Metabolic exhaustion in infection, cancer and autoimmunity.

It has become increasingly clear that changes in metabolism are not just consequences of T cell activation but instead are also essential drivers of that process that shape the extent and nature of differentiation and function. The process of T cell exhaustion has been linked to the outcome of chronic immune responses in multiple contexts, including chronic infection, cancer and autoimmunity. Factors that regulate the development and maintenance of exhaustion are of increasing interest as targets of therapeutic modulation. Studies have shown T cell immunometabolism to be integral to the control and development of T cell exhaustion. Early metabolic changes are responsible for the later emergence of exhaustion, do not simply reflect changes secondary to chronic activation and are modifiable. Increased understanding of this metabolic control promises to improve the ability to modulate T cell immunity to chronic antigen stimulation in multiple contexts.

Analysis of the B cell receptor repertoire in six immune-mediated diseases.

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

Copy number variation in bipolar disorder.

Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10(-4)). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4)).

Pilot feasibility and acceptability trial of BE REAL's BodyKind: A universal school-based body image intervention for adolescents.

Body dissatisfaction is prevalent among adolescents and a primary risk factor for eating disorders, yet there are few body image interventions for older adolescents that support development of positive body image. Therefore, we assessed the feasibility, acceptability and preliminary effectiveness of BodyKind, a four-lesson, mixed gender, teacher-led, school-based curriculum for older adolescents, that combines principles of self-compassion, compassion for others, cognitive dissonance, and social activism to address contemporary adolescent body image concerns (i.e., appearance bias, comparisons on social media) and strengthen positive body image development. The sample contained 147 adolescents, predominantly racial/ethnic minorities (>95%), 54.8% male, 41.5% female and 4.1% gender-minority students aged 15-18 years (M=16.24, SD=.96) from a low-income, inner-city high school in the Midwestern US. Two teachers received training and delivered the curriculum to students. This single arm, mixed methods trial assessed student and teacher acceptability, teacher fidelity and student intervention outcomes. Despite reasonable teacher fidelity, recruitment/attendance rates, post-intervention data loss (35% attrition) limited evaluations of program effectiveness and study feasibility. Important learnings regarding study feasibility will inform optimisation for future school-based trials. Findings demonstrate high acceptability of BodyKind among teachers and adolescents in a lower socioeconomic school setting, and further randomized controlled effectiveness trials are required.

Inhibition of the B cell by CD22: a requirement for Lyn.

Mice in which the Lyn, Cd22, or Shp-1 gene has been disrupted have hyperactive B cells and autoantibodies. We find that in the absence of Lyn, the ability of CD22 to become tyrosine phosphorylated after ligation of mIg, to recruit SHP-1, and to suppress mIg-induced elevation of intracellular [Ca2+] is lost. Therefore, Lyn is required for the SHP-1-mediated B cell suppressive function of CD22, accounting for similarities in the phenotypes of these mice.

bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells.

Immunization with T cell-dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2-transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.

Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII.

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.

Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts.

BACKGROUND: Recently, there has been a resumed interest in clinical xenotransplantation using pig organs. However, no data are available yet regarding the capacity of porcine organs to sustain the life of a primate beyond the first month. We have attempted to obtain long-term survival of nonhuman primates using human decay-accelerating factor (hDAF) transgenic pig organs and an immunosuppressive strategy particularly aimed at neutralizing the humoral component of the immune response. METHODS: hDAF transgenic or control kidneys were transplanted into 14 bilaterally nephrectomized cynomolgus monkeys (Macaca fascicularis) that underwent splenectomy and were immunosuppressed with cyclosporine A, cyclophosphamide, and steroids. All animals also received recombinant erythropoietin. Postoperatively, the primates were monitored daily. Laboratory evaluations included serum biochemistry, hematology, and measurements of hemolytic antipig antibodies. To assess the role of splenectomy in the control of humoral response, historical data were also used from a group of monkeys (n=7) that received the same immunosuppressive regimen and an hDAF transgenic porcine kidney but did not have splenectomy or receive recombinant erythropoietin. RESULTS: This immunosuppressive approach obtained the longest survival time (78 days) described to date of a primate receiving a life-supporting porcine renal xenograft. Furthermore, four of nine animals in this series survived for 50 days or more. Most biochemical measurements in this study (including plasma urea, creatinine, sodium, and potassium concentrations) remained within normal ranges for several weeks in all of the longest-surviving animals. CONCLUSIONS: Normalization of renal function (urea and creatinine) in primate recipients of porcine renal xenografts suggests that pig kidneys may be suitable for future clinical xenotransplantation. Additional immunosuppressive approaches, specifically designed to prevent humorally mediated immunological damage, should be explored to further prolong survival of primates that have received porcine xenografts.

Apoptosis and the B cell response to antigen.

The primary B cell response to T cell dependent antigens comprises two pathways of differentiation; one resulting in formation of foci of antibody forming cells in the extrafollicular regions of secondary lymphoid organs and the other giving rise to germinal centers within the follicles. Foci of antibody forming cells are detectable for only a limited time, before involuting due to apoptosis of the plasma cells. Similarly in the germinal center, regulation of cell number, selection of high affinity variants generated by somatic hypermutation, and the resolution of the germinal center itself all involve the death of unwanted B cells. In this review we describe recent experiments which have allowed determination of the role of certain forms of apoptosis in the B cell response to antigen.

De novo partial duplications 1p: report of two new cases and review.

We describe two de novo intrachromosomal duplications of 1p. One case is a dir ins dup(1)(q21p21p31) in a newborn girl with low birth weight, growth retardation, and tetralogy of Fallot. The other is a 10-month-old girl with developmental delay, craniosynostosis, plagiocephaly, and an inv dup 1p34.1p31. Although, these patients have manifestations in common with previous cases, they do not establish a syndrome. Interestingly, all males with duplications spanning 1p31 had genital anomalies, whereas females with duplications of the same region had normal genitalia. Thus, genes within 1p31 appear to control the development of male genitalia and tentatively exclude effects of tda1, a sex-determining gene in a region of mouse chromosome 4 syntenic to 1p36 in man. However, it is necessary to identify the human tda1 homologue and candidate genes within 1p31 before drawing final conclusions.

The effect of delayed nerve repair on the properties of regenerated fibres in the chorda tympani.

The characteristics of regenerated fibres in the chorda tympani have been investigated in cats after nerve section without repair or after section followed by nerve repair twelve weeks later. In the unrepaired group the animals were allowed to recover for twenty four weeks and after delayed repair there was a further recovery period of twelve or twenty four weeks. The properties of gustatory, thermosensitive and mechanosensitive units and the return of vasomotor and secretomotor responses were then investigated and data compared with that from normal controls and from animals which had undergone immediate nerve repair. After nerve section, integrated whole-nerve activity recorded from the chorda tympani during gustatory or thermal stimulation of the tongue was reduced when compared to controls, but there were only small differences between the repaired and unrepaired groups. Recordings made from single units in the chorda tympani revealed that more units were spontaneously active after repair (P < 0.05) and the gustatory units produced more impulses when stimulated (P < 0.005). Twelve weeks after delayed repair the units had slower conduction velocities than those in the unrepaired nerves (P < 0.001), but by twenty four weeks after repair they were significantly faster (P < 0.05). There was little difference in the level of recovery twelve weeks after immediate or delayed repair. We conclude that delayed nerve repair results in better recovery than leaving the nerve unrepaired and that a twelve week delay before repair has little effect.

Ectopic neural activity from myelinated afferent fibres in the lingual nerve of the ferret following three types of injury.

Sensory disturbances following nerve injury may result from abnormal neural activity initiated at the injury site. We have studied the activity generated in the lingual nerve after three types of injury which may have variable potentials for the initiation of sensory disturbances. We have also compared the results with those found after damage to the inferior alveolar nerve, another branch of the trigeminal nerve, to determine whether differences in nerve fibre type or location affect the level of abnormal activity. In anaesthetised adult male ferrets the left lingual nerve was either ligated and cut distally, chronically constricted, or sectioned and allowed to regenerate. Following recovery periods of 3 days-6 months, single unit electrophysiological recordings were made from central to the injury site. After all three types of injury, some of the damaged axons at the injury site developed spontaneous activity (up to 36% of units) and mechanical sensitivity (up to 35% of units). There were significantly fewer spontaneously active units after ligation than after the other two types of injury but the level of mechanical sensitivity was not significantly different between the three types of injury. There was a significant increase in the spontaneous activity between 3 weeks and later recovery periods following both ligation and section injuries, and this late increase was not seen in our previous studies on the inferior alveolar nerve. Differences in the time-course of ectopic activity in adjacent branches of the trigeminal nerve suggest that the fibre types or anatomical relationships affect the outcome of injury.

The re-innervation of the tongue and salivary glands after lingual nerve repair by stretch, sural nerve graft or frozen muscle graft.

The lingual nerve is sometimes injured during the surgical removal of impacted third molar teeth and may require repair. Removal of the damaged section of nerve prior to repair leaves a gap between the nerve ends, and we have investigated methods of closing the gap. THe characteristics of regenerated fibers in the chorda tympani have been recorded in cats 24 weeks after the removal of a segment of lingual nerve and repair of the defect by three methods. The nerve gap was closed either by stretching the nerve ends together and repairing under tension, or by the insertion of a sural nerve graft or freeze-thawed muscle graft. The properties of gustatory, thermosensitive, and mechanosensitive units and the return of the vasomotor and secretomotor responses were investigated by electrophysiological techniques and the data from each of the repair groups compared with those obtained from a series of normal control animals. After each method of repair, the integrated whole-nerve activity recorded from the chorda tympani during gustatory or thermal stimulation of the tongue was reduced when compared with controls, but there was little significant difference between the repair groups. Recordings made from single units in the chorda tympani revealed that conduction velocities were faster after stretch repair than after sural nerve graft or frozen muscle graft. In addition, 48% of the units had developed into principally gustatory units after stretch repair, indicating a better level of recovery than in the graft groups, which contained 33% and 32%, respectively. The secretomotor responses were also significantly greater after stretch repair than in either of the graft groups or the controls, but there was no difference in the vasomotor responses. These results reveal that repair of a short gap in the lingual nerve by stretching the ends together is followed by better overall recovery than after grafting, but where a graft is used, a similar level of recovery results from use of a frozen muscle graft or a sural nerve graft.

A quantitative morphological comparison of cat lingual nerve repair using epineurial sutures or entubulation.

Since lingual nerves may be transected during a variety of oral surgical procedures, including third molar removal, we have investigated two possible methods of repair. Quantitative morphological observations were made on feline chorda tympani and lingual nerves proximal and distal to transection injuries repaired either by epineurial suturing or by insertion of the cut ends into a perforated silicon tube. Proximal to the repair, the most prominent difference was an increase in the number of myelinated axons in the lingual nerve following epineurial suturing but not entubulation. Proximal to the repair site, the number of nonmyelinated axons increased in comparison with controls in both chorda tympani and lingual nerves after both procedures, though the difference was statistically significant only in the lingual nerve proximal to entubulation. Distal to the injury, both types of repair showed a reduction in the number, size, and sheath thickness of myelinated axons in comparison with unoperated controls, but the difference in numbers was statistically signIficant only distal to repair by entubulation. The number of non-myelinated axons distal to the repair sites was much higher than that in controls, the difference being greater distal to entubulation repair. There were more axons per Remak bundle distal to entubulation repair than to epineurial suturing, suggesting, perhaps, that fewer axons would ultimately become myelinated. Though the morphological differences between the two repair techniques are not as striking as the parallel electrophysiological differences reported previously (Smith and Robinson, 1995a,b), they are consistent with them and support the conclusion that, for transected lingual and chorda tympani nerves, epineurial suturing is the preferred approach.

A case of lung myiasis caused by larvae of Megaselia spiracularis Schmitz (Diptera: Phoridae).

A 19-year-old Japanese man in good health was found on a routine chest X-ray to have considerable lung abnormalities. An open lung biopsy was performed and 30 third-instar larvae of Megaselia spiracularis Schmitz were found in the suction tube postoperatively. This appears to be the first recorded case of lung myiasis.

Red-winged blackbird predation on periodical cicadas (Cicadidae: Magicicada spp.): bird behavior and cicada responses.

Predation by red-winged blackbirds Agelaius phoeniceus L. on 13-year periodical cicadas (Magicicada spp.) and reactions by periodical cicadas to predators were studied during emergence of Brood XIX during summer of 1985 in northwestern Arkansas (USA). Emergences of periodical cicadas are classic examples of predator satiation due to high local densities of cicadas and birds are the major predators of adult periodical cicadas. Reactions of periodical cicadas to predators were assessed by recording behaviors exhibited by cicadas when approached in trees by a human hand during the 3-week period of peak adult densitics. Most male cicadas made a noise in association with escape behaviors when approached, and 50% of the females, which are silent, attempted escape behaviors. Observations of predation attempts on cicadas by red-winged blackbirds were made during the period of peak predation pressure. Red-winged blackbirds spent less time searching for cicadas over that 2-week period of increasing predation pressure, and became increasingly efficient at capturing cicadas. Handling time of cicadas by red-winged blackbirds increased by about 20 seconds over that period, as blackbirds spent more time consuming female cicadas. The flysquawk response, used only by male cicadas, was effective in deterring red-winged blackbirds; only 5% of the attacks by blackbirds were successful when that behavior was exhibited. All cicadas that remained motionless and silent when approached by blackbirds were captured and consumed. Because females remained inactive when approached more often than did males, blackbirds may have consumed more female cicadas. Changes that appeared in reactions of preiodical cicadas to the model predator and to the attacks of blackbirds reflect both changes in the sex ratio of the cicada populations and changes in behaviors of cicadas associated with mating and egg laying. The loud noise made by male periodical cicadas at mating centers did not appear to deter predation by blackbirds. Changes in the behavior of blackbirds that appeared to be in association with greater predation on female periodical cicadas relates directly to aspects of foraging theory, particularly predictions concerning more selective foraging during periods of abundant food resources.

Online access to journal abstracts and articles.

Advances in information technology now offer several options for child and adolescent psychopharmacologists to navigate the increasingly complex terrain of scientific literature and keep abreast of the rapidly changing advances in our field. MEDLINE, the world's largest database of medical literature, can be accessed and searched by a variety of free or fee-based services. In addition to efficient retrieval of citations and abstracts based on subject, author, or title, many of these services now provide, for a fee, the entire text and graphics of articles (displayed on computer screen, faxed, or mailed). There are also current awareness services to alert the user when new requested literature become available as well as services to send via e-mail the tables of contents of requested journals (sometimes prior to paper publication). For online citation and abstract retrieval, we found that free services, such as PubMed, performed as good or better than fee-based services. Physicians' Online, sponsored by the pharmaceutical industry, offered the lowest price for full-text manuscript delivery. In this article, we review literature search, delivery, and update services and offer some tips on how to most effectively use these resources.

The reinnervation of the tongue and salivary glands after two methods of lingual nerve repair in the cat.

The recovery of fibres in the chorda tympani after repair by epineurial suture or entubulation was investigated. The combined trunk of the chorda tympani and lingual branch of the trigeminal nerve was sectioned unilaterally, repaired using either epineurial sutures or entubulation, and allowed to recover for 12 weeks. The properties of gustatory, thermosensitive and mechanosensitive units, and the return of vasomotor and secretomotor responses were then investigated. After repair by epineurial suture, integrated whole-nerve activity recorded from the chorda tympani during stimulation of the tongue with gustatory or thermal stimuli was reduced in all areas of the tongue when compared to controls. After entubulation repair, little or no activity could be recorded. Recordings made from 57 single units in the chorda tympani after repair by epineurial suture revealed a greater proportion of purely mechanosensitive units and fewer gustatory units than in the controls. Fewer units were spontaneously active, they had lower maximum discharge frequencies, and produced fewer impulses when stimulated. Recordings made from 61 single units after repair by entubulation revealed receptor characteristics with greater differences from controls than after epineurial suture and there was only one gustatory and one thermosensitive unit. Vasomotor responses were completely restored after repair by epineurial suture, but some responses were smaller after entubulation repair. Secretomotor responses were significantly smaller after both methods of repair and there was no difference between the two groups.