A longitudinal study of general practitioner consultations for psychiatric disorders in adolescence.

Patterns of psychiatric diagnoses given during adolescence to a group of individuals continuously registered with a single general practitioner in South London over 20 years were analysed first during 'early adolescence' and secondly during 'early adulthood'. Psychiatric diagnoses were found to be relatively common. Of the young adolescents who received a psychiatric diagnosis (almost one in ten of the group), 38% received a psychiatric diagnosis as young adults compared with only 16% of the remainder. Comorbidity was found to be very common--over 50% of young adults with a diagnosis of depression also had a diagnosis of anxiety and phobic neuroses. Young people with problems of a psychological nature therefore deserve more attention, particularly from the primary care team.     

Long-term culture of functional liver tissue: three-dimensional coculture of primary hepatocytes and stellate cells

One of the greatest challenges in the attempt to create functional liver tissue in vitro is the maintenance of hepatocyte-specific functions. The pharmaceutical industry has long awaited the development of engineered liver tissue, which could represent a long-term, inducible, high-fidelity model for high-throughput screening of new drug compounds. It is also anticipated that such engineered models could one day be used in liver transplants, where replacement is limited by chronic donor shortages. As isolated hepatocytes dedifferentiate rapidly in culture the use of hepatocytes in long-term studies has proved to be a difficult challenge. Here we report a system of rat hepatocytes cocultured with primary rat hepatic stellate cells on a biodegradable poly(DL-lactic acid) substratum. These coculture conditions were found to encourage the rapid self-organization of three-dimensional spheroids. The spheroids formed exhibit hepatocyte-specific functionality (CYP-450 activity and albumin secretion) after almost 2 months in static culture.     

Secretory component as the receptor for polymeric IgA on rat hepatocytes

Rat hepatocytes in short-term monolayer cultures bound radiolabeled polymeric rat IgA but not IgG. The binding of 125I-IgA was inhibited equally well by unlabeled polymeric IgA and by antiserum to rat secretory component (SC). The antibody to SC, after specific purification and radiolabeling, was bound to hepatocytes as effectively as the IgA. These results indicate that SC acts as the receptor for polymeric IgA on rat hepatocytes as it does on human gut epithelia, and that the transport of IgA from blood to bile in rats across the liver is analogous to that of IgA across human enterocytes.     

A role for thymic stromal lymphopoietin in CD4(+) T cell development

Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor alpha chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor gamma chain, gamma(c). We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, gamma(c)/TSLPR double KO mice had a greater lymphoid defect than gamma(c) KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in gamma(c) KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into gamma(c) KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti-IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4(+) single positive thymocytes and peripheral T cells in vitro. Additionally, CD4(+) T cells from TSLPR KO mice expanded less efficiently than WT CD4(+) T cells in irradiated hosts, and TSLP preferentially expanded CD4(+) T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4(+) T cells.     

Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4(+) and CD8(+) T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8(+) effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.     

Ultrasound and microbubbles: Their generation, detection and potential utilization in tissue and organ therapy—Experimental

Ultrasound-induced cavitation in tissue and organs has been well recognized and documented. Generally, this phenomenon has been seen as something to be avoided except in cases such as lithotripsy, where its production is considered an essential part of the treatment process or as a desirable contrast media in some areas of visualization enhancement. This article covers theree areas in which the phenomenon has been observed, and shows how the effect can or may be therapeutically beneficial. Studies in the pig show that implanted human gallstones and the gallbladder itself can be eliminated in a nonsurgical procedure using ultrasound-induced cavitation in the gallbladder. In the dog brain, relatively stable cavitation-induced microbubbles have been transported through the vascular system to regions outside a focal seeding site. These bubbles produce ablation of tissue volumes at a remote site when irradiated with appropriate ultrasound. The cavitation phenomenon has been observed in the dog and human prostate. In the human prostate, microbubbles transported from ultrasound-induced focal seeding sites can be readily visualized with ultrasound and may be potentially useful under controlled conditions in tissue debulking for the treatment of benign prostatic hyperplasia (BPH). A similar microbubble transport has not been seen in the dog prostate under similar ultrasound treatment parameters. The ability to detect cavitation-induced microbubbles, follow their transportation through the vascular system and excite them at the appropriate time and place provides interesting possibilities for therapy. Of course, the entire microbubble process can be avoided by working below the cavitation threshold, thereby using only the absorption of ultrasound in tissue to produce focal thermal lesions. The term microbubble is used here in the context of those bubbles which can be transported in the vascular system down to vessels diameters below the 100-μm range. This is the vessel size in the vascular field into which microbubbles are transported and can be both visualized as well as disrupted with ultrasound.     

Six-minute walk test for persons with mild or moderate disability from multiple sclerosis: performance and explanatory factors

Purpose: The primary purpose of this study was to determine the extent to which health factors, functional measures, and pulmonary impairment explain performance on 6-Minute Walk Test (6MWT) distance in ambulatory persons with multiple sclerosis (MS). Another purpose was to determine the effect of disability and age on 6MWT performance and explanatory factors.Methods: A cross-sectional study design was used to evaluate factors that explain performance on the 6MWT in 64 community-dwelling persons with MS-related disability (Expanded Disability Status Scale [EDSS] 3.8±1.6). Of the 64 participants, 43 (67.2%) exhibited mild disability (EDSS <4.0) and 21 (32.8%) had moderate disability (EDSS 4.0-6.5). A regression analysis compared 6MWT performance to measures of health factors (EDSS, number of medications, number of comorbidities, resting HR, systolic and diastolic blood pressure [BP]); physical performance (functional stair test [FST], sit-to-stand test [SST], static standing balance [BAL], Fatigue Severity Scale [FSS], Activities-specific Balance Confidence [ABC] Scale); and pulmonary function (forced expiratory volume in 1 second [FEV(1)], forced vital capacity [FVC], maximal voluntary ventilation [MVV], maximal inspiratory pressure [MIP], maximal expiratory pressure [MEP]).Results: EDSS, ABC, FST, SST, BAL, MVV, MIP, and MEP were significantly associated with 6MWT distance after adjusting for age. Multiple step-wise linear regression analysis revealed that ABC, FST, and BAL were significant and independent explanatory factors of 6MWT distance. ABC and FST explained 75% of the variance in 6MWT performance (R(2)=0.75). Curvilinear regression analysis revealed that the FST is the most significant explanatory factor for 6MWT distance, explaining 79% of the variance (R(2)=0.79).Conclusions: 6MWT performance in persons with MS was explained by balance confidence (ABC) and stair-climbing ability (FST). The ABC and FST may be practical clinical measures for explaining walking ability and determining risk for disablement in persons with MS.