12-day Course Research Articles

A Different Perspective on Global Mapping of Lymphatic Filariasis

In the article on Global Mapping of Lymphatic Filariasis by E. Michael and D.A.P. Bundy[1xMichael, E. and Bundy, D.A.P. Parasitol. Today. 1997; 13: 472–476Abstract | Full Text PDF | PubMed | Scopus (179)See all References[1], the impression is given that the highest regional prevalence for filariasis occurs in the Pacific Islands, with the three highest prevalence rates in the world apparently occurring in Tonga (48%), Papua New Guinea (39%) and the Cook Islands (39%). The authors point out that these conclusions are based on old data, collected mainly between 1950 and 1960. I provide information below to show a different perspective.The reports of the WHO Expert Committees on Filariasis that met in Geneva in December 1983 and October 1991 mentioned that 10.9 million and 3.9 million persons, respectively, had overt filariasis infection in the West Pacific Region. The prevalence based on the population living in the endemic areas was 2.9% for both reporting periods. This marked reduction in total number of cases is undoubtedly due to the achievements made in China, where (currently) less than one million cases occur; at one time, there were reports of 30 million cases.The Pacific Islands also have participated in successful filariasis control campaigns. Based on reports of the WHO/South Pacific Commission Joint Seminar on Filariasis and Vector Control held in Apia, Samoa in 1974 and the WHO Working Group on Subperiodic Wuchereria bancrofti Filariasis held in Apia in 1978, and various WHO staff assignment and consultant reports, multiple dose mass drug administration (MDA) with diethylcarbamazine (DEC) had reduced the prevalence of filariasis in American Samoa from 21% to 0.27%; Samoa (formerly called Western Samoa) from 19.1% to 0.24%; Tonga from 20.4% to 1.6%; French Polynesia from 30% to 0.3%; Aitukaki Island on Cook Islands from 30% to 0.8%; and Fiji from 15% to 1%.MDAs were also carried out in Niue and Tuvalu, where post-treatment results are not readily available. A 1977 survey on Mitiaro Island (273 persons) on Cook Islands revealed a microfilaria prevalence of 30%, where treatment had not been carried out. Prevalences below 1% will rise unless MDAs are repeated, but it is not practical to do them every year. For example, the prevalence in Samoa once had returned to 5%. However, the traditional clinical symptoms of filariasis are disappearing in Samoa and the other Pacific Island countries and areas.In the Pacific Islands where malaria and filariasis overlap, the natural decline and eradication of Wuchereria bancrofti in the Solomon Islands during the 1970s is well documented. This was entirely due to the large-scale malaria vector control operations using DDT indoor residual sprays, where the microfilaria rates dropped from 20% to zero.The large-scale vector control operations now taking place in Vanuatu for malaria control are likely to help keep filariasis controlled. From a regional perspective, the greatest need is in Papua New Guinea, where high filariasis prevalence undoubtedly occurs in certain areas. Certainly more efforts are needed there, not only for malaria, but also for filariasis control.Governments in the Pacific at this time continue to give importance to filariasis surveillance and control. Activities are limited on the basis of available resources. However, significant public health achievements have been made and several countries were pioneers (French Polynesia, Samoa, Fiji) in successfully introducing the single annual mass (DEC) drug treatments, many years before others. It is now recognized that one single annual treatment is only slightly less effective than the multiple 12-day treatment course, which is more difficult to administer. The region is planning to introduce the new combined drug therapy (DEC and ivermectin) and has formulated criteria for achieving the status of filariasis elimination. In 1996, Samoa was the first country in the world to use the new combined therapy on a country-wide basis, where the filariasis prevalence is now about 1%. A second combined MDA is planned this year. The Pacific Islands will continue to strive to maintain, strengthen and expand their surveillance and control efforts.

Cardiac Allograft Vasculopathy Is Abrogated by Anti-CD8 Monoclonal Antibody Therapy

Background. Cardiac allograft vasculopathy, a diffuse and accelerated form of arteriosclerosis, is a major cause of graft loss or heart transplant recipient death after the first transplant year. This study examined the effects of depleting host CD8+ T lymphocytes on the development of cardiac allograft vasculopathy in miniature swine. Methods. Cardiac allografts were heterotopically transplanted across a major histocompatibility complex class I barrier in partially inbred miniature swine and monitored for rejection by serial biopsies, electrocardiograms, and echocardiograms. Four control animals received cyclosporine on postoperative days 0 to 11. Another four miniswine were given 14.5 mg/kg of 76-2-11 (a mouse anti-swine CD8 monoclonal antibody) on postoperative day 0, in addition to a 12-day course of cyclosporine. Host CD8+ T cells and circulating 76-2-11 monoclonal antibodies were monitored by flow cytometry. Results. As compared with cyclosporine-treated control animals, swine receiving 76-2-11 demonstrated near-complete depletion of peripheral CD8+ T cells by postoperative day 2, which persisted for 14 to 18 days. Mean allograft survival of the antibody-treated group and the control group was not statistically different (33 days versus 39 days, respectively) and both groups demonstrated severe interstitial rejection at necropsy. Control animals demonstrated florid intimal thickening of large and small arteries at necropsy. However, swine treated with 76-2-11 showed no intimal proliferation. Conclusions. Depletion of host CD8+ T cells prevents or delays the development of intimal proliferation in miniature swine. CD8+ lymphocytes play an important role in the early development of cardiac allograft vasculopathy in large animals.

Influence of the thymus on transplantation tolerance in miniature swine

TOLERANCE to kidney allografts in miniature swine is uniformly induced by a 12-day course of cyclosporine A (CyA) across a two-haplotype class I disparity. Second kidney allografts, SLA-matched to the first donor, are accepted without additional immunosuppression, suggesting a systemic mechanism of tolerance. We studied the role of the thymus in tolerance to renal allografts in this model.

Different effects of oral and transdermal hormonal replacement on prostacyclin and thromboxane A 2

To elucidate the mechanism of cardiovascular protection of hormone replacement therapy (HRT) by comparing the effect of oral and transdermal HRTs on the production of antiaggregatory, vasodilatory prostacyclin, and its endogenous antagonist, thromboxane A2. Oral estradiol (2.0 mg/d) plus norethisterone acetate (1.0 mg/d) (n = 13) or transdermal estradiol (50 micrograms/d) plus medroxyprogesterone acetate (10 mg/d) as 12-day courses at 4-week intervals (n = 13) were given to postmenopausal women. Urinary excretion of the metabolites of prostacyclin, ie, 6-ketoprostaglandinF1 alpha and 2,3-dinor-6-ketoprostaglandinF1 alpha, as well as those of thromboxane A2, ie, thromboxane B2 and 2,3-dinor-thromboxane B2, were measured by radioimmunoassays, after purification by extraction and high performance liquid chromatography, before and during the sixth and the 12th treatment cycles. Oral HRT stimulated excretion of thromboxane B2 from 3.4 +/- 0.7 ng/mmol creatinine to 4.5 +/- 1.5 (mean +/- standard deviation, P < .05) and that of 2,3-dinor-thromboxane B2 from 16.6 +/- 8.0 ng/mmol creatinine to 26.2 +/- 10.7 (P < .01), and thus led to the dominance of thromboxane A2. No changes in prostanoids occurred during transdermal HRT. The effects of various HRTs on prostanoids may significantly differ.

A Controlled Trial of Dexamethasone to Prevent Bronchopulmonary Dysplasia in Surfactant-treated Infants

Surfactant therapy now has a well-established role in the treatment of neonates with respiratory distress syndrome but has failed to reduce the incidence of bronchopulmonary dysplasia (BPD). We conducted a double-blind, placebo-controlled trial to test the hypothesis that dexamethasone therapy given during the first 12 days of life to very low birth weight infants would be synergistic to surfactant in preventing BPD. Seventy surfactant-pretreated infants (700-1500 g) who had severe respiratory distress syndrome (a/A ratio, 0.18 +/- 0.10; mean airway pressure, 11.1 +/- 1.9 cm H2O; fraction of inspired oxygen, 0.81 +/- 0.22) were enrolled to receive a 12-day course of dexamethasone (n = 36) or saline placebo (n = 34) starting within the first 12 hours after birth. The starting dose of dexamethasone was 0.5 mg/kg per day, and it was tapered progressively. Ventilator variables at 5 to 14 days were significantly improved in those infants who received dexamethasone compared with those who received the placebo. The effect seem to be more marked in infants weighting less than 1250 g at birth. Significantly more infants could be extubated by 14 days of age in the dexamethasone group (26 of 32 vs 14 of 32). Dexamethasone therapy reduced the incidence of BPD at 28 days (odds ratio, 0.1; 95% confidence interval, 0.03 to 0.3) and eliminated BPD at 36 weeks' postconceptional age. Dexamethasone-treated infants had greater weight loss at 14 days (12.9 +/- 6.4% vs 3.7 +/- 8.6%, respectively) and higher blood pressures from days 3 to 10. However, no differences were seen in time to regain birth weight, hypertension (1 infant in each group), or incidence of intraventricular hemorrhage. We found an additive effect between dexamethasone and surfactant in improving pulmonary status and reducing the incidence of BPD. Compared with the placebo, dexamethasone therapy was more effective in reducing the incidence of BPD in surfactant-pretreated very low birth weight infants.

Cardiac allograft vasculopathy in partially inbred miniature swine. I. Time course, pathology, and dependence on immune mechanisms

To assess the role of the immune system in cardiac allograft vasculopathy in large animals, heterotopic heart transplantation was done between partially inbred miniature swine, animals in which transplantation can be done across defined major histocompatibility barriers in a reproducible fashion. Porcine hearts transplanted into untreated recipients across a class I, class II, or full major histocompatibility mismatch were acutely rejected in 6 to 8 days ( n = 4). Hearts transplanted into untreated recipients across minor histocompatibility barriers survived for 21 to 44 days ( n = 5) and showed no evidence of cardiac allograft vasculopathy. When recipients were treated with a 12-day course of cyclosporine, hearts transplanted across minor histocompatibility barriers survived 42, 64, and 56 days and did not develop vascular lesions. However, hearts transplanted into cyclosporine-treated recipients across a full major histocompatibility disparity survived 20, 22, and 23 days and all three developed biopsy-proven vasculopathy. In one animal, the progression of intimal proliferation was followed in vivo by intracoronary ultrasonography. The degree of intimal thickening documented by ultrasonography correlated well with the intimal proliferation found on tissue histologic samples. These results are the first to show that in large animals, an immune response stimulated by donor major histocompatibility antigens is involved in the induction of cardiac allograft vasculopathy. In addition, these studies point out the utility of a large-animal model of cardiac allograft vasculopathy in which transplantation across defined major histocompatibility barriers can be done reproducibly and in which accurate determinations of the progression or regression of coronary vascular lesions in individual animals can be accurately assessed in vivo. (J T HORAC C ARDIOVASC S URG 1996;111:1230-9)

Vancomycin or vancomycin plus netilmicin for methicillin- and gentamicin-resistant Staphylococcus aureus aortic valve experimental endocarditis.

Using a rabbit model of aortic valve endocarditis, we studied the efficacy of vancomycin alone or in combination with netilmicin and/or rifampin against a methicillin- and gentamicin-resistant strain of Staphylococcus aureus (MGRSA). Antibiotics were given for 6 to 12 days, as follows: vancomycin (15 mg/kg of body weight every 12 h [BID] intravenously), vancomycin plus netilmicin (2.5 mg/kg BID intramuscularly), vancomycin plus rifampin (10 mg/kg BID intramuscularly), and vancomycin plus netilmicin plus rifampin at the same routes, dosages, and schedules mentioned above. Netilmicin was given to two additional groups at a higher dosage (6 mg/kg every 24 h intramuscularly) alone or in combination with vancomycin (15 mg/kg BID intravenously) for 12 days. All regimens resulted in undetectable bacterial counts in a significant proportion of vegetations (except netilmicin alone) or reduced the bacterial counts in the vegetations compared with the counts in the untreated controls (P<0.01 to P<0.001). No resistance to rifampin or netilmicin developed during therapy. It is concluded that in the treatment of experimental aortic valve endocarditis caused by MGRSA (i) vancomycin as monotherapy is as efficacious as the triple combination, (ii) the addition of netilmicin (once daily or BID) to vancomycin does not improve the efficacy of the latter antibiotic, even in the presence of rifampin, and (iii) a 12-day course in more effective than a 6-day one, but not at a statistically significant level.

INDUCTION OF TOLERANCE TO RENAL ALLOGRAFTS ACROSS SINGLE-HAPLOTYPE MHC DISPARITIES IN MINIATURE SWINE

We have previously demonstrated that a 12-day course of cyclosporine A (CsA) leads to the induction of tolerance to renal allografts in 100% of recipients selectively mismatched at class I for both haplotypes, and in 71% of recipients selectively mismatched at class II for both haplotypes, but in 0% of recipients mismatched for two haplotypes at both class I and class II. We have postulated that the mechanism by which tolerance is induced may therefore require matching for either class I or class II antigens. One might predict from this hypothesis that tolerance would also be induced in donor-recipient combinations sharing one full haplotype (e.g., AC-->AD), which mimics the clinically relevant transplant combination of parent to offspring. We have therefore investigated the effects of the CsA regimen on renal transplants in this combination. Without immunosuppression, such kidney allografts were uniformly rejected (n = 12; 10.6 +/- 2.4 days). In contrast, a course of CsA (10-13 mg/kg/day) during the first 12 postoperative days induced long-term acceptance of the allograft in 67% (4/6) of recipients. Some acceptor animals also showed specific unresponsiveness to donor antigens as measured by in vitro assays and by failure to develop anti-donor antibodies. Tolerance was confirmed in four of these animals by failure to reject a second transplant SLA-matched to the first kidney donor without additional immunosuppression. These results suggest the feasibility of inducing specific tolerance across a single-haplotype mismatch in the majority of the cases, which could have clinical implications for living-related transplants.

Lymphoscintigraphic Assessment of the Effect of Diethylcarbamazine Treatment on Lymphatic Damage in Human Bancroftian Filariasis

Despite many millions of doses administered over the past 40 years, basic and crucial issues regarding the use, mode of action, and effectiveness of diethylcarbamazine (DEC) in many clinical situations remain unresolved. To directly investigate whether the well-known microfilaricidal and macrofilaricidal actions of DEC actually result in subsequent improvement in existing damage to lymphatic vessels or lymph nodes, 29 study subjects in Recife, Brazil were stratified into three groups according to the severity of clinical manifestations of lymphatic insufficiency. After baseline radionuclide lymphoscintigraphy was performed, subjects were treated with two courses of DEC separated by at least a six-month interval and then rescanned one year after the baseline scan. A side-by-side comparison of images obtained at baseline with those obtained at follow-up in 13 asymptomatic microfilaremic individuals, six individuals with filarial fever, and in 10 individuals with chronic pathology demonstrated essentially unchanged lymphatic morphology in all but one individual whose disease actually progressed in the face of therapy. We conclude that two 12-day treatment courses of DEC did not have a demonstrable direct or indirect effect on existing structural damage to the lymphatic system even in those individuals with preclinical disease.

TRANSPLANTATION TOLERANCE INDUCED BY CTLA4-Ig1

The rejection of the transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD28. CTLA4-Ig is a fusion protein that has previously been shown to block the CD28-mediated costimulatory signal and inhibit immune responses in vitro and in vivo. In this report we show that treatment of the C3H/He recipient of a BALB/c vascularized cardiac allograft with a 12-day course of CTLA4-Ig produced indefinite graft survival (> 100 days) in the majority of recipients. In addition, these recipients demonstrated donor-specific transplantation tolerance when tested with donor-specific (BALB/c) and third-party (C57BL/10) skin grafts. These results demonstrate that CTLA4-Ig can induce transplantation tolerance in the adult murine cardiac allograft model.

RETRANSPLANTATION IN MINIATURE SWINE

In miniature swine, one-haplotype class I disparate renal allografts are accepted without exogenous immunosuppression by approximately 35% of recipients. Alternatively, transplants bearing a two-haplotype class I mismatch are always rejected acutely. However, long-term acceptance in the latter animals can be achieved uniformly with a 12-day course of cyclosporine. In vitro studies of recipient cell-mediated lymphocytotoxicity responses have shown donor-specific cytotoxic T lymphocyte clones in tolerant animals, suggesting that tolerance may be a local phenomenon or a central phenomenon activated in the milieu of the graft. Six animals were retransplanted with kidneys MHC-matched to their original allograft to determine whether (1) tolerance is a central phenomenon; (2) host tolerance can be broken with a fresh challenge of donor antigen and antigen-presenting cells; and (3) graft adaptation is required for maintenance of tolerance. Four of the retransplanted animals had been spontaneous acceptors of one-haplotype class I-disparate grafts and two had been rendered tolerant to two-haplotype class I-mismatched kidneys with CsA induction. All six explanted allografts showed no histological evidence of rejection and all six retransplants were accepted without exogenous immunosuppression. These findings suggest that in miniature swine tolerance of class I-disparate kidneys is a stable, centrally mediated phenomenon that cannot be broken with a challenge of fresh donor antigen and donor-type APCs. Furthermore, successful retransplantation without immunosuppression in animals receiving CsA induction therapy for their first transplant suggests that graft adaptation is not necessary for the maintenance of tolerance.

Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone replacement therapy

Our purpose was to clarify the mechanisms by which postmenopausal estrogen replacement therapy exerts its protective effect on cardiovascular risk. By means of a bidirectional Doppler ultrasonographic system we measured pulsatility index variations the internal carotid artery and middle cerebral artery in 25 early postmenopausal women during a 6-month period of hormone replacement therapy. Transdermal estradiol (50 micrograms/day) was continuously administered. A 12-day course of medroxyprogesterone acetate (10 mg/day) was added every second month. The pulsatility index showed a significant (p = 0.0001) reduction in both arteries after 6 weeks. At 22 weeks a 25% reduction was measured. No variation of the estrogen-induced pulsatility index reduction was observed at the end of every cyclic progestogen supplementation. In early postmenopausal women hormone replacement therapy causes a rapid reduction of pulsatility index in brain arteries. Cyclical progestational supplementation does not modify this positive effect on reactivity of the blood vessels.

Successful induction of long-term specific tolerance to fully allogeneic renal allografts in miniature swine.

Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts.

Diffusion of cefmenoxime and latamoxef into prostatic fluid in the patients with acute bacterial prostatitis.

Twenty-two patients with acute bacterial prostatitis were treated with cefmenoxime (CMX) or latamoxef (LMOX), which have susceptibilities against various gram-negative bacteria. First 11 patients received a 5- to 12-day course of cefmenoxime and the next 11 received a 6- to 13-day course of latamoxef. All patients were treated successfully except 1 patient with a drug allergy. Diffusion of CMX or LMOX into prostatic fluid in these patients and healthy controls were evaluated. The mean value of CMX in the expressed prostatic fluid was 12.8 micrograms/ml in the patients receiving 2 g of CMX intravenously and 0.7 micrograms/ml in the controls. The mean value of LMOX was 14.0 micrograms/ml in the patients receiving 2 g of LMOX intravenously and 1.2 micrograms/ml in the controls. The diffusion of CMX and LMOX into prostatic fluid in the patients with acute bacterial prostatitis was strikingly higher than that of controls.

Case 29-1991

Presentation of Case A 56-year-old woman was admitted to the hospital because of recurrent intermittent fever after renal transplantation. There was a history of interstitial nephritis that led to chronic renal failure six years earlier. Extracorporeal hemodialysis was begun. Three months before entry a cadaveric renal-transplantation procedure was performed. The patient's postoperative course was complicated by fever, with the temperature rising as high as 38.9°C on the seventh postoperative day. A diagnosis of acute rejection was made. Management of her care included three 500-mg boluses of methylprednisolone by vein and a 12-day course of OKT3 monoclonal antibodies; ganciclovir was administered . . .

Differential induction of vitellogenin gene transcription and total transcriptional activity by estrogen in Xenopus laevis liver.

The effects of estrogen on liver gene expression in Xenopus laevis were examined using a nuclear transcription "run-on" assay. Vitellogenin transcription was detected 2 h after a single dose of estradiol and reached a maximum on day 4. By 12 days after hormone treatment vitellogenin transcription declined to low levels. Within 3 h after estrogen, total transcriptional activity increased 9-fold relative to control values, reaching a maximum level of 40-fold by 12 h. Total transcription remained elevated throughout the following 12-day time course. These data indicate that changes in vitellogenin transcription and total nuclear transcription are uncoupled. Steady-state levels of vitellogenin mRNA demonstrated a close correlation with the level of vitellogenin gene transcription at all time points. In another series of experiments, animals treated repeatedly with estrogen demonstrated an elevated steady-state level of vitellogenin transcription, an elevated steady-state level of vitellogenin mRNA, and a constant elevated level of total nuclear transcriptional activity. Neither hormonal treatment regimen had an effect on the transcription of actin or induced the embryonic gene DG42. Finally, the increase in total transcriptional activity is associated with increased activities of RNA polymerase I and/or III in addition to stimulation of RNA polymerase II activity.

CLINICAL CONFERENCE

Dr. Scaglione: During the past 2 years in the Babies Hospital, two instances have been observed of severe disturbance of the central nervous system in patients in an edematous phase of nephrosis and undergoing rapid diuresis during adrenal steroid therapy. The first patient to show this alarming reaction was a 6-year-old white girl who, while being treated with intramuscular adrenocorticotropin (ACTH), rapidly lost fluid and developed marked hypochloremic, hypokalemic alkalosis. She became comatose for several weeks and, since that time, has had a convulsive disorder resistant to therapy. She also underwent severe impairment of intellect and is now considered to be hopelessly retarded. The second patient, to be presented in greater detail, is a child who reacted in a similar manner while receiving prednisone, but she has apparently suffered no permanent alteration in intellectual function. Patty H. is an 8-year-old Negro female who had the onset of edema in July 1955. During the first 6 months of the disease, she was given two courses of prednisone therapy in a local hospital and this resulted in prompt diuresis, but there was equally rapid re-accumulation of edema following cessation of therapy. The urine showed persistent proteinuria, cylindruria and hematuria. In January of 1956 she was treated again with prednisone at the Duke University Hospital in North Carolina. A moderate diuresis was obtained but she required admission 3 months later because of marked anasarca. The patient was then treated with a 12-day course of ACTH-gel (20 units/ day) following which she underwent a massive diuresis and lost approximately 14 liters of urine in 4 days.

CONTINUOUS THERAPY OF NEPHROTIC SYNDROME IN CHILDREN WITH CORTICOTROPIN GEL

INTERMITTENT treatment with adrenocorticotropic hormone, first described by Farnsworth,¹is a definite milestone in the management of the nephrotic syndrome. Diuresis is accomplished in 45 to 80% of the cases,* and in many improvement is maintained. Those who require repeated courses, however, swing from an edematous state to a dehydrated, washed-out, debilitated condition and are rarely well enough to live normal lives. They eat voraciously at times and are anorectic at others. In the summer of 1951, when a 3-year-old child failed to have her usual diuretic response following a 12-day course of corticotropin (ACTH) treatment was resumed at a lower dosage level for two more weeks, after which complete diuresis occurred. The child (L. H.) had had a series of 10 courses by March 3, 1952. Between courses albuminuria would disappear, only to reappear in a few days followed by edema. She was never well enough to permit