Loss of suppressor T cells in adult NZB/NZW mice.

We have investigated suppressor T-cell activity in female NZB/NZW F1 mice using PWM-driven IgM biosynthesis in vitro as an indicator system. In initial we studied we observed that spleen cells from normal mice (BALB/c, C57BL/6), as well as from young (4 wk) and adult (18 wk) NZB/NZW mice, cultured in the presence of PWM synthesize 860 +/- 120 ng IgM/10(6) cells/7 days. However, when Con A (at 2 mug/ml) was added directly to the cultures (along with PWM), cells obtained from adult normal mice and young NZB/NZW mice showed a 94% suppression of IgM synthesis, whereas cells obtained from adult NZB/NZW mice were suppressed significantly less. To analyze these findings we studied the effect of Con A-induced suppressor cells (cells cultured with Con A for 24 h and washed free of Con A) on PWM-driven IgM biosynthesis. Spleen cells obtained from normal mice cultured in the presence of Con A-pulsed cells obtained from normal mice and young NZB/NZW mice showed an 83-88% suppression of PWM-driven IgM synthesis. Similarly, supernates obtained from Con A-pulsed cells of normal mice or of young NZB/NZW mice suppressed PWM-driven IgM synthesis. This suppression by Con A-pulsed cells and their supernates required T cells since T-cell fractions but not B-cell fractions eluted from anti-Fab Sephadex columns mediated suppression of co-cultured normal cells; in addition, Con A-pulsed cells treated with anti-theta and complement do not mediate suppression. These studies of Con A-induced suppressor cell activity in normal mice and young NZB/NZW mice contrast with studies of Con A-induced suppressor cell activity in adult NZB/NZW mice. We found that adult NZB/NZW Con A-pulsed cells and supernates obtained from the Con A-pulse cells had vastly decreased suppressor potential; in this case the Con A-pulse cells and supernatant fluids derived from such cells did not suppress PWM-driven IgM synthesis by normal cells. Finally, whereas spleen cells from young and adult NZB/NZW mice differ in their suppressor cell potential, cells from both sources could respond equally to suppressor signals in that Con A-pulsed normal cells or supernates derived from such cells caused equivalent suppression of PWM-driven IgM synthesis by young and adult NZB/NZW cells. These observations allow us to conclude that NZB/NZW mice lose suppressor T-cell activity as they age.

Lymphocyte stimulation: selective destruction of cells during blastogenic response to transplantation antigens.

The blastogenic response of human lymphoid cells toward any individual's transplantation antigens can be deleted by the addition of tritiated thymidine of high specific activity during the incubation of the lymphoid cells in mixed leukocyte culture. After the immunocompetent clones which responded to histocompatibility antigens had been destroyed, the remaining population still retained its capacity to respond to unrelated antigens, including other transplantation antigens.

Prevention of autoimmunity in experimental lupus erythematosus by soluble immune response suppressor.

Young NZB/W mice, treated with injections of soluble immune response suppressor (SIRS)(supernatant from mouse spleen cells exposed to concanavalin A), showed decreased immunoglobulin levels, less antibody to cell nuclei, less proteinuria, and less renal pathology as compared with NZB/W mice receiving a control preparation. Thus, SIRS administration beginning at an early age appears to be an effective therapy of the autoimmune disease in NZB/W mice.

Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer's Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?

BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.

Development of systemic lupus erythematosus after thymectomy for myasthenia gravis. Studies of suppressor cell function.

Systemic lupus erythematosus developed in an 18-year-old man three years after thymectomy for myasthenia gravis. The patient had considerable defects in suppressor cell function that seemed to be partially reversed in vitro by the addition of thymic hormone.

Circulating immune complexes in rheumatoid arthritis. Selective removal by cryogelation with membrane filtration.

We have developed a system of extracorporeal circulation that removes proteins of the molecular weight of the circulating immune complexes of rheumatoid arthritis by cryogelation with hollow-fiber membrane filtration. A 52-year-old woman with a 36-year history of severe, unremitting, high-titer, seropositive rheumatoid arthritis who had failed to respond to anti-inflammatory, antirheumatic, and cytotoxic drugs was chosen for a trial of this system. A rapid and sustained decrease in circulating immune complexes as measured by C1q binding occurred, accompanied by a much slower improvement in clinical factors of disease activity. Rheumatoid factor changed very little and loss of other serum proteins by the procedure was relatively modest. This new procedure was successful in removing circulating immune complexes in a patient with rheumatoid arthritis, and in inducing a remission in one who has not had such in 36 years, while sparing volume and other plasma proteins.

Digoxin concentration in choroid plexus, brain, and myocardium in old age.

Thirteen aged persons receiving digoxin until the time of death were examined by autopsy, and digoxin concentrations were determined in samples from various tissues (the choroid plexus, grey and white brain matter, left and right ventricular and left and atrial myocardium, diaphragm, and musculus psoas major). These concentrations were related to the digoxin dose and duration of treatment. No significant difference was found between the concentration of digoxin in the choroid plexus and left ventricular myocardium, whereas there were significantly lower concentrations in the right ventricular myocardium and still lower concentrations in the other tissues analyzed. Independent of the digoxin dose, the digoxin concentrations in the choroid plexus tended to be lower in persons treated for a short time before death than in those treated for longer periods of time. Similar differences were not observed in the other tissues, suggesting a slower rate of digoxin uptake in the chroid plexus compared with the myocardium and other tissues. The implications of these findings for the effects of digoxin treatment on the production of cerebrospinal fluid are discussed.

A quantitative assay for low levels of IgM by solid-phase immunofluorescence.

A quantitative immunofluorescent assay capable of detecting between 15 and 1450 ng of IgM on a strictly linear standard curve has been developed. The assay system is unique in that in vitro biosynthesized polyclonal IgM in culture supernatants can be quantitated with a minimal quantity of supernatant. Interference created by lectins and bead-surface interactions have been analyzed. This easily operated assay has been validated and is reliable. A very important feature of the system is the considerable cost reduction in comparsion with radiometric techniques.

Therapeutic trial of cryofiltration in patients with rheumatoid arthritis.

Cryofiltration, a new technique for on-line plasma separation and its treatment by cold filtration, enables the selective removal of immune complexes and eliminates the need for replacement proteins. Fifteen patients with rheumatoid arthritis were treated for nine to 10 consecutive sessions over a three- to five-week period. Circulating immune complexes decreased by an average of 78 percent and rheumatoid factor by 32 percent. This was accompanied by significant clinical improvement in morning stiffness, articular index, 50-foot walking time, grip strength, and target joint circumference. Cryofiltration might thus be beneficial for a subgroup of rheumatoid arthritis patients in whom conventional therapy has failed.

Abnormalities of immunoregulation in progressive systemic sclerosis. Evidence for excess helper-cell function and altered B-cell function.

We investigated immunoregulatory function in patients with progressive systemic sclerosis (PSS) in terms of in vitro IgM synthesis. Suppressor-cell function seems normal in regard to the ability of concanavalin A-treated cells to inhibit IgM synthesis by normal cells. At 4 x 10(5) T cells to 3 x 10(5) allogeneic normal B cells per milliliter, T cells from patients with PSS induce significantly more IgM synthesis by normal B cells than do normal T cells. This increased helper T-cell function might be involved in the pathogenesis of the disease.

Suppressor cell function in psoriasis.

Recent studies suggest that autoimmunity may play a role in the pathogenesis of psoriasis. In view of these findings, it is postulated that the immunologic defect may be associated with regulation of the immune system. A study was undertaken to determine whether a suppressor cell defect was present. Two groups of patients with active psoriasis who were receiving no therapy were selected. Peripheral blood lymphocytes were pulsed with concanavalin A, 40 microgram/cc, for 48 hours. Their ability to suppress a mixed lymphocyte reaction with both autologous and allogeneic responding cells was assessed. There was a significant decrease in suppressor activity in psoriasis patients compared with normal individuals. Although we have not demonstrated that this mechanism is implicated directly in a causal relationship to psoriasis, it nevertheless gives further support to the possible role of the immune system in the pathogenesis of psoriasis.

Survey of health planning proposals.

It is important that physicians participate in the debate and planning process that will ultimately guide how we reform the way health care is financed and delivered in the United States. Herein is offered a perspective on the problem, one which is not necessarily appreciated by health planners. While we deliver the best quality of care in the world to most of our population, our system has been severely criticized because we fail to provide for access to a substantial minority of our population. Additionally, the cost of the product is considerably greater than that in comparable countries. Attempts to control costs without diminishing quality have introduced expensive complexities into our system without any real success in cutting costs. Several proposals have been advanced to address the issues of cost and access. One of these is a single payer system, common in Europe and Canada, whereby a single agent or group of agents finances all health care through universal rules and means. A system operating in Hawaii is a simple employer mandate to provide health insurance. A uniquely American plan is the Jackson Hole Plan or Managed Competition (now called "Managed Cooperation"). This system is currently popular among national health planners, and involves a defined minimum managed health plan offered by various groups of providers to employees and individuals through health plan purchasing cooperatives. This plan is interesting, but has not been implemented in any jurisdiction, and it is not certain it would accomplish its goals in practice since it is difficult to predict behavior of all parties to such a system.

[Urinary symptoms in elderly women in nursing homes. Frequency and social consequences of urinary incontinence in elderly women living in nursing homes]. / Urinvejsgener hos gamle plejehjemsboende kvinder. Hyppighed og sociale konsekvenser af urin-inkontinens hos gamle plejehjemsboende kvinder.

All 278 female residents of nursing homes in the County of Roskilde were assessed as regards the extent and severity of urinary incontinence and possible urinary infections. A total of 168 (58.5%) were incontinent. Culture of the urine was performed in 210 women and significant bacteriuria was demonstrated in 50%. Thirty-four out of the total of 287 women (12%) had indwelling catheters. In incontinent women without catheters, great quantities of urine were often voided involuntarily. Despite this, only few were subjectively inconvenienced or inhibited in their social activities. The investigation revealed a connection between urinary incontinence and reduced mobility while no connection was observed with current urinary infections, intake of medicaments and parity. It is emphasized that these results are based on findings in very old women living in nursing homes.

Oral zinc therapy in geriatric patients with selected skin manifestations and a low plasma zinc level.

A geriatric population comprising 585 inhabitants of an institution for the aged was studied. Twenty-six persons with a mean age of 82 years were selected because of skin manifestations suggestive of chronic zinc deficiency. In 10 of the patients a subnormal plasma zinc level was found. This hypozincaemic group underwent a 4 week trial with zinc sulphate tablets, 0.6 g daily. The therapy failed to alleviate the skin condition in any of the patients, thus indicating that the changes were not caused by zinc deficiency. In the hypozincaemic group, plasma albumin was subnormal in all patients and significantly lower than in the normozincaemic subjects. The correlation between plasma zinc and plasma albumin levels in all 34 patients studied was highly significant (rs = 0.69, p less than 0.001). As plasma albumin tends to fall to subnormal concentrations with age, this explains why plasma zinc may be low in the elderly without indicating a state of zinc deficiency. After 2 and 4 weeks' zinc therapy, the mean plasma zinc concentration of the hypozincaemic group rose significantly from 9.5 to 17.6 and 23.4 mumol/1. This increase is higher than the rise observed in younger patients receiving an identical zinc sulphate dosage.

Relative reference values for clinical chemical and haematological quantities in 'healthy' elderly people.

A search of the literature revealed a paucity of data on reference values for clinical chemical and haematological quantities in reasonably 'healthy' ambulant persons above 65 years of age. On the basis of 90 papers, concerning 37 different types of quantities, the median values for men and for women at 30, 50, 65, and 80 years are calculated relative to the value in men at 30 years. This transformation reduces influences of analytical and demographic factors that have caused considerable systematic differences in the original data. The reference distribution is described as regards symmetry and the change in dispersion with age. The results are given in a table and show four types of changes with age: no significant variation, a fall, an increase or a maximum somewhere between 30 and 80 years; the type of change often depends on sex.