3-year prospective multicenter study on one-stage implant surgery and early loading in the edentulous mandible

Background: The long‐term success rates achieved in dental implantology suggest that flexibility might well exist within the various implant systems to a degree that an altered protocol (ie, one‐stage surgery and immediate or early loading) can be performed under controlled conditions. However, before variations of the protocol can be considered for general use, they must be subjected to critical analysis, particularly with respect to the predictability of osseointegration, alteration of soft tissue barrier, and relative change in bone height around the implants. Purpose: The aim of this prospective multicenter study was to evaluate implant survival and periimplant conditions around endosseous implants placed in a one‐stage surgical procedure and early loading. Materials and Methods: A total of 170 implants were placed in 40 patients with mandibular edentulism and were functionally loaded within 6 weeks with overdentures (n = 30) or fixed prostheses (n = 10). All patients and prosthetic constructions were evaluated according to a standardized protocol during 3 years of follow‐up. Cumulative implant survival rates were calculated, and implant loss in relation to implant size and bone quality and quantity were evaluated. Furthermore, the protocol included assessment of clinical (plaque and bleeding scores, prosthesis stability) and radiographic parameters. Results: Over a period of 3 years, the implant survival rate was 93% for both implants and prostheses (fixed or removable). No implants were lost after the first year of loading. The periimplant tissues were in a healthy condition. Mean marginal bone resorption from the time of loading to the 3‐year follow‐up was 0.41 mm (SD 0.52). Conclusions: From this study it may be concluded that early loading results in good implant survival and proper periimplant health in edentulous mandibles.     

Evidence for a single-step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia

High hyperdiploidy (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is characterized by nonrandom multiple trisomies and tetrasomies involving in particular chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21. This characteristic karyotypic pattern, the most common in pediatric ALL, may arise via a tetraploid state with subsequent loss of chromosomes, by sequential gains of chromosomes in consecutive cell divisions, or by simultaneous gain of chromosomes in a single mitosis. These alternatives may be distinguished by investigation of the allelic ratios of loci on the tetrasomic and disomic chromosomes. Previous studies of tetrasomy 21 and of the occurrence of uniparental disomies (UPDs) have suggested that the most likely mechanism is simultaneous gain. However, the other pathways have not been definitely excluded because complete analyses of all disomies and tetrasomies have never been performed. In the present study, we investigated 27 hyperdiploid ALLs by using 58 polymorphic microsatellite markers mapped to 23 of the 24 human chromosomes. Twenty-six tetrasomies were analyzed (involving chromosomes X, 8, 10, 14, 18, and 21), and the frequency of UPDs was determined in 10 cases. In total, 200 chromosomes were studied. Equal allele dosage was observed in 24 of 26 tetrasomies, and only 7 UPDs were found. These data strongly suggest that hyperdiploidy in childhood ALL generally arises by a simultaneous gain of all additional chromosomes in a single abnormal mitosis.     

Formation of der(19)t(1;19)(q23;p13) in acute lymphoblastic leukemia

The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)- and der(19)-positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)-both copies of a chromosome being derived from only one parent-for chromosome 1 would be present in all der(19)-harboring cases arising via the duplication pathway and in one-third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)- and four der(19)-positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1.     

Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies

Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in approximately 1% of karyotypically abnormal acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS). The MYC gene at 8q24 has been reported to be amplified in the majority of the cases, and generally it has been assumed that MYC is the target gene. However, only a few studies have focused on the extent of the amplicon or on the expression patterns of the amplified genes. We have studied six cases (five AML and one MDS) with MYC-containing dmin. Detailed fluorescence in situ hybridization analyses identified a common 4.3 Mb amplicon, with clustered proximal and distal breakpoints, harboring eight known genes (C8FW, NSE2, POU5FLC20, MYC, PVT1, AK093424, MGC27434 and MLZE). The corresponding region was deleted in one of the chromosome 8 homologues in five of the six cases, suggesting that the dmin originated through extra replication (or loop-formation)--excision--amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results exclude MYC as the target gene and indicate that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS.     

Caffeine reverses antinociception by oxcarbazepine by inhibition of adenosine A1 receptors: Insights using knockout mice

Oxcarbazepine is an anticonvulsant drug that has been explored as a novel therapeutic agent to treat neuropathic pain in humans. It produces antinociception in several preclinical models of pain, and these actions are blocked by methylxanthine adenosine receptor antagonists which implicates adenosine it its actions. In this study, the antinociceptive effect of oxcarbazepine, and the ability of caffeine to reverse its actions, were examined using the formalin test (2%) in wild-type mice and in mice lacking adenosine A₁ receptors by way of further exploring the involvement of adenosine in its actions. Oxcarbazepine produced dose-related suppression of formalin-evoked flinching responses in wild-type mice following both systemic and intraplantar administration, and this action was reversed by systemic and intraplantar administration of caffeine, respectively. The ability of oxcarbazepine to inhibit flinching after systemic and intraplantar administration was unaltered in homozygous (−/−) and heterozygous (+/−) adenosine A₁ receptor knockout mice. However, caffeine no longer reversed this antinociception. Our results indicate that, while adenosine A₁ receptors are not required for oxcarbazepine to produce antinociception in knockout mice, such receptors are essential in order to see caffeine reversal of this antinociceptive effect.     

FLT3 mutations in a 10 year consecutive series of 177 childhood acute leukemias and their impact on global gene expression patterns

During 1995-2004, 209 children/adolescents were diagnosed with acute lymphoblastic or myeloid leukemia (ALL, AML) in Southern Sweden, of which 177 (85%), comprising 128 B-lineage ALL, 34 AML, and 15 T-cell ALL, could be analyzed for internal tandem duplications (ITD) and activating point mutations in the second tyrosine kinase domain (ATKD) of FLT3. Seventeen (10%) FLT3 mutations (6 ITD, 11 ATKD; mutually exclusive) were detected. None of the T-cell ALL harbored any mutations. ITD and ATKD were found in 2% and 6% of the B-lineage ALL and in 12% and 9% of the AML, being particularly common in high hyperdiploid ALL (14%), ALL (20%), and AML (23%) with 11q23/MLL rearrangements, and in AML with a normal karyotype (60%). All ATKD-positive AML with MLL rearrangements harbored the t(9;11)(p21;q23). Global gene expression data were available for 76 of the B-lineage ALL and 19 of the AML, of which 6 (8%) and 3 (16%) had FLT3 mutations, respectively. No distinct expression pattern associated with FLT3 mutations was identified.     

Trust, social support and patient type--associations between patients perceived trust, supportive communication and patients preferences in regard to paternalism, clarification and participation of severely injured patients

Objective

Trust is an important aspect of physician–patient-interaction, both in terms of compliance and patient- and physician-reported outcomes. Trust-building communication is especially important in terms of severely injured patients because of severity of their injuries and frequently associated physical and psychological consequences. Patients preferences concerning medical treatment (patient type) is also regarded to be important in terms of trust. The objective of this study was to investigate the relationships between patients perceived trust, supportive communication of physicians and patient type of severely injured patients.

Methods

Seventy-one severely injured patients, who were predominantly injured in the workplace or in traffic accidents and were treated in one of four hospitals in Northrhine-Westfalia between 2001 and 2005, completed a self-administered questionnaire. “Trust in physicians_short form” (TRIP_sf) describes different aspects, such as general trust, competence of doctors and the feeling to be in good hands. “Informational support” and “emotional support” comprise verbal and non-verbal aspects, such as clear and understandable information or devotion and empathic manner. “Patient type” measures patients preferences in regard to paternalism of physician, clarification of medical facts and participation in treatment.

Results

Trust is strongly correlated with informational (.628**) and emotional support (.542**) and is less correlated with patients preferences of “paternalism” (.250*)“, “clarification” (.438**) and participation” (.378**). Informational and emotional support are in general not significantly correlated with type of patient, all correlations were adjusted for age, gender, marital and socioeconomic status, length of hospital stay, and severity of injury.

Conclusions

Trust is significantly related to patient type but more related to doctor support: the results confirm the importance of supportive communication in terms of emotional and informational support.

Practice implications

Medical education should integrate sound knowledge about the psychosocial aspects of physician patient interaction to enable doctors to provide effective social support and to identify and consider patients preferences.     

Sequence-specific stalling of DNA polymerase γ and the effects of mutations causing progressive ophthalmoplegia

A large number of mutations in the gene encoding the catalytic subunit of mitochondrial DNA polymerase γ (POLγA) cause human disease. The Y955C mutation is common and leads to a dominant disease with progressive external ophthalmoplegia and other symptoms. The biochemical effect of the Y955C mutation has been extensively studied and it has been reported to lower enzyme processivity due to decreased capacity to utilize dNTPs. However, it is unclear why this biochemical defect leads to a dominant disease. Consistent with previous reports, we show here that the POLγA:Y955C enzyme only synthesizes short DNA products at dNTP concentrations that are sufficient for proper function of wild-type POLγA. In addition, we find that this phenotype is overcome by increasing the dNTP concentration, e.g. dATP. At low dATP concentrations, the POLγA:Y955C enzyme stalls at dATP insertion sites and instead enters a polymerase/exonuclease idling mode. The POLγA:Y955C enzyme will compete with wild-type POLγA for primer utilization, and this will result in a heterogeneous population of short and long DNA replication products. In addition, there is a possibility that POLγA:Y955C is recruited to nicks of mtDNA and there enters an idling mode preventing ligation. Our results provide a novel explanation for the dominant mtDNA replication phenotypes seen in patients harboring the Y955C mutation, including the existence of site-specific stalling. Our data may also explain why mutations that disturb dATP pools can be especially deleterious for mtDNA synthesis.