Proliferation of Ly-1 B cells in autoimmune NZB and (NZB x NZW)F1 mice

Spontaneous autoimmune disease in NZB and (NZB x NZW)F1 (B/W) mice is associated with a spectrum of lymphoproliferative abnormalities, but the relationship between autoimmunity and lymphoproliferation is poorly understood. Lymphomas occur commonly in NZB mice, but they appear to be rare in B/W mice, perhaps because B/W mice die of murine lupus before the lymphomas are evident. We recently reported that autoimmune disease in B/W mice could be reversed by weekly treatment with monoclonal antibodies to the L3T4 antigen on "helper/inducer" T cells. This has enabled us to examine the evolution of lymphoproliferation in B/W mice that survive beyond the usual life span, both in long-term survivors of treatment with anti-L3T4 and in the occasional B/W mouse that spontaneously survives beyond 1 year of age. We find that all of these mice develop marked proliferation of a distinct subpopulation of B cells that express the Ly-1 antigen in low density. These Ly-1+ B cells account for a 2-10-fold increase in the number of splenic, lymph node and peripheral blood lymphocytes. The Ly-1 B cells in individual mice are restricted in their expression of immunoglobulin light chains, suggesting a clonal origin. NZB mice. develop similar proliferation of Ly-1 B cells, suggesting that this is due to underlying genetic and/or viral factors in NZB and B/W mice, and that it is not the result of treatment with anti-L3T4. Although recent studies have implicated Ly-1 B cells in the production of autoantibodies, proliferation of Ly-1 B cells in B/W mice was not associated with production of anti-DNA antibodies or with any paraprotein.     

Induction of Th1 cytokine responses by mycobacterial antigens in leprosy.

Twelve mycobacterial antigens were compared for induction of gamma interferon (IFN-gamma) secretion by human blood mononuclear cells of patients with leprosy. Fractionated Mycobacterium leprae antigens containing cell wall proteins or cytosolic and membrane proteins induced good IFN-gamma responses in tuberculoid leprosy patients. Lipoarabinomannan from M. tuberculosis Erdman and M. leprae mycolylarabinogalactan peptidoglycan were the poorest IFN-gamma inducers.     

Extended epidemic of nosocomial urinary tract infections caused by Serratia marcescens

In recent years a significant increase in the incidence of Serratia marcescens infections was noted at the Chang Gung Memorial Hospital, Taoyuan, Taiwan. A review of laboratory (1991 to 2002) and infection control (1995 to 2002) records showed the possibility of an extended epidemic of nosocomial urinary tract infections (UTIs) caused by S. marcescens. Therefore, in 1998 and 1999, 87 isolates were collected from patients with such infections and examined and another 51 isolates were collected in 2001 and 2002. The patients were mostly elderly or the infections were associated with the use of several invasive devices. S. marcescens was usually the only pathogen found in urine cultures in our study. Neither prior infections nor disseminated infections with the organism were observed in these patients. Resistance to most antibiotics except imipenem was noted. Two genotyping methods, pulsed-field gel electrophoresis and infrequent-restriction-site PCR, were used to examine the isolates. A total of 12 genotypes were identified, and 2 predominant genotypes were found in 72 (82.8%) of the 87 isolates derived from all over the hospital. However, 63.9% of the isolates of the two genotypes were from neurology wards. A subsequent intervention by infection control personnel reduced the infection rate greatly. The number and proportion of the two predominant genotypes were significantly reduced among the 51 isolates collected in 2001 and 2002. Thus, a chronic and long-lasting epidemic of nosocomial UTIs caused by S. marcescens was identified and a successful intervention was carried out. Both a cautious review of laboratory and infection control data and an efficient genotyping system are necessary to identify such a cryptic epidemic and further contribute to the quality of patient care.     

Synergistic antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of Vibrio vulnificus infection.

BACKGROUND AND PURPOSE: Vibrio vulnificus causes primary bacteremia and necrotizing wound infection, leading to high morbidity and mortality in humans. This study aimed to evaluate the antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of V. vulnificus infection. METHODS: We investigated the dynamics of proinflammatory cytokines and their modulation by antimicrobial agents using a murine model of V. vulnificus infection. The change in cytokine levels was followed over a time course to identify the antimicrobial activity of the drugs against V. vulnificus. BALB/c female mice were challenged with an intraperitoneal infection using a clinical invasive isolate of Vv05191, and their cytokine levels were assayed over various time points. RESULTS: Serum levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 post-infection were found to be inoculum dose-dependent and positively correlated to the subsequent fatality rate in the infected mice. With an inoculum of 6.6 x 10(6) colony-forming units and intraperitoneal administration of cefotaxime, minocycline, or both, the serum and peritoneal fluid cytokine levels increased and then declined gradually. Comparison of the 3 antimicrobial regimens revealed that the magnitude of reduction in cytokine levels was greatest in mice treated with cefotaxime-minocycline combination. Moreover, the peritoneal fluid cytokine level in the combination group was significantly lower than that in the groups treated with minocycline or cefotaxime alone. CONCLUSIONS: The current results support the superiority of the combination therapy in treating invasive V. vulnificus infections.     

De novo mutation in the BTK gene of atypical X-linked agammaglobulinemia in a patient with recurrent pyoderma.

BACKGROUND: X-linked agammaglobulinemia (XLA), characterized by a profound deficiency of all immunoglobulins and the absence of mature B cells, is caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). Most patients have recurrent sinopulmonary infection. Infections usually occur in multiple locations across time, but single infection may be limited to one anatomic location. OBJECTIVES: To report a case of atypical XLA with recurrent pyoderma and to observe the immunologic changes in the patient in 10 years. METHODS: Immunologic investigations, skin wound culture, and molecular study with DNA sequencing were performed. RESULTS: The patient was originally diagnosed as having common variable immunodeficiency disease because of the presence of circulating B cells (CD19+ B cells: 7%) at 11 years old. On further evaluation at the age of 20 years, flow cytometric analysis of lymphocytes showed only 0.4% B cells. The molecular study with DNA sequencing of the patient showed a point mutation in complementary DNA 1630 A>G(p.R544G) in the BTK gene, indicating that the patient has XLA. The mutation analysis of the BTK gene revealed a normal DNA sequence in the other family members. CONCLUSIONS: This case is an important example of a possible presentation of XLA with a predominant skin manifestation, and it demonstrates that maintaining a high level of clinical suspicion is essential for the diagnosis of XLA in a child with recurrent pyoderma.     

Effects of GABA receptor antagonist on trigeminal caudalis nociceptive neurons in normal and neonatally capsaicin-treated rats

We have recently demonstrated that significant increases in cutaneous mechanoreceptive field (RF) size and spontaneous activity occur in nociceptive neurons of trigeminal subnucleus caudalis (Vc, the medullary dorsal horn) of adult rats depleted of C-fiber afferents by neonatal treatment with capsaicin. These neuronal changes in capsaicin-treated (CAP) rats are suggestive of central neuroplasticity and involve N-methyl-D-aspartic acid (NMDA) receptor mechanisms. The present study examined whether the GABA(A) receptor antagonist bicuculline (BIC) or the GABA(B) receptor antagonist 2-hydroxysaclofen (SAC) can influence the RF properties and activity of Vc nociceptive neurons classified as either nociceptive-specific or wide-dynamic range in CAP adult rats or in neonatally vehicle-treated (CON) rats. C-fiber depletion was confirmed in the CAP rats by a significant decrease in plasma extravasation of Evans blue dye in a skin area receiving topical application of mustard oil, a small-fiber excitant and inflammatory irritant. As previously reported, marked increases in cutaneous RF size and spontaneous activity occurred in Vc nociceptive neurons of adult CAP rats, compared with CON rats. GABA(A) receptor blockade by BIC (i.t.) in CON rats produced a significant increase in spontaneous activity and in pinch RF size and tactile RF size (or appearance of a tactile area in the RF of nociceptive-specific neurons), as well as a significant lowering of the mechanical threshold and a significant enhancement of responses to pinch stimuli applied to the RF. In CAP rats, GABA(A) receptor blockade also produced significant changes similar to those documented in CON rats, except for a paradoxical and significant decrease in pinch RF size and no noticeable changes in responses to pinch stimuli. GABA(B) receptor blockade by SAC (i.t. ) did not produce any significant changes in Vc nociceptive neurons in either CON or CAP rats. These results suggest that GABA(A) receptor-mediated inhibition may be involved in maintaining the functional expression of Vc nociceptive neuronal properties in normal conditions, and that in animals depleted of their C-fiber afferents, some features of this GABA(A) receptor-mediated modulation may be disrupted such that a GABA(A) receptor-mediated excitation is manifested.     

The significance of somatosensory stimulations to the human foot in the control of postural reflexes

 The purpose of this study was to investigate the possible pathways in the somatosensory system that relate to the postural reflexes in the leg muscles during a sudden, toes-up platform rotation. The inputs to the cutaneous mechanoreceptors in the sole of the foot as well as to the joint receptors in the ankle joint were modulated by standing on different supporting surfaces and by immobilizing the ankle joints; and three leg muscle responses (characterized by short latency, medium latency, and long latency) to the platform movement were recorded in 15 healthy young subjects. It was found that: (1) the short latency was not affected by the changes in either plantar pressure or ankle joint movement; (2) the medium latency was regulated by the plantar pressures under the foot, as sensed by the cutaneous mechanoreceptors in the sole of the foot, and by the ankle joint movement, as perceived by the joint receptors in the ankle joint; (3) the long latency was also related to the ankle joint movement, but this relation seems to be modulated by the plantar pressures under the foot; and (4) both medium and long latencies were well correlated with the time derivative of the pressure difference between the forefoot and the rear foot regions (r=0.7), as well as with the static pressure in the antagonist foot region (r>0.6). Received: 12 January 1996 / Accepted: 30 September 1996     

Ventral specification and perturbed boundary formation in the mouse midbrain in the absence of Hedgehog signaling.

Although Hedgehog (HH) signaling plays a critical role in patterning the ventral midbrain, its role in early midbrain specification is not known. We examined the midbrains of sonic hedgehog (Shh) and smoothened (Smo) mutant mice where HH signaling is respectively attenuated and eliminated. We show that some ventral (Evx1+) cell fates are specified in the Shh-/- mouse in a Ptc1- and Gli1-independent manner. HH-independent ventral midbrain induction was further confirmed by the presence of a Pax7-negative ventral midbrain territory in both Shh-/- and Smo-/- mice at and before embryonic day (E) 8.5. Midbrain signaling centers are severely disrupted in the Shh-/- mutant. Interestingly, dorsal markers are up-regulated (Wnt1, Gdf7, Pax7), down-regulated (Lfng), or otherwise altered (Zic1) in the Shh-/- midbrain. Together with the increased cell death seen specifically in Shh-/- dorsal midbrains (E8.5-E9), our results suggest specific regulation of dorsal patterning by SHH, rather than a simple deregulation due to its absence.