Effectiveness of Contour Augmentation with Guided Bone Regeneration: 10-Year Results.

In aesthetic sites, the integrity of the facial bone wall dimension in the anterior maxilla is jeopardized by physiologic and structural changes postextraction. An effective regenerative protocol is key to reestablish and maintain the hard and soft tissue dimensions over time. The present prospective case series study examined the effectiveness of early implant placement with simultaneous contour augmentation through guided bone regeneration with a 2-layer composite graft in postextraction single-tooth sites over an observation period of 10 y among 20 patients. The median peri-implant bone loss was 0.35 mm between the 1- and 10-y examination. A success rate of 95% was obtained, with pleasing aesthetic outcomes and a high median Pink Esthetic Score (8). Implant crowns (ICs) revealed significant median facial recession between IC10y and IC1y (0.17 mm). The facial bone wall dimensions were assessed by preoperative cone beam computed tomography and 2 subsequent scans taken at 6 and 10 y. The median facial bone wall thickness increased significantly from 0 mm at surgery to 1.67 mm at the 10-y examination. The facial vertical bone wall peak (DIC) was located at a median distance of 0.16 mm coronal to the implant shoulder. The facial vertical bone loss of DIC amounted to 0.02 mm between 6 and 10 y. Equivalence testing was performed for the null hypothesis of a difference of >0.2 mm per year between 2 respective time points, showing stable bone conditions. Modulating factors influencing the regenerative outcomes at 10 y were the preoperative proximal crest width and soft tissue thickness. In conclusion, the present study confirmed the long-term effectiveness of early implant placement with simultaneous contour augmentation through guided bone regeneration with a 2-layer composite graft in postextraction single-tooth sites offering stable bone conditions with low risks of mucosal recessions over an observation period of 10 y ( ClinicalTrials.gov NCT03252106).

Long-term stability of early implant placement with contour augmentation.

In this prospective case series study, 20 patients with an implant-borne single crown following early implant placement with simultaneous contour augmentation were followed for 6 years. Clinical, radiologic, and esthetic parameters were assessed. In addition, cone beam computed tomography (CBCT) was used at 6 years to examine the facial bone wall. During the study period, all 20 implants were successfully integrated, and the clinical parameters remained stable over time. Pleasing esthetic outcomes were noted, as assessed by the pink esthetic scores. None of the implants developed mucosal recession of 1 mm or more. The periapical radiographs yielded stable peri-implant bone levels, with a mean DIB of 0.44 mm at 6 years. The CBCT scans showed that all 20 implants had a detectable facial bone wall at 6 years, with a mean thickness of around 1.9 mm. In summary, this prospective case series study demonstrated stable peri-implant hard and soft tissues for all 20 implants, and pleasing esthetic outcomes overall. The follow-up of 6 years confirmed that the risk for mucosal recession is low with early implant placement. In addition, contour augmentation with guided bone regeneration (GBR) was able to establish and maintain a facial bone wall in all 20 patients.

The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage.

The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development. However, very little is known about the physiological mediators of cellular senescence induced by p53. CEACAM1 is an immunoglobulin superfamily member whose expression is frequently lost in human tumors and exhibits tumor-suppressor features in several experimental systems, including Ceacam1 knockout mice. There is currently little understanding of the pathways and mechanisms by which CEACAM1 exerts its tumor-suppressor function. Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway. Stable silencing of CEACAM1 showed that CEACAM1 is required for p53-mediated cellular senescence, but not initial cell growth arrest, in response to DNA damage. These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53.

Combined spinal-epidural analgesia for labor in a patient with Marfan's syndrome.

We report the management of a patient with Marfan's syndrome for labor analgesia and vaginal delivery using a combined spinal-epidural technique. The rapid onset of analgesia for the first stage of labor provided by the intrathecal opioid, combined with the slow and controlled onset of sensory anesthesia and sympathetic block provided by the dilute epidural local anesthetic, may make this technique particularly useful for labor and delivery in patients with Marfan's syndrome.

A chimeric MIP-1alpha/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors.

Human RANTES (CCL5) and MIP-1alpha (CCL3) bind and activate several CC chemokine receptors. RANTES is a high-affinity ligand for CCR1 and CCR5, and it binds CCR3 with moderate affinity and CCR4 with low affinity. MIP-1alpha has similar binding characteristics to RANTES except that it does not bind to CCR3. Here we have generated a chimera of human MIP-1alpha and RANTES, called MIP/RANTES, consisting of the eight amino terminal residues of MIP-1alpha preceding the CC motif, and the remainder of the sequence is RANTES. The chimera is able to induce chemotaxis of human monocytes. MIP/RANTES has >100-fold reduction in binding to CCR1 and does not bind to CCR3 but retains full, functional binding to CCR5. It has equivalent affinity for CCR5 to MIP-1alpha and RANTES, binding with an IC(50) of 1.12 nM, and is able to mobilize calcium and induce endocytosis of CCR5 in PBMC in a manner equi-potent to RANTES. It also retains the ability to inhibit R5 using HIV-1 strains. Therefore, we conclude that the amino terminus of RANTES is not involved in CCR5 binding, but it is essential for CCR1 and CCR3.

A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.

CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4(-/-)) mice by gene targeting. CCR4(-/-) mice developed normally. Splenocytes and thymocytes isolated from the CCR4(-/-) mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1alpha. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inflammation. However, CCR4(-/-) mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4(+/+) mice. After high dose LPS treatment, serum levels of tumor necrosis factor alpha, interleukin 1beta, and MIP-1alpha were reduced in CCR4(-/-) mice, and decreased expression of MDC and MIP-2 mRNA was detected in peritoneal exudate cells. Analysis of peritoneal lavage cells from CCR4(-/)- mice by flow cytometry also revealed a significant decrease in the F4/80(+) cell population. This may reflect a defect in the ability of the CCR4(-/-) macrophages to be retained in the peritoneal cavity. Taken together, our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.

The formation and early evolution of the Milky Way galaxy.

Recent observations indicate that the Milky Way may have formed by aggregation of gas and stars from a reservoir of preexisting small galaxies in the local universe. The process probably began more than 12 billion years ago with material of different original angular momentum following two separate evolutionary lines, one into the slowly rotating halo and central bulge and the other into the rapidly rotating disk. The existence of distinct thick and thin disks shows that continuing mergers of satellite galaxies likely also determined the early evolution of the main structural component of the luminous Galaxy.

Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors.

Modification of the amino terminus of regulated on activated normal T-cell expressed (RANTES) has been shown to have a significant effect on biological activity and produces proteins with antagonist properties. Two amino-terminally modified RANTES proteins, Met-RANTES and aminooxypentane-RANTES (AOP-RANTES), exhibit differential inhibitory properties on both monocyte and eosinophil chemotaxis. We have investigated their binding properties as well as their ability to activate the RANTES receptors CCR1, CCR3, and CCR5 in cell lines overexpressing these receptors. We show that Met-RANTES has weak activity in eliciting a calcium response in Chinese hamster ovary cells expressing CCR1, CCR3, and CCR5, whereas AOP-RANTES has full agonist activity on CCR5 but is less effective on CCR3 and CCR1. Their ability to induce chemotaxis of the murine pre-B lymphoma cell line, L1.2, transfected with the same receptors, consolidates these results. Monocytes have detectable mRNA for CCR1, CCR2, CCR3, CCR4, and CCR5, and they respond to the ligands for these receptors in chemotaxis but not always in calcium mobilization. AOP-RANTES does not induce calcium mobilization in circulating monocytes but is able to do so as these cells acquire the macrophage phenotype, which coincides with a concomitant up-regulation of CCR5. We have also tested the ability of both modified proteins to induce chemotaxis of freshly isolated monocytes and eosinophils. Cells from most donors do not respond, but occasionally cells from a particular donor do respond, particularly to AOP-RANTES. We therefore hypothesize that the occasional activity of AOP-RANTES to induce leukocyte chemotaxis is due to donor to donor variation of receptor expression.

Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.

The chemokine receptors CXCR4 and CCR5 have recently been shown to act as coreceptors, in concert with CD4, for human immunodeficiency virus-type 1 (HIV-1) infection. RANTES and other chemokines that interact with CCR5 and block infection of peripheral blood mononuclear cell cultures inhibit infection of primary macrophages inefficiently at best. If used to treat HIV-1-infected individuals, these chemokines could fail to influence HIV replication in nonlymphocyte compartments while promoting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activation of cells by chemokines is not a prerequisite for the inhibition of viral uptake and replication. Chemokine receptor antagonists like AOP-RANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1-infected individuals.

Effect of a training program on community pharmacists' detection of and intervention in drug-related problems.

OBJECTIVE: To develop and present a pharmaceutical care training program for pharmacists, and to examine the ability of these pharmacists to provide pharmaceutical care in a community pharmacy setting. DESIGN: Prospective, randomized study. INTERVENTION: A 40-hour pharmaceutical care training program was developed and presented to pharmacists, and 1,078 patients were randomly assigned to receive either (1) traditional pharmacy services or (2) pharmaceutical care, consisting of initial patient work-up and follow-up with documentation in a patient record. MEASUREMENTS: The study period was six months. Pharmacists documented problems identified, actions taken, and time required for all patients. RESULTS: Pharmacists consistently identified and intervened to address problems in both study groups. Patients receiving pharmaceutical care were more than seven times as likely to have any problems identified (odds ratio [OR] 7.5; confidence interval [CI] 4.2-13.1), more than eight times as likely to have an intervention performed (OR, 8.1; CI 4.7-14.2), and more than eight times as likely to have a drug-related problem identified (OR 8.6; CI 4.8-15.5) than were patients receiving traditional pharmacy services only. Time spent counseling patients was similar for the two groups. CONCLUSIONS: The training program proved to be an effective way to increase the number of problems identified and addressed by pharmacists.

Adrenalectomy, corticosteroid replacement and their importance for drug-induced memory-enhancement in mice.

Adrenalectomy blocks the memory-improving effect of piracetam-like compounds in mice. If this blockade is due to the removal of endogenous corticosteroids, replacement therapy with exogenous corticosteroids should reinstate the effects on memory. The present experiments were designed to determine the appropriate replacement dose (concentration in the drinking fluid) for corticosterone and aldosterone, the main corticosteroids in mice. Based on the effects of corticosterone on thymus weight, replacement with 3 micrograms/ml corticosterone given in the drinking fluid (0.9% NaCl) for one week was found to be appropriate. The appropriate replacement dose for aldosterone was found by giving aldosterone to adrenalectomized (ADX) mice in the drinking fluid in combination with 3 micrograms/ml corticosterone. The combination of 3 micrograms/ml corticosterone + 30 ng/ml aldosterone resulted in a plasma ratio of corticosterone/aldosterone which most closely approximated the ratio seen in sham-ADX control animals. The physiologic adequacy of the corticosteroid replacement doses resulting from this study were clearly demonstrated in subsequent behavioral experiments where blockade of the memory-enhancing effects of piracetam by adrenalectomy were overcome by replacement with either 3 micrograms/ml corticosterone or 30 ng/ml aldosterone given in the drinking fluid.

Decay kinetics of (4)F(3/2) fluorescence of Nd(+3) in YAG at room temperature.

By means of localized time constant measurements, the fluorescent behavior for the principal transition of YAG:Nd emanating from the (4)F(3/2) state has been analyzed at room temperature as a function of concentration. It is found that the overall decay process is the superposition of multiexponential components over the concentration range of 0.9-1.6 at. % of Nd. The dependence of decay rate on excitation intensity was examined to register monomolecular kinetics for the case associated with each exponential decay process. From these results it is predicted that the YAG:Nd crystals are inhomogeneously broadened in nature similar to glass.

Pulse code modulation of CO(2) TEA laser pulse.

The tail of the CO(2) TEA laser pulse has been successfully pulse code modulated with an electrooptic modulator. A CdTe crystal Pockels cell used in a double-pass configuration produced a train of optical pulses 100 nsec wide at a 5-MHz repetition rate. With this multifunctional capability, the CO(2)TEA laser can be utilized for both precision ranging and information transfer. A 92% depth of modulation was observed using this Pockels cell modulator configuration.

Index of refraction turbulence effects on thermal blooming in laboratory experiments.

A laboratory experiment has been carried out to determine the effect of index of refraction turbulence on thermal blooming for cw CO(2) laser radiation. The turbulence is generated by the forced mixing of two gases of different indices of refraction; helium and nitrogen. The thermal blooming is obtained by adding small amounts of propylene to the mixture. The construction of the test cell and methods of measuring the turbulence are discussed in detail. The experimental results are compared with the root-sum-squared (RSS) theory, i.e., that the blooming and turbulence effects may be considered separately and that the total beam area is given by A = (AO) + A(B) + A(T), where A(B) and A(T) are the increase in the time-averaged area of the beam due to blooming and turbulence. Agreement is excellent for the particular case considered.

Turbulence-degraded beam quality: improvement obtained with a tilt-correcting aperture.

In this paper, we have calculated the degradation in the focal-plane irradiance distribution due to atmospheric turbulence and the potential improvement realizable by employing a wavefront filt-correcting aperture. It has been shown that, when the aperture diameter is of the order of the outer scale of turbulence, virtually no improvement is realized relative to the uncompensated case. For the case when the long-term coherence length is small compared with the diameter, there is a several-decibel improvement over the longterm case; however, for a full phase-compensating aperture (e.g., COAT), peak intensity can be increased an additional several decibels. When the coherence length is not much smaller than the diameter, close to diffraction- limited performance can be expected. Comparisons are also made of the reduction of on-axis intensity with no compensation, tilt-correction, and a full phase-compensating aperture. It is shown that the effective coherence length of the compensated aperture due to the residual amplitude fluctuations is greater than the long-term coherence length by a factor proportional to the square root of the Fresnel number of the aperture. Approximate formulas are also presented for the tilt-corrected MTF for arbitrary aperture irradiance distributions.

Transient thermal blooming of long laser pulses.

Existing theory for stationary laser pulse propagation in absorbing media for times greater than the acoustic transit time is compared with experiments. Collimated and focused Gaussian beams as well as unstable resonator type beams are investigated. Good agreement is reached for all experimental conditions for collimated beams, and at higher energy deposition significant deviations are observed for focused beams.

Transient thermal blooming of single and multiple short laser pulses.

Energy transfer through absorbing media with pulses short compared to the acoustic transit time has been investigated experimentally and theoretically for collimated beams in a homogeneous wind field. Two experimental approaches were used: a low intensity cw CO(2) laser probe beam technique giving a continuous record of the lensing of the medium following the transmission of a coaxial high power TEA laser pulse and a direct determination of high power pulse train blooming using a thermofax covered drum. The experimental results support the predictions of a geometric optics perturbation solution as well as those of existing propagation codes. An interesting case, namely, enhancement resulting in a 20-30% increase of the original nonbloomed peak intensity is observed when the pulse separation time is approximately 1-2 times the wind flow time across the beam.

Phase Difference and Angle-of-Arrival Fluctuations in Tracking a Moving Point Source.

The correlation function and power spectrum of phase difference fluctuations and angle-of-arrival fluctuations are calculated for tracking a moving spherical wave optical source through atmospheric turbulence. For Kolmogorov turbulence, it is shown that, in order to freeze effectively the received wavefront, the scanning frequency must be essentially equal to the highest frequency contained in the power spectrum.