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BACKGROUND: Although nine of 16 federal states in Germany conduct public health surveillance for Lyme borreliosis (LB), the extent of under-ascertainment is unknown. OBJECTIVE: As a model for European countries that conduct LB surveillance, we sought to estimate the population-based incidence of symptomatic LB after adjusting for under-ascertainment. METHODS: Estimating seroprevalence-derived under-ascertainment relies on data from seroprevalence studies, public health surveillance, and published literature. The number of symptomatic LB cases in states that conduct LB surveillance was estimated from studies reporting the seroprevalence of antibodies against Borrelia burgdorferi sensu lato, the proportion of LB cases that are asymptomatic, and the duration of antibody detection. The number of estimated incident symptomatic LB cases was compared with the number of surveillance-reported LB cases to derive under-ascertainment multipliers. The multipliers were applied to the number of 2021 surveillance-reported LB cases to estimate the population-based incidence of symptomatic LB in Germany. RESULTS: Adjusting for seroprevalence-based under-ascertainment multipliers, the estimated number of symptomatic LB cases in states that conducted surveillance was 129,870 (408 per 100,000 population) in 2021. As there were 11,051 surveillance-reported cases in 2021 in these states, these data indicate there were 12 symptomatic LB cases for every surveillance-reported LB case. CONCLUSIONS: We demonstrate that symptomatic LB is underdetected in Germany and that this seroprevalence-based approach can be applied elsewhere in Europe where requisite data are available. Nationwide expansion of LB surveillance would further elucidate the true LB disease burden in Germany and could support targeted disease prevention efforts to address the high LB disease burden.

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Hepatitis C virus is the most common chronic blood-borne infection in the USA. Based on results of a serosurvey, national prevalence is estimated to be 1·3% or 3·2 million people. Sub-national estimates are not available for most jurisdictions. Hepatitis C surveillance data was adjusted for death, out-migration, under-diagnosis, and undetectable blood RNA, to estimate prevalence in New York City (NYC). The prevalence of hepatitis C infection in adults aged ⩾20 years in NYC is 2·37% (range 1·53-4·90%) or 146 500 cases of hepatitis C. This analysis presents a mechanism for generating prevalence estimates using local surveillance data accounting for biases and difficulty in accessing hard to reach populations. As the cohort of patients with hepatitis C age and require additional medical care, local public health officials will need a method to generate prevalence estimates to allocate resources. This approach can serve as a guideline for generating local estimates using surveillance data that is less resource prohibitive.

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BACKGROUND: Because baboons are being considered as a source of xenografts for human liver transplantation in patients with hepatitis B virus- (HBV) induced cirrhosis to forestall infection of the graft by the virus, we undertook a study to ascertain if baboons are resistant to HBV infection. METHODS: Six chacma baboons were inoculated with serum containing HBV and were followed for 52 weeks to detect transmission of infection. RESULTS: Anti-HBc was detected in the serum of four baboons 16 weeks after inoculation. Virions, small spherical particles, and tubular forms were seen at this time in the serum of the one baboon studied by transmission electron microscopy. HBV DNA was detected by polymerase chain reaction in the serum of the same four baboons throughout the period of follow-up, as well as in liver tissue obtained after 52 weeks. The specificity of the DNA was confirmed by Southern hybridization. Nucleotide sequences showed complete sequence identity between the HBV DNA in each of the baboon sera and one of the two HBV genotypes inoculated. Serum transaminase levels tested at 4-weekly intervals were always normal and histological examination of liver tissue after 52 weeks showed no evidence of chronic hepatitis. Examination of squash preparations of liver tissue by electron microscopy in one baboon revealed core-like particles. CONCLUSIONS: Chacma baboons are susceptible to HBV infection and appear to develop a chronic carrier state. The use of xenografts from baboons should preferably be avoided, but if they are used again for HBV-infected patients it would be prudent to treat the patients as if they had received an organ from a human donor.

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The effects of gamma-linolenic acid (GLA), the lithium salt of gamma-linolenic acid (LiGLA) and arachidonic acid (AA) were compared at doses of 50 microg/ml for periods of 6 and 24 h on cell cycle progression and apoptosis induction in transformed and in normal cells. In WHCO3 (oesophageal cancer) cells and on primary embryonic equine lung cells, we found LiGLA to be the most effective in apoptosis induction. After 24 h, 94% of the WHCO3 cancer cells and 44% of the primary embryonic equine lung cells exposed to LiGLA were apoptotic. The WHCO3 cancer cells were also very susceptible to the apoptosis-inducing effects of AA (56%) and GLA (44%), whereas the embryonic equine lung cells were much less affected by these two fatty acids. After 6 h exposure to all three compounds, most of the cycling WHCO3 cancer cells were blocked in S-phase. After 24 h treatment, some of the S-phase cells exposed to AA and GLA were apparently able to move into the G2/M phase, the LiGLA exposed cells were mostly apoptotic and no cycling cells were present. The primary embryonic equine lung cells were fairly resistant to the cytotoxic effects of GLA and AA. From our studies we conclude that, although LiGLA was the most toxic to the cancer cells, it is apparently less selective, compared to AA and GLA, in the killing of cancer and normal cells. It would also appear that the lithium might have added to the cytotoxic effects of LiGLA. The mechanism needs to be clarified.

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Melatonin was previously shown to inhibit proliferation of MCF-7 human breast cancer cells. In this study the effect of melatonin on MCF-7 cells was further examined, while human cervical carcinoma (HeLa), osteosarcoma (MG-63) and lymphoblastoid (TK6) cells were tested for the first time. Haemocytometer counts, DNA content, flow cytometry and indirect immunofluorescence for nucleolar proteins, actin and beta-tubulin showed no differences in the growth, cell cycle or morphology between melatonin-exposed and control cells. The direct antiproliferative effect of melatonin thus seems to be confined to a melatonin-responsive subclone of MCF-7 cells and not applicable to the majority of cancer cells.

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The interspecies differences in CyA pharmacokinetics necessitate the establishment of optimal immunosuppressive doses in the baboon, especially as its use as host for preclinical xenografts is anticipated. We assessed the immunosuppressive effects of CyA and FK 506 on lymphocytes from chacma baboons, using human cells for comparison. At concentrations up to 100 mumol/l, neither drug was toxic to lymphocytes. FK 506 inhibited baboon and human lymphocyte proliferation and IL-2 synthesis equally. In contrast, approximately four times higher doses of CyA were needed to inhibit baboon lymphocytes responding to alloantigens. This may explain the inadequate immunosuppression of baboon graft recipients treated with clinically acceptable doses of CyA. We propose that CyA whole blood target levels of +/- 1500 ng/ml should be used in this species and we provide evidence that chacma baboons are able to tolerate such doses without nephrotoxicity.

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Pretransplant conditioning of baboons with total lymphoid irradiation allows long-term renal allograft acceptance in one third of the recipients. Brief additional immunosuppression was given to some animals, but always for less than 14 days after transplant. This enabled us to study mechanisms of graft tolerance in the absence of long-term, nonspecific drug immunosuppression. While 3 patterns of unresponsiveness were noted, this study concentrated on serum-mediated suppression. Eleven of 16 (69%) baboons destined to become tolerant to their grafts developed a nonspecific MLC inhibitory factor in their sera. In most animals it appeared within 3-5 weeks after transplantation and persisted over the period of study (91-793 days after Tx). The suppressor factor was absent in sera from 38 control animals and 8/9 rejectors. It was shown to be a low affinity IgG antibody that inhibited MLC by binding to stimulator cells, an effect that could be overcome by addition of rIL-2 to cultures. NK cell lysis, cell-mediated lympholysis, and polyclonal mitogenesis were unaffected. Antibody binding to purified baboon T cells could not be demonstrated, though binding to EBV-transformed B cells was readily shown. Our study shows that total lymphoid irradiation permits the generation of blocking antibodies directed against APCs as one mechanism of maintaining T cell unresponsiveness. These observations are consistent with the masking of ligands involved in antigen presentation or costimulation leading to a sustained state of autoenhancement.

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This study assessed the ability of 11 established and potential radiosensitizing agents to retard the repair of radiation-induced DNA damage with a view to enhancing the immunosuppressive effects of in vivo lymphoid irradiation. The capability of irradiated rat thymocytes to repair DNA damage was assessed by an adaptation of the fluorimetric unwinding method. Three compounds, 3-aminobenzamide (3-AB), novobiocin and flavone-8-acetic acid (FAA), inhibited repair significantly. We also report the effect of low-dose irradiation combined with repair inhibitors on the relationship between DNA strand breaks, fragmentation, cell viability and use of nicotinamide adenine dinucleotide (NAD). DNA fragmentation was increased by 1 mM/1 FAA, 1 mM/l novobiocin and 50 microM/l RS-61443 within 3 h of incubation. The latter two compounds also proved cytotoxic. All three drugs augmented the effect of ionizing radiation on the use of NAD. Of the agents investigated, FAA showed the most promise for augmenting the immunosuppressive action of irradiation at nontoxic, pharmacokinetically achievable concentrations.

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TLI has potent immunosuppressive effects, but there is concern over its possible carcinogenic properties. The aim of the study was to assess to what degree TLI may compromise natural killer (NK) and lymphokine activated killer (LAK) cell function. There was a significant increase (P less than 0.0001) in both NK-cell function (measured against K562 targets) and spontaneous LAK-cell function (measured against DAUDI targets) in fresh blood lymphocytes throughout a course of 8 x 100 cGy fractionated TLI. This may be related to a three- and sevenfold increase, respectively, in CD16+ CD8- and CD56+ CD2- cell frequencies over the same period. Mitogen-induced interleukin 2 (IL-2) synthesis from blood lymphocytes was inhibited by up to 75% with as little as 100 cGy of TLI. Expression of IL-2 receptors on fresh lymphocytes did not vary and remained low. Therefore spontaneous LAK occurrence appeared to be triggered through an IL-2-independent pathway. The in vitro addition of IL-2 verified that cells retained their ability to respond to this lymphokine resulting in greatly enhanced induced LAK function. This was most probably mediated by CD56+ cells which were found to readily express IL-2 receptors upon mitogen stimulation. In conclusion, fractionated low-dose TLI appears to enhance MHC unrestricted immune surveillance in a manner independent of IL-2 production.

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Predictions of an increasing shortage of donor organs for the future has led to a resurgence of interest in xenotransplantation. We have methodically assessed the immunological compatibility of humans against the chacma baboon with a view to narrowing the gap of concordance by careful immunological screening. The necessity of major blood group compatibility in xenotransplantation is now established. While no group O universal donor exists in the baboon, groups A (45%), B (15%), and AB (40%) are well represented. Baboon histocompatibility antigens could not be precisely defined using human antisera. This does not necessarily imply lack of homology between the species, as we have shown specific crossreactivity of numerous antihuman monoclonal antibodies with baboon leukocytes. Normal humans do not exhibit preformed agglutinins to erythrocytes of the chacma baboon (Papio ursinus orientalis)) but cytotoxic antibodies are occasionally found. Sera from allosensitized patients may contain crossreacting hemagglutinins, leukoagglutinins and complement-dependent cytotoxic antibodies. Binding of human immunoglobulin-G and -M to baboon targets was demonstrated by flow cytometry. Negative crossmatch combinations for antibodies of the IgG subclass were easily found, but IgM antibodies from allosensitized patients were polyspecific in their action. In vitro assessment of lymphocyte mediated cytotoxicity showed that preformed cellular immunity between the species was rare. The response of human lymphocytes to xenoantigen stimulation in mixed lymphocyte cultures showed a normal distribution, permitting the selection of low-responding combinations. Screening for viruses, especially HTLV-1 and Coxsackie-BL34, is important. These findings demonstrate a closer degree of concordance than has previously been suspected.

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The predictive value of varying levels of antibody activity, its class and antigen specificity in sera of 81 recipients of cadaver renal allografts was evaluated. Recipients for transplantation were selected on the basis of a negative dye uptake T-cell crossmatch, after which the more sensitive 51Cr release technique was employed in a blind study using unseparated donor target cells. Recipient sera with peak panel reactivity and current samples were evaluated before and after reduction with dithiothreitol to destroy the IgM subclass. Double absorption with pooled platelets allowed antibodies against HLA class I antigens to be distinguished from those against HLA class II/non-HLA antigens. Optimal levels of cytotoxicity were established, giving a sensitivity of 73%. Data were assessed in terms of positive predictive value, and showed that conventional T-cell crossmatching is adequate for the primary transplant group, but more sensitive ancillary tests are indicated for regrafts. In this category of patients, IgG antibodies, whether against HLA class I antigens or HLA class II/non-HLA antigens, were highly predictive of early graft loss (positive predictive value 50%-100%). Using this protocol for patient selection, 1-month graft survival would have improved from 73% to 96%.

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