Treatment of NZB/NZW F1 hybrid mice with Mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.     

Female double urethra: a case report

Female double urethra is a very rare anomaly, with less than 40 cases reported since 1970. Most reported cases of double urethra are in the sagittal plane and tend to be stenotic. We describe a 4-year-old girl with double urethra, which was not stenotic and was in the coronal plane. Double urethra should be excluded among other causes in any girl who is incontinent beyond the continence age.     

Diabetic Foot Disease: Emerging Technologies: Diabetic Peripheral Neuropathy and Gait: Does Footwear Modify This Association?

Background

Gait-related fall risk is the leading cause of mortality among patients with diabetes, especially those older than 65 years. Deterioration in balance and loss of protective sensation in lower extremities contribute significantly to fall risk in patients with diabetic peripheral neuropathy (DPN). This study aimed to explore the impact of neuropathy and foot ulcer on gait.

Methods

We recruited 39 participants (age, 56.9 ± 8.2 years; body mass index, 29.6.3 ± 4.7 kg/m²), including 15 DPN patients without foot ulcers, 16 DPN patients with foot ulcers, and 8 healthy aged-matched controls. Patients with active foot ulcers wore an offloading device during gait examination, including removable cast walker.

Results

Results suggest that neuropathy alters gait mainly by increasing gait initiation, gait variability (coefficient of variation of gait velocity), and double support (DS) time, while reducing knee range of motion and center of mass sway (p < .05). Interestingly, the presence of foot ulcer does not impact gait velocity (p > .1) but enhances some of the gait parameters such as gait variability and DS time.

Conclusions

This study demonstrates that neuropathy deteriorates gait, but the presence of foot ulcers does not alter gait parameters further than neuropathy. In addition, patients with foot ulcers demonstrated a better gait compared with DPN patients without ulcers. We speculate that offloading footwear may be enhancing the somatosensory feedback from sensate skin, thereby positively affecting gait parameters. A study with a larger sample is required to explore the effect of prescribed footwear in the DPN population in order to validate the findings of this research study.     

Delayed androgen treatment prolongs survival in murine lupus.

Female NZB/NZW F1 mice were treated as adults with 5-alpha-dihydrotestosterone powder packed into subcutaneous implants. Two treatment protocols were followed: (a) 3-mo-old mice received 6 mg of androgen, and (b) 6-mo-old mice were castrated and given 12 mg of androgen. Sham females received empty implants. Mice were followed monthly for surival, for antibodies to DNA and polyadenylic acid, and for renal histopathology. The percent survival at 11 mo was 74% for mice treated at 3 mo, compared to 11% for the sham controls, and 100% for mice treated at 6 mo, compared to 20% for their sham controls. Androgen-treated mice had less immune complex glomerulonephritis as determined by immunofluorescent and electron microscopy. Surprisingly, treated mice had no significant sustained reduction in antibodies to DNA although they had reduced antibodies to polyadenylic acid. These results suggest that androgens can still prolong survival and reduce immune complex deposition even when treatment is delayed to an age when disease is relatively established. After delayed androgen treatment, mice survive despite the presence of high levels of IgG antibodies to DNA.     

Lymphocyte subsets in Sjogren's syndrome: a quantitative analysis using monoclonal antibodies and the fluorescence-activated cell sorter

Lymphocyte subsets in the peripheral blood of 18 patients with Sjogren's syndrome (SS) were studied using monoclonal antibodies and the fluorescence-activated cell sorter (FACS). The percentage of T cells was decreased when compared to normal controls. In primary SS, there was a proportional decrease in both suppressor/cytotoxic (anti-Leu-2a reactive) and helper/inducer (anti-Leu-3a reactive) T cells with an unchanged helper/suppressor ratio (1.8 vs. 1.7 for normals). In SS with an associated connective tissue disorder, there was a significant decrease only in the suppressor/cytotoxic subset. There was increase in B cells and null cells in primary SS compared to controls. Quantitative immunofluorescence allowed the calculation of determinant density per cell. Cells expressing low antigen density Leu-2a were increased in 8 patients (4 with primary SS and 4 with SS with an associated disorder). Thus, in addition to quantitative changes in lymphocyte subsets, we found changes in Leu-2a expression suggesting abnormal differentiation of the suppressor/cytotoxic subset. These changes may contribute to the immunoregulatory disturbance in Sjogren's syndrome.     

Epitope specificity of anti-La antibodies from patients with Sj?gren's syndrome

To investigate patterns of autoreactivity in Sj?gren's syndrome, the epitope specificity of anti-La antibodies was determined using recombinant antigens bearing sequences of the amino, middle, and carboxyl portions of the La molecule. Sera from patients with primary as well as secondary Sj?gren's syndrome reacted with all three fragments, although the magnitude of the responses varied markedly among individuals. Furthermore, the proportion of antibody binding directed to the different La epitopes showed considerable individual variations, but these patterns were not correlated with specific clinical manifestations. These results suggest that quantitative and qualitative aspects of anti-La responses in Sj?gren's syndrome are determined by factors distinct from those determining the clinical expression of disease.     

Androgenic Hormones Modulate Autoantibody Responses and Improve Survival in Murine Lupus

Antibodies to native DNA and to polyadenylic acid (Poly A) occur spontaneously and undergo a regulated switch from IgM to IgG during the course of autoimmune disease in NZB/NZW F₁ (B/W) mice. B/W females have higher titers and earlier commitment to 7S antibodies to DNA and Poly A, whereas B/W males bind DNA and Poly A primarily by 19S antibodies. We have performed castration experiments to determine the effects of sex hormones on this switch from IgM to IgG.     

Thymosin Corrects the Abnormal DNA Synthetic Response of NZB Mouse Thymocytes

New Zealand Black (NZB) mice develop after 16 weeks of age an autoimmune and lymphoproliferative disease which is a model for systemic lupus erythematosus and lymphoid malignancy in humans. At this age, the mice manifest a progressive decline in T lymphocyte (thymus-derived lymphocyte) functions and serum thymosin levels. Thymocytes from 8-week old NZB mice exhibit an abnormal DNA synthetic response when transplanted into lethally irradiated C57B1/6 recipients. DNA synthesis (measured as the incorporation of radioactively labeled 5-iodo-2'-deoxyuridine) is delayed in onset and still increasing 6 days after cell transfer. By contrast, 2-week old NZB thymocytes show a normal response which is rapid in onset and completed by day 6.NZB mice were injected with thymosin fraction 5 or with bovine serum albumin starting at 2 weeks of age. Thymocytes from 8-week old thymosin-treated mice showed a normal DNA synthetic response, whereas the albumin-treated controls showed the abnormal response expected at this age. The ability of thymosin to correct the DNA synthetic response was related to dose and duration of treatment. These results suggest that thymosin can induce a more normal state of thymocyte differentiation in NZB mice. If abnormal thymocyte differentiation is related to the subsequent emergence of autoimmunity and lymphoid malignancy, then continuous treatment with thymosin may have therapeutic potential. These experiments suggest that an endocrine disturbance may contribute to autoimmune and lymphoproliferative disease in NZB mice and possibly in humans.