Allogeneic cell-mediated immunotherapy for eradication of minimal residual disease: comparison of T-cell and IL-2 activated killer (LAK) cell-mediated adoptive immunotherapy in murine models

In the course of allogeneic bone marrow transplantation (BMT), avoiding graft-versus-host disease (GVHD) while retaining the antileukemic effects of the T cells remains a major challenge. T-cell depletion (TCD) reduces the incidence of GVHD but increases the relapse rate after allogeneic BMT. We attempted to develop a regimen that would retain or increase the graft-versus-leukemia effect induced by donor T cells while preventing GVHD. Immunosuppressed mice were given immunocompetent donor cells, i.e., fresh lymphocytes or lymphokine-activated killer (LAK) cells differing from the host in major (MHC) or minor (MiHC) histocompatibility antigens. Engraftment of donor cells was documented by polymerase chain reaction analysis. Administration of MHC- and MiHC-incompatible allogeneic LAK cells, especially in conjunction with recombinant interleukin-2 (rIL-2), increased disease manifestations and mortality associated with GVHD. On the other hand, irradiated LAK cells or TCD-LAK cells prevented GVHD in both mice models studied. Phenotypic analysis of LAK cells demonstrated that CD8(+)-equivalent (Lyt-2) T cells are of significance in aggravation of GVHD. The in vitro cytotoxic capacity of LAK cells against MHC-nonrestricted target cells was not reduced by either irradiation or TCD. These results provide the background for designing improved protocols for immunotherapy of residual disease after BMT. In addition, the data imply that antitumor effects may be retained by irradiated rIL-2-activated allogeneic cells without causing GVHD. Whereas unmodified allogeneic LAK cells can induce more effective graft-versus-leukemia effects at the cost of GVHD, irradiated allogeneic donor LAK cells might play some role in eradication of minimal residual disease following autologous or allogeneic BMT without causing GVHD.     

An innovative care model coordinated by a physical therapist and nurse practitioner for osteoarthritis of the hip and knee in specialist care: a prospective study

The subject of the study is to investigate whether health-related quality of life (HRQoL), pain and function of patients with hip or knee osteoarthritis (OA) improves after a specialist care intervention coordinated by a physical therapist and a nurse practitioner (NP) and to assess satisfaction with this care at 12 weeks. This observational study included all consecutive patients with hip or knee OA referred to an outpatient orthopaedics clinic. The intervention consisted of a single, standardized visit (assessment and individually tailored management advice, to be executed in primary care) and a telephone follow-up, coordinated by a physical therapist and a NP, in cooperation with an orthopaedic surgeon. Assessments at baseline and 10 weeks thereafter included the short form-36 (SF-36), EuroQol 5D (EQ-5D), hip or knee disability and osteoarthritis outcome score (HOOS or KOOS), the intermittent and constant osteoarthritis pain questionnaire (ICOAP) for hip or knee and a multidimensional satisfaction questionnaire (23 items; 4 point scale). Eighty-seven patients (57 female), mean age 68 years (SD 10.9) were included, with follow-up data available in 63 patients (72 %). Statistically significant improvements were seen regarding the SF-36 physical summary component score, the EQ-5D, the ICOAP scores for hip and knee, the HOOS subscale sports and the KOOS subscales pain, symptoms and activities of daily living. The proportions of patients reporting to be satisfied ranged from 79 to 98 % per item. In patients with hip and knee OA pain, function and HRQoL improved significantly after a single-visit multidisciplinary OA management intervention in specialist care, with high patient satisfaction.     

Exploring young people's expectations of a youth mental health care service

Client expectations about mental health services relate to the client's and the therapist's role, the therapeutic process and therapeutic outcomes. Research with adults shows that such expectations affect service engagement and clinical outcomes. Aim: The present study investigated expectations for adolescents and young adults, which have not been adequately investigated and may partly explain the reluctance of young people to seek professional help. Methods: Participants included 20 young people aged 12–24 attending their initial session at a youth mental health service, who were interviewed immediately prior to their initial session. Data were analysed using qualitative methods to draw main themes around each of the four expectancy types. Results: Overall, the strongest theme was that young people were unsure of what to expect from attending a mental health service. The key theme for expectations of their role as a client was readiness for therapy, and for the therapist's role the key themes were who they expected to see, the directiveness and likeability of the therapist, and the type of help they expected they would receive. The young people expected that the therapy process would involve simply talking and expected their engagement to be dependent on how much they liked their first few sessions. Outcome expectations were non‐specific and the theme of hopefulness was most evident. Conclusion: As unrealistic and unmet expectations can lead to poorer engagement and outcomes in therapy, the study highlights a need for young people to be better informed about what to expect when coming to mental health services.     

Accuracy of a newly developed integrated system for dental implant planning

Objectives: To evaluate the accuracy of the first integrated system for cone-beam CT (CBCT) imaging, dental implant planning and surgical template-aided implant placement.
Materials and methods: On the basis of CBCT scans, a total of 54 implant positions were planned for 10 partially edentulous anatomical patient-equivalent models. Surgical guides were ordered from the manufacturer (SICAT). Two different types of guidance were assessed: for assessment of the SICAT system inherent accuracy vendor's titanium sleeves of 2 mm internal diameter and 5 mm length were utilized for pilot drills. The guide sleeves of the NobelGuide system were implemented for fully guided surgery and implant insertion. Deviations perpendicular to the implant axes at the crestal and apical end, as well as the angle deviations between the virtual planning data and the surgical results, were measured utilizing a follow-up CBCT investigation and referential marker-based registration.
Results: The SICAT system inherent mean deviation rates for the drilled pilot osteotomies were determined to be smaller than 500 μm even at the apical end. Mean angle deviations of 1.18° were determined. Utilizing the NobelGuide sleeve-in-sleeve system for fully guided implant insertion in combination with the investigated template technology enabled to insert dental implants with the same accuracy. Crestal deviations, in general, were significantly lower than the apical deviations.
Conclusion: Although hardly comparable due to different study designs and measurement strategies, the investigated SICAT system's inherent accuracy corresponds to the most favourable results for computer-aided surgery systems published so far. In combination with the NobelGuide surgical set for fully guided insertion, the same accuracy level could be maintained for implant positioning.     

2,6,8-trisubstituted 1-deazapurines as adenosine receptor antagonists

In this study we developed a refined pharmacophore model for antagonists of the human adenosine A1 receptor, based on features of known pyrimidine and purine derivatives. The adoption of these updated criteria assisted us in synthesizing a series of 1-deazapurines with consistently high affinity as inverse agonists for the adenosine A1 receptor. These 1-deazapurines (otherwise known as 3H-imidazo[4,5-b]pyridines) were substituted at their 2- and 6-positions, yielding a series with five of the derivatives displaying Ki values in the subnanomolar range. The most potent of these, compound 10 (LUF 5978), displayed an affinity of 0.55 nM at the human adenosine A1 receptor with >300-fold and 45-fold selectivity toward A2A and A3 receptors, respectively. Compound 14 (LUF 5981, Ki = 0.90 nM) appeared to have the best overall selectivity with respect to adenosine A2A (>200-fold) and A3 (700-fold) receptors.     

Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells

Multiple myeloma (MM) is characterized by accumulation and dissemination of malignant plasma cells (PCs) in the bone marrow (BM). Gene expression profiling of 2 MM cell lines (OH-2 and IH-1) indicated that expression of PRL-3, a metastasis-associated tyrosine phosphatase, was induced by several mitogenic cytokines. Cytokine-driven PRL-3 expression could be shown in several myeloma cell lines at both the mRNA and protein levels. There was significantly higher expression of the PRL-3 gene in PCs from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and myeloma than in PCs from healthy persons. Among 7 MM subgroups identified by unsupervised hierarchical cluster analysis, PRL-3 gene expression was significantly higher in the 3 groups denoted as "proliferation," "low bone disease," and "MMSET/FGFR3." PRL-3 protein was detected in 18 of 20 BM biopsies from patients with MM. Silencing of the PRL-3 gene by siRNA reduced cell migration in the MM cell line INA-6, but had no detectable effect on proliferation and cell-cycle phase distribution of the cells. In conclusion, PRL-3 is a gene product specifically expressed in malignant plasma cells and may have a role in migration of these cells.     

Persistent diarrhea associated with AIDS

Chronic diarrhea and wasting are very common manifestations of AIDS in adults in developing countries. Etiologic studies show that protozoa (including Cryptosporidium parvum, Isospora belli , and Enterocytozoon bieniusi ) and Mycobacterium avium-intracellulara are the most frequently identified pathogens. Limited data in children suggest that common enteric pathogens are equally as likely in HIV⁺ and HIV^- babies. Preliminary analysis of an ongoing longitudinal study of 469 babies born to mothers with known HIV serostatus in Kinshasa, Zaire, reveals progression of acute to persistent diarrhea is six times greater in HIV⁺ compared to HIV^- babies, and 3.5 times greater in HIV^- babies born of HIV⁺ mothers in comparison to HIV^- babies with HIV^- mothers. HIV⁺ babies were also at greater risk than HIV^- babies to have recurrent episodes of diarrhea (RR = 2.3). Fifty percent of the deaths were due to acute or persistent diarrhea, and were strongly associated with HIV infection. Efforts to improve child survival in AIDS infected populations will need to address HIV infections in both mothers and infants.     

Low and undetectable breast milk interleukin-7 concentrations are associated with reduced risk of postnatal HIV transmission

OBJECTIVE: To investigate if breast milk interleukin [IL]-7 concentrations are associated with postnatal HIV transmission. DESIGN: A case-control study nested within a cohort of women recruited in Lusaka, Zambia. METHODS: IL-7 breast milk concentrations were measured in samples from 24 HIV-infected breast-feeding women who transmitted HIV to their child after the neonatal period and from 47 women who did not transmit. Samples were frequency-matched by the time of sample collection (1 week and 1 month postpartum). Logistic regression was used to adjust for possible confounders. For comparison, samples from 18 HIV-uninfected women from the same community were included in the analysis, and plasma IL-7 was determined. RESULTS: Breast milk IL-7 concentrations were significantly higher than plasma IL-7 concentrations in all 3 groups. In contrast to levels among transmitters and HIV-uninfected women, breast milk IL-7 concentrations exhibited a bimodal distribution among nontransmitters. Breast milk IL-7 concentrations undetectable or less than 30 pg/mL were significantly associated with less HIV transmission (odds ratio = 0.13, 95% confidence interval: 0.03 to 0.64). The association remained strong after adjustment for breast milk viral load and sodium, maternal CD4 cell counts, parity, and time of sample collection. CONCLUSION: Breast milk IL-7 may be necessary for effective HIV transmission.