μM, respectively, and hepatitis B virus (HBV, EC50 4.1 μM). Cyclic phosphate 10a was the most effective analogue against HBV (EC50 0.8 μM).

The Z- and E-isomers of fluoromethylenecyclopropane analogues 11a−d and 12a−d were synthesized, and their antiviral activities were evaluated. The purine (Z,E)-methylenecyclopropane carboxylates 13 and 24 were selectively fluorinated using lithium diisopropylamide, LiCl, and N-fluorobenzenesulfonimide to give (Z,E)-fluoroesters 22 and 25. Reduction with LiBH4 or diisobutylaluminum hydride gave after chromatographic separation Z-isomers 11a and 11e and E-isomers 12a and 12e. The O-demethylation of 11e and 12e afforded guanine analogues 11b and 12b. Fluorination of (Z,E)-cytosine and thymine esters 15 and 16 afforded (Z,E)-fluoroesters 26 and 27, which were resolved before the reduction to analogues 11c and 11d and 12c and 12d. Adenine Z-isomer 11a was the most effective against Towne and AD169 strains of human cytomegalovirus (HCMV, EC50 3.6 and 6.0 μM, respectively), but it was less effective against murine virus (MCMV, EC50 69 μM). Thymine Z-isomer 11d was effective against HSV-1 in BSC-1 cells (ELISA, EC50 2.5 μM) but inactive against HSV-1 or HSV-2 in Vero or HFF cells. All of the analogues with the exception of 12d were effective at least in one of the assays against Epstein−Barr virus (EBV) in Daudi or H-1 cells in a micromolar or submicromolar range. Cytosine and thymine Z-isomers 11c and 11d were active against varicella zoster virus (VZV) with EC50 0.62 μM. Adenine Z- and E-isomers 11a and 12a were effective against HIV-1 in MT-2 or MT-4 cells with EC50 12−22 and 2.3−7.6 μM, respectively, whereas only 12a was effective against hepatitis B virus (HBV) with EC50 15 μM. Analogues 11a and 12a were weak substrates for adenosine deaminase.

Abstract Freely propagating surface gravity waves are observed to slow down and to stop at a beach when the bottom has a relatively gentle upward slope toward the shore and the frequency range of the waves covers the most energetic wind waves (sea and swell). Essentially no wave reflection can be seen and the measured reflected energy is very small compared to that transmitted shoreward. One consequence of this is that the flux of the wave’s linear momentum decreases in the direction of wave propagation, which is equivalent to a time rate of change of the momentum. It takes a force to cause the time rate of change of the momentum. Therefore, the bottom exerts a force on the waves in order to decrease the momentum flux. By Newton’s third law (action equals reaction) the waves then impart an equal but opposite force to the bottom. In shallow (but finite) water depths the wave force per unit bottom area is calculated, for normal angle of incidence to the beach, to be directly proportional to the square of the wave amplitude and to the bottom slope and inversely proportional to the mean depth; it is independent of the wave frequency. Constants of proportionality are: 1/4, the fluid density and the acceleration of gravity. Swell attenuation near coasts and some characteristics of sand movement in the near-shore region are not inconsistent with the algebraic structure of the wave force formula. Since the force has a depth variation which is significantly faster than that of the dimensions of the particle orbits in the vertical direction, the bottom induces a torque on the fluid particles that decreases the angular momentum flux of the waves. By an extension of Newton’s third law, the waves also exert an equal but opposite torque on the bottom. And because the bottom force on the waves exists over a horizontal distance, it does work on the waves and decreases their energy flux. Thus, theoretically, the fluxes of energy, angular and linear momentum are not conserved for shoaling surface gravity waves. Mass flux, associated with the Stokes drift, is assumed to be conserved, and the wave frequency is constant for a steady medium.

The second generation of methylenecyclopropane analogues of nucleosides 5a−5i and 6a−6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation−elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g−5i and 6b, 6e, 6g−6i. Alkylation−elimination of N⁴-acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N⁴-benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine (25) with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC50 = 0.27−0.49 μM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC50 = 2.0−3.5 μM) whereas adenine Z-isomer 5a was less potent (EC50 = 3.6−11.7 μM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein−Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino- and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC50 ≈ 0.3 μM), whereas only the thymine Z-isomer 5d was active (EC50 = 4.6 μM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC50 = 7 μM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC50 = 3.3 μM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC50 = 4 μM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase.

A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N⁶-alkyl compounds 2a, 2b, 2c, 2d, 2e, 2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K2CO3 afforded O⁶-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S⁶-alkyl compounds 4h and 4i. The N⁶-alkyl derivatives 2a, 2b, O⁶ analogues 3a, 3c, 3h, 3i, and S⁶ compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.

Alkylation−elimination of adenine and 2-amino-6-chloropurine with gem-difluorocyclopropane dibromide 10 gave E- and Z-methylene−gem-difluorocyclopropanes 11a, 11b, 12a, and 12b and gem-difluorocyclopropenes 13a and 13b. Debenzylation of intermediates 11a, 11b, 12a, and 12b afforded E- and Z-methylenecyclopropanes 4a, 4b, 5a, and 5b. Hydrolysis of 2-amino-6-chloropurine derivatives 4b and 5b afforded guanine analogues 4c and 5c. Composition of products (except 14b) obtained from alkylation−elimination reflects thermodynamically controlled cyclopropene−methylenecyclopropene rearrangement. The E-isomer 4a was moderately active against human cytomegalovirus and along with the Z-isomer 5a was active against leukemia L1210 and solid tumors in vitro.

ABSTRACTDendrimers are large highly branched macromolecules synthesized from a polyfunctional core. They have shown a variety of biological properties, including, in some instances, antiviral activity. In this study, five dendrimers were evaluated for in vitro activity against herpes simplex virus (HSV) types 1 and 2 by cytopathic effect (CPE) inhibition and plaque reduction (PR) assay in human foreskin fibroblast cells. All of the compounds were active against both virus types in the CPE inhibition assay, in which drug was added to the cells prior to the addition of virus. Antiviral activity was reduced or lost in the PR assays, in which the cells were incubated with the virus before the drug was added. The prophylactic efficacy suggested that the dendrimers might have potential as topical microbicides, products intended to be applied to the vaginal or rectal mucosa to protect against sexually transmitted infections. Three dendrimers were evaluated for this application against genital HSV infection in mice. Two of the compounds, BRI-2999 and BRI-6741, significantly reduced infection rates when 15 μl of a 100-mg/ml solution was administered immediately prior to intravaginal challenge, and the most effective compound, BRI-2999, provided significant protection even when applied 30 min before challenge. This is the first report of microbicidal activity by dendrimers in vivo.

Two wooden buoyant croquet balls of identical weight (in air) were released simultaneously at the bottom of a swimming pool. One ball’s surface had grooves that were arranged in concentric rings. Water resistant wood putty filled the grooves of the second ball which was then sanded to make a smooth spherical surface. Small holes were drilled through the balls along the axes of the concentric rings to guide their vertical movement up taut lines held fixed at the bottom of the pool and at the top above the water surface. Twenty runs were made: the grooved ball reached the surface first in every run by a significant time difference. It is concluded that grooves on the surface of a ball can substantially reduce the frictional interaction between the water and the ball, compared with that on a ball with a smooth surface.

Die für ein Bewässerungsprojekt in Saudi Arabien hergestellte Proberinne aus Stahlfaserbeton lagerte 23 Jahre lang in Deutschland in Freien. Es wird über Zustand und die Ergebnisse von werkstoffmechanischen Untersuchungen an dem Bauteil berichtet.

Die Dauerhaftigkeit von Betonbauwerken wird in erster Linie durch die Nachbehandlung der Betonoberfläche bestimmt. Es werden verschiedene Möglichkeiten der Nachbehandlung zur Verminderung der Zwangsbeanspruchung vorgestellt und ihre Wirksamkeit beurteilt. Als optimal erweist sich die Unterwasserlagerung bzw. das Abdecken mit Folie oder Jute bei dauernder Feuchthaltung der Betonoberfläche während des Abbindens des Betons

The interaction between an ocean eddy and incoming swell is investigated numerically producing characteristic refraction patterns of wave number and energy. The velocity distribution in the model eddy follows observations off Pt. Conception that are discussed in Sheres and Kenyon in this issue. The energy refraction patterns exhibit focus regions (caustics) where wave energy is concentrated; adjacent regions have a reduced wave energy concentration. Due to the eddy-induced refraction of incoming Pacific swell frequently observed in the area, approximately 20 km of coastline near Pt. Conception and about 5 km of coastline south of Morro Bay (California) would have relatively high waves. The Santa Maria Basin in between, as well as part of the entrance to the Santa Barbara Channel, would have relatively low waves. These gradients of wave energy depend on the velocity distribution of the eddy and the group velocity of the waves. Change in both the velocities while maintaining their ratio constant produces the same refraction patterns in the limited number of cases that were tested. During the 30 days residency of the eddy off Pt. Conception, the gradients of wave energy were likely to be significant. The potential effect of such gradients on the momentum exchange between wind and water (wind stress) and between waves and surface flow are discussed briefly.

Observations of ocean features and their interaction near Pt Conception, California, are reported for a two-month period during the early spring of 1983 at the time of the El Nino. The development of a body of warm water into a clockwise rotating eddy is described and the observed increase in the spatial scale of the eddy is found to compare favourably with the value calculated rrom a model of geostrophic adjustment. The subsequent interaction of the warm core eddy with a cold coastal jet directed offshore is discussed in relation to the approximate one-month lifetime observed for the eddy. The interaction of the eddy with incoming swell, and the resulting gradients in wave energy and wind stress are discussed in an accompanying paper in this issue (Sheres and Kenyon 1989). The measurements in this report are based mainly on NOAA-7 infrared images, but in situ current and wind data from moorings and temperature and salinity data from a California Cooperative Fisheries Investigation (CALCOFI) cruise are used as well. Water velocities up to 55cm/s (averaged over 12-24 hours) were calculated from tracing temperature features in successive infrared images; they compare well with CALCOFI and moored near-surface current data, when available.

A systematic approach to the various common aesthetic problems of the lower lateral cartilages is presented. Since this approach and technique may be applied to a wide variety of problems, we have taken the liberty of calling this the universal tip. These concepts have emerged from study of the literature and have evolved over the past thousand rhinoplasties. A classification of lower lateral cartilage problems includes five basic variations: (1) the wide, amphorous, ill-defined tip, (2) insufficient projection of the tip, (3) overprojection of the tip, (4) dependent tip with lack of definition, and (5) asymmetrical tip. It is important to realize that any of these five categories may be found in various combinations with each other. The details and fundamental steps of this universal tip technique are presented along with illustrative case examples in each of the five basic variations. In approximately 4 percent of patients there is a postoperative asymmetry in the position of cartilaginous flaps in the region of the dome of the lower lateral cartilage. These abnormalities plus abnormal ridges or bossa can usually be corrected at the time of secondary surgery under local anesthesia.

A combination and modification of two existing methods, which involves balancing static and dynamic pressure differences between points along the surface and conserving mass through cross sections below the surface in the reference frame moving with the phase velocity, is applied to surface gravity waves of arbitrary amplitude in water of finite depth. For a given still water depth and wave height the method determines in closed form the phase velocity, wavelength, and wave profile of the stable wave. The main assumption is that the horizontal component of the fluid velocity be independent of depth. The motion is not assumed to be irrotational. The wavelength of the stable wave is found to be about 3.6 times the still water depth for infinitesimal amplitude, and at finite amplitude the wavelength decreases as the amplitude increases. Therefore, shallow water waves are concluded to be unstable even at infinitesimal amplitude, for which the assumption is accurate. Previously it has been argued that only at finite amplitude will shallow water waves change form as they propagate. The wave profile is found to be sinusoidal for infinitesimal amplitude and to be asymmetric at finite amplitude, the crests being higher and narrower and the troughs shallower and broader. These results are consistent with well-known theoretical work and laboratory measurements.

Pregnant female mice, after intravaginal inoculation with Herpesvirus hominis (HVH) type 2, developed vaginitis on days 5 to 7 after virus challenge, followed by hunching and hind limb paralysis on days 7 to 9 and death from encephalitis on days 9 to 11. After initial replication in the mucous membranes of the genital tract, virus spread to the spinal cord and ascended to involve the brain. Viremia or replication of H. hominis type 2 in the liver or spleen was not detected. Virus was cleared from vaginal secretions by days 8 to 10 after infection. Pregnant mice were more susceptible to the infection than nonpregnant mice. This experimental infection in female mice provides a model for genital herpesvirus infection and for herpesvirus infection and for herpesvirus encephalitis in which one can evaluate potentially promising antiviral chemotherapeutic agents.

Über den Einsatz von hochfestem Beton B 85 beim Bau eines 165 m hohen Hochhauses aus der Sicht der Qualitätssicherung, Herstellung und Baustoffprüfung. Die hohe Druckfestigkeit wurde im wesentlichen durch niedrigen Wasserzementwert unter Verwendung von Fliessmittel und Silicastaub erzielt.

Es wird die Entwicklung der Leistungsfähigkeit und Vielseitigkeit des Betons anhand einzelner Beispiele gezeigt. Neben der hohen Festigkeit, der einfachen Verarbeitung und Formgebung, werden auch wichtige Eigenschaften wie Dichtigkeit und Beständigkeit gegen aggresive Medien erläutert.

Die wichtigsten Entwicklungen beim Herstellen, Fördern und Verarbeiten von Beton sind der Transportbeton, die hydraulische Betonpumpe und das Fließ‐ mittel. Es wird im wesentlichen auf die Verwendung von Transportbeton eingegangen. Die Zusammensetzung von Transportbeton unterliegt im Gegensatz zum Baustellen‐ beton unmittelbar dem Wettbewerb. Die Baustelle muß dem Transportbetonwerk eindeutig und umfassend die jeweils benötigten Betoneigenschaften und Betonzusammensetzung beschreiben; die Bestellung nach Konsistenz und Druck‐ festigkeit reicht nicht aus. Auf die zunehmende Sortenvielfalt bei den Ausgangsstoffen und die damit verbundenen Risiken wird hingewiesen. Die Baustelle muß den Betonierablauf zusammen mit dem Transportbetonwerk planen und organisieren, damit der Betoneinbau unter dem Zeitdruck beginnender Hydratation auch sicher gelingt. Durch ein wirksames Kontroll‐ system ist sicherzustellen, daß der gelieferte Beton der Bestellung entspricht.

Es wird der Stand der Technik im Jahr 1976 für Einsatzmöglichkeiten und Anwendungsbedingungen für Fließbeton beschrieben.

New nucleoside analogues 14−17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N⁶,N⁶-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation−elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E ~ 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were converted to N⁶-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The ¹H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, ¹H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein−Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1−2.1, 0.04−2.1, and 0.8−5.6 μM), MCMV (IC50 2.1, 0.3, and 0.3 μM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 μM) and Daudi cells (IC50 3.2, 5.6, and 1.2 μM). Adenine analogue 14 was active against HBV (IC50 2 μM), VZV (IC50 2.5 μM), and HHV-6 (IC50 14 μM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.

Summary Some controlled clinical trials have demonstrated that early or immediate operation for acute cholecystitis produces better results than delayed operation or conservative treatment. From 1969 to 1983 397 patients have been operated for acute cholecystitis at the Surgical University Hospital Würzburg, the results are discussed here.

Summary The production and cost calculation of a surgical journal are dependent on several complicated factors, which are outlined. The attitude of authors and readers have changed. A vital question is whether or not English will continue to replace German as the international scientific language. The relevance of new communications media on the fate of today's journals is still unclear.

Summary The surgical patient is subjected to psychological stress through fear of pain, operation, anesthesia and finally death. The exact definition of psychic stress and the patient's resistance to it is even more problematic than the definition of somatic stress. It is the doctor's task to alleviate the psychic stress of the patient, to instill confidence and to recognise the limits of his resistance and finally to take all this into consideration in planning his treatment.