High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti–integrin αIIbβ3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for αIIbβ3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti–αIIbβ3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies.     

Family-directed cognitive adaptation pilot: Teaching cognitive adaptation to families of individuals with schizophrenia

ABSTRACT

Cognitive deficits are a major determinant of functional outcome in schizophrenia. A promising treatment involves teaching individuals to use cognitive adaptation strategies to minimize the functional impact of cognitive difficulties. We developed Family-Directed Cognitive Adaptation (FCA) to train caregivers to help their relatives with schizophrenia use cognitive adaptations to improve living skills. The goal of this open pilot trial was to examine the feasibility of FCA. Ten adults with schizophrenia, each with at least one relative, participated in FCA and were evaluated at baseline, posttreatment, and 6-month follow-up. Domains assessed included adaptive functioning, psychiatric symptoms, school/work involvement, hospitalizations, family burden, and treatment satisfaction. Participants reported high levels of satisfaction with FCA, and all families completed the 16-session intervention. Relatives reported reduced burden at termination and follow-up. No participants were hospitalized during the treatment or follow-up period, and rates of work/school involvement increased from 30% at baseline to 50% at the end of treatment and follow-up. Individuals improved in negative symptoms and adaptive functioning over the course of treatment, but these gains were not maintained. This pilot provides preliminary support for the acceptability and feasibility of FCA and points to the need to address the maintenance of treatment gains after termination.     

Urban malaria in Yaounde (Cameroon). 2. Entomologic study in 2 suburban districts]

A one year entomological survey was carried out to precise the malaria vectors and the malaria transmission in Yaounde, the Cameroon capital (800,000 inhabitants). The study was done in two districts not yet fully urbanized: Nkol Bikok and Nkol Bisson. The latter is located at the periphery and has a pool. Anopheles gambiae was the only human malaria vector. Its agressivity for man depended on the urbanization of the district. Annual man biting rate was 284 in Nkol Bikok and 1,813 in Nkol Bisson. The densities were maximum in May-June and in October-November, corresponding to the end of the short and long rainy seasons. The presence of A. gambiae was permanent except in August-September in Nkol Bikok. In Nkol Bisson the density was higher in the houses near the pool. The yearly inoculation rate (h) was 14 in Nkol Bikok and 30 in Nkol Bisson. The vectorial transmission was observed in may in Nkol Bikok and during four months (June, August, January, February) in Nkol Bisson. These entomological data showed clearly that malaria transmission actually occurred in Yaounde and that the probability to receive at least one infected anopheline bite per year was very near to 1 for inhabitants unprotected against mosquito bites.     

The variable occurrence of CD45RA on CD8+ thymocytes correlates with the presence of Mtv sequences; its expression on other thymocytes is rare

While all thymocytes express CD45, only a small fraction (<3% in mice) bear the high molecular weight isoform, CD45RA. It has been suggested that these cells alone constitute the generative thymocyte lineage and should, therefore, occur within every ontogenic subset. To test this, we determined CD45RA expression among thymocyte subsets defined by CD4 and CD8. In some strains, exemplified by C57BL/Icrf, very few (< 0.2%) Tthymocytes expressed CD45RA and were mostly CD4^?CD8^? or CD4⁺CD8⁺, inconsistent with them constituting the generativelineage. In others, exemplified by BALB/c, CD45RA was expressed on up to 3% of T thymocytes, which were mostly CD4^?CD8⁺. The limited occurrence of CD4^?CD8⁺CD45RA⁺ thymocytes suggests that they are a nonconstitutive subset playing a role in the thymus of only some strains. Their occurrence correlates with that of Mtv proviruses within the mouse genome; however, their T cell receptor V_β repertoire is diverse, suggesting they are not uniquely selected by Mtv superantigens. We propose that they may be mature CD8 T cells, possibly responsible for introducing viral superantigens into the thymus.     

Functional interaction between B cell subpopulations defined by CD23 expression

Using the CD23 monoclonal antibody (mAb) MHM6 and sheep anti-mouse Ig bound to magnetic beads we have obtained highly purified populations of MHM6+ and MHM6- tonsil B cells. We have found that the increased expression of MHM6 reactivity seen on B cells after activation results from up-regulation of antigen on cells already weakly positive and not from expression of new antigen on the previously negative population. The strong proliferative responses of MHM6+ cells seen in the presence of anti-IgM (alpha mu) and interleukin 4 (IL4) or the CDw40 mAb G28-5, and with Staphylococcus aureus Cowan I (SAC), and to a lesser extent with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), resemble that seen among unfractionated B cells. In contrast, the MHM6- population cultured alone responds only weakly to alpha mu + G28-5 or SAC and exhibits virtually no response to alpha mu + IL4 or TPA. With all these mitogenic stimuli, tritiated thymidine uptake by the MHM6- population is augmented three- to sixfold by the addition of mitomycin C (MC)-treated MHM6+ cells. Pretreatment of cells with anti-leukocyte functional antigen 1 mAb has little effect on the subsequent proliferation of the MHM6- population but shows cell contact to be critical for the proliferation of MHM6+ cells. Such pretreatment has revealed that the functional interaction observed between MHM6+ and MHM6- cells is dependent on both cell contact and the presence of an MHM6+ cell-derived soluble component. We have found that addition of soluble CD23, purified from Epstein-Barr virus-transformed lymphoblastoid cell line supernatant, increases the proliferative response of MHM6- tonsil B cells to mitogenic stimuli in the presence of inactivated MHM6+ cells but has no effect on proliferation when MHM6+ cells are absent. By way of contrast to normal B lymphocytes, we have examined functional responses of prolymphocytic leukemia (PLL) B cells. Although these cells, when freshly isolated, show comparable levels of CD23 expression to normal B cells, this expression is not increased upon activation. In addition, in contrast to normal B cells, the PLL MHM6- population cultured alone shows a strong proliferative response to various mitogenic stimuli, comparable to that of MHM6+ or unfractionated cells, and this response is not augmented by the addition of MC-treated MHM6+ cells. Thus, a novel functional interaction is described between normal, but not leukemic, B cell populations defined by their expression of CD23.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anatomic basis of venous drainage in donor flaps

Summary The venous architecture in donor flaps was observed in 17 fresh cadavers by injection of latex or ink into the vessels or by making corrosion-cast specimens. The pattern of the veins resembles that of the arteries, with the difference that there is another set of venous trunks which do not accompany the arteries. Because these trunks are of larger caliber, they are the main drainage route for flaps. There are three types of drainage based on the anatomical architecture: 1) the superficial trunk is the main drainage path; 2) the deep trunk is the main path; 3) both superficial and deep veins are involved. These morphological considerations are the basis for selection of veins for anastomosis in microsurgery. The axial veins in temporal, frontal and facial flaps on the dorsum of the hand and the foot usually loosely accompany the axial arteries. The characteristics of these vascular pedicules should be studied in transplant operation.

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Bases anatomiques du drainage veineux des lambeaux cutanés libres

Résumé Le drainage veineux des lambeaux cutanés libres a été étudié sur 17 cadavres frais par injection de latex ou d'encre dans les vaisseaux, ou en réalisant des moulages par injection-corrosion. La distribution des veines ressemble à celle des artères à la différence près qu'il existe des troncs veineux qui n'accompagnent pas les artères. Ces troncs ont un calibre plus important et représentent une voie de drainage principale pour les lambeaux. On peut individualiser trois types de drainages basés sur l'architecture veineuse : 1. Le tronc superficiel est la principale voie de drainage ; 2. le tronc profond est la principale voie; 3. les veines superficielles et profondes sont impliquées simultanément. Ces considérations morphologiques sont les bases de la sélection des axes veineux pour les anastomoses en micro-chirurgie. Les veines axiales au niveau temporal, frontal et facial et pour les lambeaux de la face dorsale de la main et du pied sont habituellement relativement éloignées du trajet artériel. Les caractéristiques de ces pédicules veineux doivent être précisées pour la réalisation des lambeaux.

     

Bulimia in male patients

Bulimia is not exclusively a disorder of women. Twelve men with bulimia were evaluated and found to have demographic variables and eating behaviors similar to those of female bulimia patients. Eleven of the 12 men were binge eating more than once a day, and ten of the 12 also self-induced vomiting on a regular basis. Three patients had initiated bulimic behavior in association with athletic training. Eight patients followed through with treatment referrals and responded favorably to therapy.     

Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction

Y chromosome deletions encompassing the AZFc region have been reported in 13% of azoospermic men and 7% of severely oligozoospermic men. We examined the impact of these Y deletions on the severity of testicular defects in 51 azoospermic men undergoing intracytoplasmic sperm injection (ICSI) after testicular sperm extraction (TESE) and 30 men with severe oligozoospermia undergoing ICSI after ejaculation of spermatozoa. In addition, five azoospermic patients shown previously to have Y chromosome deletions underwent histological evaluation of their previously obtained testis biopsy specimens. A further 27 azoospermic men underwent TESE-ICSI, but not Y chromosome DNA testing. Ten of 51 azoospermic men (20%) who underwent TESE-ICSI and Y-DNA testing were found to be deleted for portions of the Y chromosome AZFc region. Of these 10, five had spermatozoa retrievable from the testis, and in two cases the wives became pregnant. Of the 41 azoospermic men with no Y chromosome deletion, 22 (54%) had spermatozoa retrievable from the testis, and in 12 cases (29%) the wives became pregnant. Four of 30 (13%) severely oligozoospermic patients were found to be deleted for AZFc and in three (75%) of these pregnancy was achieved. The other 26 severely oligozoospermic couples who had no AZFc deletions underwent ICSI, and 12 (46%) have an ongoing or delivered pregnancy. The embryo implantation rate was not significantly different for azoospermic (22%), oligozoospermic (16%), Y-deleted (14%) or Y-intact (18%) men. Of the total of 19 infertile men who had Y chromosome deletions, 14 had deletions within Y chromosome intervals 6D-6F, in the AZFc region. Twelve of those 14 had some spermatozoa (however few in number) in the ejaculate or testis. Five of the Y-deleted men had deletions that extended more proximally on the Y chromosome, and in none of these could any spermatozoa be observed in either ejaculate or testis. These results support the concept that, in azoospermic or oligozoospermic men with Y chromosome deletions limited to intervals 6D-6F (AZFc), there are generally very small numbers of testicular or ejaculated spermatozoa. Larger Y deletions, including and extending beyond the AZFc region and encompassing more Y genes, tend to be associated with a total absence of testicular spermatozoa. In those cases where spermatozoa were retrieved, the presence of Y deletions had no obvious impact on fertilization or pregnancy rate.