Primary biliary cirrhosis. A retrospective survey at Groote Schuur Hospital, Cape Town

Primary biliary cirrhosis (PBC) or chronic non-suppurative destructive cholangiohepatitis is rare in southern Africa. Eight patients with this diagnosis were identified and fully investigated at Groote Schuur Hospital between 1980 and 1988. Seven patients were female, all were white or coloured, and their ages ranged from 49 years to 80 years. All patients presented with a history of malaise, fatigue, night sweats and pruritus, which had been present for 3 months--12 years before diagnosis of PBC. Initial misdiagnosis had resulted in unnecessary invasive investigations including laparotomies. Signs of chronic liver disease, such as xantholasmas, evidence of pruritus, the sicca syndrome or hepatomegaly, were invariably present. Marked elevation of serum alkaline phosphatase level and IgM were present in all cases. Antimitochondrial antibodies were positive in significant titre in 7 of the 8 patients. Liver biopsies demonstrated stage II-III disease in all patients. Therapy was chiefly supportive and symptomatic although most patients received immunosuppressive agents. Despite the late presentation, the subsequent course was similar to that seen elsewhere where patients are recognised earlier.     

A novel strategy for the detection and definition of HLA-specific antibodies in patients awaiting renal transplantation

Abstract Conventional testing for HLA-specific antibodies employs complement-dependent cytotoxicity (CDC) which is labour intensive and dependent on a supply of viable lymphocytes. Our strategy to minimise CDC screening is initially to screen sera by ELISA (Quikscreen) to detect HLA Class I-specific antibodies. Negative sera are then screened by flow cytometry (FCS) using lymphoblastoid cell line pools to detect HLA Class II-specific antibodies. Only Quikscreen-or FCS-positive sera are then tested by CDC and, when indicated, with an ELISA kit (PRA-STAT) for specificity definition. Of 3680 sera, 886 (24.1%) were Quikscreen positive. Of the 2794 Quikscreen-negative sera, 374 (13.4%) were FCS positive. Therefore, only 1265 of the 3680 (34.3%) sera contained HLA-specific antibodies requiring specificity definition. This novel screening strategy has significantly reduced the CDC workload of the laboratory whilst enabling the detection of additional HLA-specific antibodies.     

Burn sepsis

Sepsis in the burned individual can arise from multiple causes. However, the unique source is the burn wound itself. It is clear that health is association with maintenance of a bacterial equilibrium in the wound and that infection is a result of an imbalance in favor of the bacteria. The primary host defense mechanism, an intact epithelial barrier, has been lost at the time of burning. A portal of entry has been created, and the bactericidal defenses have been neutralized. All of the host defense mechanisms associated with inflammation are evoked but may be limited by the avascular isolation of much of the wound. In addition to alteration in vascular response associated with the burns, there are adverse changes in the neutrophils themselves. The alterations in nutrition that may follow burn injury further reduce systemic host resistance. Associated diseases, such as diabetes, may present a further hazard. All of the local factors influencing host resistance are adversely affected in the burn wound. There is necrotic tissue, decreased local tissue perfusion, and loss of the mechanical barrier. Quantitative techniques have demonstrated that bacteria are present in the depths of the wound from the time of injury. Infection and burn wound sepsis are clearly represented by the quantitative increase in bacteria to numbers exceeding 10(5) per gram of tissue. In no other instance has the importance of the "amphibiont" organisms been more clearly demonstrated than in the burn wound. Today's nonpathogen has all too often become tomorrow's killer. As therapeutic control becomes effective against the current organism, the ecologic void is filled by another, which, by definition, is resistant to the treatment being employed.     

Angiotensin-(1–7) stimulates water transport in rat inner medullary collecting duct: evidence for involvement of vasopressin V2 receptors

The peptide angiotensin-(1–7) [Ang-(1–7)] is known to enhance water transport in rat inner medullary collecting duct (IMCD). The aim of this study was to determine the mechanism of the Ang-(1–7) effect on osmotic water permeability (P _f). P _f was measured in the normal rat IMCD perfused in vitro in presence of agonists [Ang-(1–7), arginine vasopressin (AVP) and Ang-(3–8)], and antagonists of the angiotensin and the vasopressin cascade. Ang-(1–7), but not Ang-(3–8), increased P _f significantly. The effect of Ang-(1–7) on P _f was abolished by its selective antagonist, A-779, added before or after Ang-(1–7). Prostaglandin E₂ and the protein kinase A inhibitor H8 also blocked the Ang-(1–7) effect. Blockade of vasopressin V₁ receptors by antagonists did not change the Ang-(1–7) effect, but pre-treatment with a V₂ antagonist abolished the effect of Ang-(1–7) on P _f. Similarly, pre-treatment with A-779 inhibited AVPs effect on P _f. Forskolin-stimulated P _f was blocked both by A-779 and by the V₂ antagonist. Finally, Ang-(1–7) increased cAMP levels in fresh IMCD cell suspensions whilst the forskolin-stimulated cAMP synthesis was decreased by A-779 and the V₂ antagonist. These data provide evidence that Ang-(1–7) interacts via its receptor with the AVP V₂ system through a mechanism involving adenylate-cyclase activation.     

Performance characteristics of a rapid new immunochromatographic test for detection of antibodies to human immunodeficiency virus

A new immunochromatographic rapid test (Rapid Check HIV 1 and 2; Núcleo de Doen?as Infecciosas) for the detection of antibodies to human immunodeficiency virus type 1 and type 2 in human samples (whole blood, serum, and plasma) was evaluated and compared to the commercially available Determine (Abbott Laboratories). When whole-blood samples were evaluated, the specificity and sensitivity of both tests were 100%. However, when plasma samples were used, sensitivity for the Rapid Check HIV 1&2 and the Determine tests were 100 and 98.58%, respectively. The observed specificity for plasma samples was 98.94% for the Rapid Check HIV 1&2 and 96.97% for the Determine test. The results presented here are encouraging and support the adoption of both tests as an alternative to enzyme-lined immunosorbent assay and/or Western blots in regions where laboratorial infrastructure is not available or for use in the management of occupational accidents for healthcare workers.     

Lack of directed Vα14-Jα281 rearrangements in NK1+ T cells

NK1.1⁺ T cells are an unusual subset of TCRαβ cells distinguished by their highly restricted Vβ repertoire and predominant usage of an invariant Vα14-Jα281 chain. To assess whether a directed rearrangement mechanism could be responsible for this invariant α chain, we have analyzed Vα14 rearrangements by polymerase chain reaction and Southern blot in a panel of cloned T-T hybrids derived from thymic NK1.1⁺ T cells. As expected a high proportion (17/20) of the hybrids had rearranged Vα14 to Jα281. However, Vα14-Jα281 rearrangements always occurred on only one chromosome and were accompanied by other Vα-Ja rearrangements (not involving Vα14) on the homologous chromosome. These data argue that rigorous ligand selection rather than directed rearrangement is responsible for the high frequency of Vα14-Jα281 rearrangements in NK1.1⁺ T cells.     

Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes

Notch proteins influence cell fate decisions in many developmental systems. During lymphoid development, Notch1 signaling is essential to direct a bipotent T/B precursor toward the T cell fate, but the role of Notch1 at later stages of T cell development remains controversial. We have recently reported that tissue-specific inactivation of Notch1 in immature (CD44(-) CD25(+)) thymocytes does not affect subsequent T cell development. Here, we demonstrate that loss of Notch1 signaling at an earlier (CD44(+)CD25(+)) developmental stage results in severe perturbation of alpha beta but not gamma delta lineage development. Immature Notch1(-/-) thymocytes show impaired VDJ beta rearrangement and aberrant pre-TCR-independent survival. Collectively, our data demonstrate that Notch1 controls several nonredundant functions necessary for alpha beta lineage development.