BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Peroxisome proliferator-activated receptor-(gamma) receptor ligand partially prevents the development of endometrial explants in baboons: a prospective, randomized, placebo-controlled study

A prospective, randomized, placebo-controlled study was conducted in a baboon model to determine if a thiazolidinedione agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone, can impede the development of endometriosis. Endometriosis was induced using laparoscopic, intrapelvic injection of eutopic menstrual endometrium, previously incubated with placebo or pioglitazone for 30 min, in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity. At this point, the 12 baboons were randomized into two groups and treated from the day of induction. They received either PBS tablets (n = 6, placebo control, placebo tablets once a day by mouth) or pioglitazone (n = 6, test drug, 7.5 mg by mouth each day). A second and final laparoscopy was performed in the baboons to record the extent of endometriotic lesions between 24 and 42 d after induction (no difference in length of treatment between the two groups, P = 0.38). A videolaparoscopy was performed to document the number and surface area of endometriotic lesions. The surface area and volume of endometriotic lesions were significantly lower in pioglitazone treated baboons than the placebo group (surface area, 48.6 vs. 159.0 mm(2), respectively, P = 0.049; vol, 23.7 vs. 131.8 mm(3), respectively, P = 0.041). The surface area (3.5 vs. 17.8 mm(2), P = 0.017, pioglizatone vs. placebo) and overall number (1.5 vs. 9.5, P = 0.007, pioglizatone vs. placebo) of red lesions were lower in the pioglitazone group. A peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, effectively reduced the initiation of endometriotic disease in the baboon endometriosis model. Using this animal model, we have shown that thiazolidinedione is a promising drug for preventive treatment of endometriosis.

Prosthetic rehabilitation and treatment outcome of partially edentulous patients with severe tooth wear: 3-years results

The purpose of this study was to report on the management and treatment outcomes of partially edentulous elderly patients with severe tooth wear.

Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis

BACKROUND ; AIMS: Topical corticosteroids are effective in inducing clinical and histologic remission in patients with eosinophilic esophagitis (EoE). However, the best long-term management strategy for this chronic inflammatory disease has not been determined.

Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs.

10-Year Survival and Success Rates of 511 Titanium Implants with a Sandblasted and Acid-Etched Surface: A Retrospective Study in 303 Partially Edentulous Patients

Purpose: This retrospective study assessed the 10-year outcomes of titanium implants with a sandblasted and acid-etched (SLA) surface in a large cohort of partially edentulous patients. Materials and Methods: Records of patients treated with SLA implants between May 1997 and January 2001 were screened. Eligible patients were contacted and invited to undergo a clinical and radiologic examination. Each implant was classified according to strict success criteria. Results: Three hundred three patients with 511 SLA implants were available for the examination. The mean age of the patients at implant surgery was 48 years. Over the 10-year period, no implant fracture was noted, whereas six implants (1.2%) were lost. Two implants (0.4%) showed signs of suppuration at the 10-year examination, whereas seven implants had a history of peri-implantitis (1.4%) during the 10-year period, but presented with healthy peri-implant soft tissues at examination. The remaining 496 implants fulfilled the success criteria. The mean Plaque Index was 0.65 (±0.64), the mean Sulcus Bleeding Index 1.32 (±0.57), the mean Probing Depth 3.27 mm (±1.06), and the mean distance from the implant shoulder to the mucosal margin value -0.42 mm (±1.27). The radiologic mean distance from the implant shoulder to the first bone-to-implant contact was 3.32 mm (±0.73). Conclusion: The present retrospective analysis resulted in a 10-year implant survival rate of 98.8% and a success rate of 97.0%. In addition, the prevalence of peri-implantitis in this large cohort of orally healthy patients was low with 1.8% during the 10-year period.

A pilot study to evaluate the success and survival rate of titanium-zirconium implants in partially edentulous patients: results after 24 months of follow-up

Implants made from a new titanium-zirconium (TiZr) alloy (Roxolid) have shown good osseointegration with no adverse effects in animal studies. This single-cohort pilot study was performed to evaluate the performance and safe use of reduced-diameter implants made from this new TiZr alloy for the first time in human subjects, in a prospective case-controlled series.

Avoidant coping partially mediates the relationship between patient problem behaviors and depressive symptoms in spousal Alzheimer caregivers

OBJECTIVE: Caring for a loved one with Alzheimer disease is a highly stressful experience that is associated with significant depressive symptoms. Previous studies indicate a positive association between problem behaviors in patients with Alzheimer disease (e.g., repeating questions, restlessness, and agitation) and depressive symptoms in their caregivers. Moreover, the extant literature indicates a robust negative relationship between escape-avoidance coping (i.e., avoiding people, wishing the situation would go away) and psychiatric well-being. The purpose of this study was to test a mediational model of the associations between patient problem behaviors, escape-avoidance coping, and depressive symptoms in Alzheimer caregivers. METHODS: Ninety-five spousal caregivers (mean age: 72 years) completed measures assessing their loved ones' frequency of problem behaviors, escape-avoidance coping, and depressive symptoms. A mediational model was tested to determine if escape-avoidant coping partially mediated the relationship between patient problem behaviors and caregiver depressive symptoms. RESULTS: Patient problem behaviors were positively associated with escape-avoidance coping (beta = 0.38, p < 0.01) and depressive symptoms (beta = 0.26, p < 0.05). Escape-avoidance coping was positively associated with depressive symptoms (beta = 0.33, p < 0.01). In a final regression analysis, the impact of problem behaviors on depressive symptoms was less after controlling for escape-avoidance coping. Sobel's test confirmed that escape-avoidance coping significantly mediated the relationship between problem behaviors and depressive symptoms (z = 2.07, p < 0.05). CONCLUSION: Escape-avoidance coping partially mediates the association between patient problem behaviors and depressive symptoms among elderly caregivers of spouses with dementia. This finding provides a specific target for psychosocial interventions for caregivers.

Point mutations in the stem region and the fourth AAA domain of cytoplasmic dynein heavy chain partially suppress the phenotype of NUDF/LIS1 loss in Aspergillus nidulans

Cytoplasmic dynein performs multiple cellular tasks but its regulation remains unclear. The dynein heavy chain has a N-terminal stem that binds to other subunits and a C-terminal motor unit that contains six AAA (ATPase associated with cellular activities) domains and a microtubule-binding site located between AAA4 and AAA5. In Aspergillus nidulans, NUDF (a LIS1 homolog) functions in the dynein pathway, and two nudF6 partial suppressors were mapped to the nudA dynein heavy chain locus. Here we identified these two mutations. The nudAL1098F mutation resides in the stem region, and nudAR3086C is in the end of AAA4. These mutations partially suppress the phenotype of nudF deletion but do not suppress the phenotype exhibited by mutants of dynein intermediate chain and Arp1. Surprisingly, the stronger DeltanudF suppressor, nudAR3086C, causes an obvious decrease in the basal level of dynein's ATPase activity and an increase in dynein's distribution along microtubules. Thus, suppression of the DeltanudF phenotype may result from mechanisms other than simply the enhancement of dynein's ATPase activity. The fact that a mutation in the end of AAA4 negatively regulates dynein's ATPase activity but partially compensates for NUDF loss indicates the importance of the AAA4 domain in dynein regulation in vivo.

Performance of dental implants after staged sinus floor elevation procedures: 5-year results of a prospective study in partially edentulous patients

OBJECTIVES: The aim of this prospective study was to evaluate the 5-year performance and success rate of titanium screw-type implants with the titanium plasma spray (TPS) or the sand-blasted, large grit, acid-etched (SLA) surface inserted in a two-stage sinus floor elevation (SFE) procedure in the posterior maxilla. MATERIAL AND METHODS: A total of 59 delayed SFEs were performed in 56 patients between January 1997 and December 2001, using a composite graft with autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) or synthetic porous beta-tricalcium phosphate (beta-TCP). After a healing period averaging 7.75 months, 111 dental implants were inserted. After an additional 8-14-week healing period, all implants were functionally loaded with cemented crowns or fixed partial dentures. The patients were recalled at 12 and 60 months for clinical and radiographic examination. RESULTS: One patient developed an acute infection in the right maxillary sinus after SFE and did not undergo implant therapy. Two of the 111 inserted implants had to be removed because of a developing atypical facial pain, and 11 implants were lost to follow-up and were considered drop-outs. The remaining 98 implants showed favorable clinical and radiographic findings at the 5-year examination. The peri-implant soft tissues were stable over time; the mean probing depths and mean attachment levels did not change during the follow-up period. The measurement of the bone crest levels (DIB values) indicated stability as well. Based on strict success criteria, all 98 implants were considered successfully integrated, resulting in a 5-year success rate of 98% (for TPS implants 89%, for SLA implants 100%). CONCLUSION: This prospective study assessing the performance of dental implants inserted after SFE demonstrated that titanium implants can achieve and maintain successful tissue integration with high predictability for at least 5 years of follow-up in carefully selected patients.

High-volume FES-cycling partially reverses bone loss in people with chronic spinal cord injury

Spinal cord injury (SCI) leads to severe bone loss in the paralysed limbs and to a resulting increased fracture risk thereof. Since long bone fractures can lead to comorbidities and a reduction in quality of life, it is important to improve bone strength in people with chronic SCI. In this prospective longitudinal cohort study, we investigated whether functional electrical stimulation (FES) induced high-volume cycle training can partially reverse the loss of bone substance in the legs after chronic complete SCI. Eleven participants with motor-sensory complete SCI (mean age 41.9+/-7.5 years; 11.0+/-7.1 years post injury) were recruited. After an initial phase of 14+/-7 weeks of FES muscle conditioning, participants performed on average 3.7+/-0.6 FES-cycling sessions per week, of 58+/-5 min each, over 12 months at each individual's highest power output. Bone and muscle parameters were investigated in the legs by means of peripheral quantitative computed tomography before the muscle conditioning (t1), and after six (t2) and 12 months (t3) of high-volume FES-cycle training. After 12 months of FES-cycling, trabecular and total bone mineral density (BMD) as well as total cross-sectional area in the distal femoral epiphysis increased significantly by 14.4+/-21.1%, 7.0+/-10.8% and 1.2+/-1.5%, respectively. Bone parameters in the femoral shaft showed small but significant decreases, with a reduction of 0.4+/-0.4% in cortical BMD, 1.8+/-3.0% in bone mineral content, and 1.5+/-2.1% in cortical thickness. These decreases mainly occurred between t1 and t2. No significant changes were found in any of the measured bone parameters in the tibia. Muscle CSA at the thigh increased significantly by 35.5+/-18.3%, while fat CSA at the shank decreased by 16.7+/-12.3%. Our results indicate that high-volume FES-cycle training leads to site-specific skeletal changes in the paralysed limbs, with an increase in bone parameters at the actively loaded distal femur but not the passively loaded tibia. Thus, we conclude that high-volume FES-induced cycle training has clinical relevance as it can partially reverse bone loss and thus may reduce fracture risk at this fracture prone site.

Implant loading protocols for partially edentulous maxillary posterior sites

PURPOSE: To evaluate early and immediate loading of implants in the posterior maxilla and to investigate whether there is a difference in success rates, survival rates, and peri-implant parameters, including marginal bone level changes. MATERIALS AND METHODS: A comprehensive systematic review of the literature was conducted. The selection of publications reporting on human clinical studies was based on predetermined inclusion criteria and was agreed upon by two reviewers. RESULTS: Twelve papers were identified on early loading (two randomized controlled clinical trials [RCTs] and 10 prospective case series studies). Six papers were found on immediate loading (one RCT, four prospective case series, and one retrospective study). CONCLUSIONS: Under certain circumstances it is possible to successfully load dental implants in the posterior maxilla early or immediately after their placement in selected patients. The success rate appears to be technique sensitive, although no study has directly assessed this. A high degree of primary implant stability (high value of insertion torque) and implant surface characteristics play an important role. It is not possible to draw evidence-based conclusions concerning contraindications, threshold values for implant stability, bone quality and quantity needed, or impact of occlusal loading forces. As for the impact of the surgical technique on implant outcome in different bone densities, no studies prove significant superior results with one technique over another. Well-designed RCTs with a large number of patients are necessary to make early/immediate loading protocols in posterior maxilla evidence based, but ethical and practical considerations may limit the real possibility of such studies in the near future.

An outbreak of mumps in a population partially vaccinated with the Rubini strain

Since 1991, 6 years after the recommendation of universal childhood triple vaccination against measles, mumps and rubella (M + M + R), Switzerland has been confronted with an increasing number of mumps cases affecting both vaccinated and unvaccinated children. The M + M + R vaccine mainly used in the Swiss population after 1986 contains the highly attenuated Rubini strain of mumps virus. We analysed an outbreak of 102 suspected mumps cases by virus isolation, determination of IgM antibodies to mumps virus in 27 acute phase sera, and verification of vaccination histories. Mumps was confirmed by virus isolation in 88 patients, of whom 72 had previously received the Rubini vaccine strain. IgM antibodies to mumps virus were detected in 24/27 acute phase serum samples. A group of 92 subjects from the same geographic area without signs of mumps virus infection served as controls. IgG antibodies to mumps virus and vaccination status were assessed in these children. The vaccination rate in these controls was 61%, with equal seropositivity for unvaccinated and Rubini-vaccinated subjects. These data support other recent reports which indicate an insufficient protective efficacy of current mumps vaccines.