Long-term treatment outcomes in edentulous patients with implant-fixed prostheses: the Toronto study

PURPOSE: The aim of this prospective study was to report long-term treatment outcomes (prosthetic and implant related) of edentulous patients treated with implant-supported fixed prostheses who participated in the first clinical implant study in North America. MATERIALS AND METHODS: Forty-five patients were treated with Br?nemark implants supporting a total of 47 fixed prostheses (42 mandibular and 5 maxillary) between 1979 and 1984. All patients were recalled regularly for comprehensive prospective clinical and radiographic assessments. RESULTS: Thirty-one patients (33 prostheses) attended a final recall visit in 2002; 71% of patients had been followed for 20 years (range 18 to 23 years), with overall prosthetic plan and implant outcome success rates of 84% and 87%, respectively. Mean marginal bone loss around the implants after the first year of loading was small (0.05 mm/year), with high individual variations. Poor oral hygiene, smoking history, and implant position appeared to be predictors of marginal bone loss. Prosthetic maintenance was ongoing and included fractured components and replacement of prostheses; the longevity of a fixed prosthesis for this group of patients was 8.39+/-5.30 years. CONCLUSION: This study confirmed the overall long-term treatment outcome success of patients treated with fixed prostheses supported by Br?nemark implants. Successful osseointegration with a small mean bone loss was maintained as study patients aged, although prosthetic maintenance was required. The latter consideration should be discussed with all patients seeking such treatment.     

Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion

BACKGROUND: Normothermic perfusion has been shown to resuscitate and maintain viability of non-heart-beating donor (NHBD) livers that have undergone significant warm ischemic injury. However, the logistics of clinical organ retrieval are complex, and a period of cold storage before warm preservation would simplify the process. We have investigated the effects of short duration of cold preservation before normothermic preservation on the function of porcine NHBD livers. METHODS: Porcine livers were subjected to 60 minutes of warm ischemia and then assigned to the following groups: group W (n=5), normothermic preservation for 24 hours; and group C (n=4), cold preservation in University of Wisconsin solution for 4 hours followed by normothermic preservation for 20 hours (total preservation time 24 hours). Outcome parameters that were measured included bile production, serum transaminases and hyaluronic acid levels (cellular damage), and base deficit and glucose use (metabolic function). RESULTS: Group W livers had superior bile production, metabolic activity (base deficit and greater glucose use), and less evidence of hepatocellular damage (alanine aminotransferase, aspartate aminotransferase), and sinusoidal endothelial cell dysfunction (hyaluronic acid). Group C livers showed greater necrosis and destruction of architecture on histology. CONCLUSION: Normothermic perfusion failed to resuscitate porcine livers after 60 minutes of warm ischemia and 4 hours of cold preservation. Even a short period of cold ischemia is significantly deleterious to the function of ischemically damaged (NHBD) livers.     

The molecular structure of the DNA fragments eliminated during chromatin diminution in Cyclops kolensis

Presumptive somatic cells of the copepod Cyclops kolensis specifically eliminate a large fraction of their genome by the process of chromatin diminution. The eliminated DNA (eDNA) remains only in the germline cells. Very little is known about the nature of the sequences eliminated from somatic cells. We cloned a fraction of the eDNA and sequenced 90 clones that total 32 kb. The following organizational patterns were demonstrated for the eDNA sequences. All do not contain open reading frames. Each fragment contains 1-3 families of short repeats (10-30 bp) highly homologous within families (87%-100%). Most repeats are separated by spacers up to 50 bp long. Homologous regions were found between fragments, motifs from 15-300 bp in length. Among fragments there occur groups in which the same motifs are ordered in the same fashion. However, spacers between the motifs differ in length and nucleotide composition. Ubiquitous motifs (those occurring in all fragments) were identified. Analysis of motifs revealed submotifs, each occurring within several motifs. Thus, motifs may be regarded as mosaic structures composed of submotifs (short repeats). Taken together, the results provide evidence of a high organizational ordering of the DNA sequences restricted to the germline. With this in mind, it appears incorrect to refer to this part of the genome as junk. Moreover, eDNA is redundant for only the somatic cells-its function is to be sought in germline cells.     

Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2

At the end of an immune response, most activated T cells spontaneously undergo programmed cell death (apoptosis). In the present study we show that all-trans retinoic acid (atRA), a major vitamin A metabolite, can inhibit the spontaneous apoptosis of activated human T lymphocytes in vitro. Isolated peripheral blood T lymphocytes were activated by 12-O-tetradecanoyl phorbol 13-acetate and cultured for up to 11 days without any further stimuli. With time, a gradual increase in cell death was observed. This spontaneous death of activated T cells was apoptotic, as demonstrated by cell shrinkage, DNA fragmentation and depolarization of the mitochondrial membrane. In the presence of physiological concentrations of atRA, the percentage of T cells exhibiting these apoptotic features was significantly reduced. After 5 days of stimulation, the percentage of TUNEL+ T cells decreased from 28 to 12% in the presence of atRA. The anti-apoptotic effect of atRA was mimicked by the retinoic acid receptor (RAR)-selective agonists 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and AM-580, and totally abrogated by the RAR-selective antagonist Ro 41-5253. Cytokines of the IL-2 family have been shown to improve the survival of activated T cells. Strikingly, we found that the ability of atRA to inhibit apoptosis was significantly correlated with its ability to increase the production of IL-2. Furthermore, a blocking anti-IL-2 receptor antibody completely abrogated the anti-apoptotic effect of atRA. Together, these results suggest that retinoic acid inhibits spontaneous apoptosis of activated T lymphocytes through a RAR-dependent increase in IL-2 production.     

Diagnostic blocks: a truth serum for malingering

Malingering is not a diagnosis. It is a behavior for which there are no established diagnostic criteria. Guidelines have been published according to which malingering might be suspected, but those guidelines do not discriminate between patients who are malingering and ones with genuine sources of chronic pain. In such patients, malingering cannot be proven, but it can be refuted if a genuine source of pain can be established. In patients with no apparent cause of pain, the source of that pain can be established using controlled diagnostic blocks. A positive response to diagnostic blocks demonstrates that the complaint of pain is genuine and, by implication, refutes any contention that the patient is malingering. When positive, diagnostic blocks provide objective data by which disputes based on opinion can be resolved, as to whether a patient is malingering or not. Negative responses do not exclude a genuine complaint of pain, for patients may have a source of pain that is not amenable to testing with diagnostic blocks. Diagnostic blocks have proved particularly useful in the investigation of spinal pain for which the cause is not evident on conventional medical imaging. They can also confirm or refute purported mechanisms of certain clinical features in complex regional pain syndromes.     

Genomics and proteomics tools for compound mode-of-action studies in drug discovery

A broad range of genomics and proteomics technologies are increasingly being integrated into emerging research fields such as pharmacogenomics, pharmacoproteomics, chemogenomics, chemical genetics, and chemical biology. Here we review applications of genomic and proteomic technologies to drug mechanism-of-action studies and how these are beginning to impact the drug discovery process.     

Clonidine increases caspase-3 mRNA level and DNA fragmentation in the developing rat brainstem

The densities of alpha2-adrenergic receptors, labeled by 3H-clonidine or 3H-RX821002, reach a peak in the rat brainstem during the first week of its life. This enables the agonist of alpha2-adrenergic receptor clonidine, which is used as a component of anaesthetic solution in infants and children, to have specific effects in this structure of the developing brain. Clonidine was injected into the fetal brain (5 microg in 5 microl of saline) or subcutaneously to the pups (1, 10 microg in 50 microl of saline) 3 days before investigation. Clonidine increased the level of apoptotic enzyme caspase-3 mRNA expression, as measured by RT-PCR and enhanced the DNA fragmentation, as determined by gel electrophoresis, in the brainstem of the 21-day-old fetuses and 8-day-old rats. In the cortex of 8-day-old rat, the alpha2-adrenergic receptors are at a much lower level than the brainstem. Clonidine treatment had no evident effects on caspase-3 mRNA level and DNA fragmentation in the cortex of an 8-day-old rat. The data suggest that clonidine facilitates cell death in the developing brainstem. This drug effect provides a potential mechanism whereby clonidine during early life could induce long-lasting alterations in brain neurochemistry, autonomic functions and behavior.     

Naltrexone for heroin dependence treatment in St. Petersburg, Russia

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main way HIV is being spread in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available.