Anti-Gal activity In diabetic patients transplanted with fetal porcine Islet cell clusters

Abstract: The natural anti-Gal antibody seems to create a major obstacle for discordant xenotransplantation in humans. It is produced in large amounts in humans (20–100 μg/ml serum), and interacts specifically with the carbohydrate structure Galα1–3Galβ1–4GlcNAc-R (termed, the a-galactosyl epitope). The a-galactosyl epitope is produced in large amounts on porcine cells, as on cells of other nonprimate mammals (1×10⁶ to 35×10⁶ epitopes per cell). The interaction of anti-Gal with α-galactosyl epitopes on the xenograft was found to mediate the immune destruction of discordant xenografts. In view of the intensive production of anti-Gal under physiologic conditions, it was of interest to determine whether the immune system in humans reacts against α-galactosyl epitopes on xenografts by increasing the activity (i.e., titer and affinity) of this antibody. For this purpose, anti-Gal titer and affinity were studied in sera of diabetic patients transplanted with fetal porcine islet cell clusters (ICC) by Groth and colleagues (Lancet 1994:344:1402). Titers of anti-Gal were determined by a hemagglutination assay with rabbit red blood cells and by ELISA with mouse laminin as a solid-phase antigen. Affinity of the antibody was estimated by equilibrium dialysis with the radiolabeled free haptenic form of the a-galactosyl epitope, i.e. [³H]Galα1–3Galβ1–4GlcNAc. All assays revealed a marked increase in anti-Gal activity within 5–8 weeks posttransplantation. The increase in anti-Gal titers ranged between eight-and sixty-four fold. A similar increase was observed in the affinity of anti-Gal, as assayed in equilibrium dialysis. Immunoglobulin concentration did not increase posttransplantation, suggesting that the observed increase in anti-Gal activity is the result of a specific immune response against α-galactosyl epitopes on the xenograft. The elevation in anti-Gal activity was observed in all three immunoglobulin classes and the highest activity was found within the IgG class. Furthermore, analysis of antibodies against porcine endothelial cells in ELISA has indicated that most of the increased activity against these cells in the serum of the transplanted patients, may be attributed to the elevation in activity of anti-Gal. These findings raise the possibility that anti-Gal, which is highly active in patients with xenotransplants, may contribute to chronic rejection of the xenograft by binding effectively to α-galactosyl epitopes on the xenograft cells and inducing inflammatory reactions against the graft.     

Pesticides and cancer

Epidemiologic evidence on the relationship between chemical pesticides and cancer is reviewed. In animal studies, many pesticides are carcinogenic, (e.g., organochlorines, creosote, and sulfallate) while others (notably, the organochlorines DDT, chlordane, and lindane) are tumor promoters. Some contaminants in commercial pesticide formulations also may pose a carcinogenic risk. In humans, arsenic compounds and insecticides used occupationally have been classified as carcinogens by the International Agency for Research on Cancer. Human data, however, are limited by the small number of studies that evaluate individual pesticides. Epidemiologic studies, although some-times contradictory, have linked phenoxy acid herbicides or contaminants in them with soft tissue sarcoma (STS) and malignant lymphoma; organochlorine insecticides are linked with STS, non-Hodgkin's lymphoma (NHL), leukemia, and, less consistently, with cancers of the lung and breast; organophosphorous compounds are linked with NHL and leukemia; and triazine herbicides with ovarian cancer. Few, if any, of these associations can be considered established and causal. Hence, further epidemiologic studies are needed with detailed exposure assessment for individual pesticides, taking into consideration work practices, use of protective equipment, and other measures to reduce risk.     

Hormone replacement therapy and symptom reporting in menopausal women: a population-based study of 35-65-year-old women in mid-Sweden.

OBJECTIVE: To measure the prevalence rate of hormone replacement therapy (HRT) in the general population and to see whether HRT users report less symptoms, better general health and less use of other palliative than non-users and previous users. METHODS: The study was performed in 1995 as a cross-sectional postal questionnaire study in seven counties in mid-Sweden. The questionnaire was sent to a random sample of 4200 35-64-year-old women of whom 2991 responded. The age distribution of responders and non-responders was similar 49.6+/-8.5 and 49.8+/-8.7 years, respectively. The main outcome measures were vasomotor and general symptoms in relation to menstrual status and HRT. RESULTS: Fifteen percent were on HRT and 2.3% had stopped treatment during the past year. Thirteen percent used other palliatives. Twenty-five percent of premenopausal women experienced any vasomotor symptoms, as compared with 51% of menopausal and 40% of postmenopausal women. Those on HRT reported higher frequencies than non-users of all symptoms except for sweating during the daytime. In addition, menopausal women experienced more of other symptoms, usually not associated with the menopause, than premenopausal and postmenopausal women. HRT users reported a significantly worse perceived health and they took other palliatives drugs to a larger extent than HRT non-users. CONCLUSION: HRT seemed to be effective in relieving some vasomotor symptoms but did not affect the prevalence of other symptoms or perceived health, in spite of the fact that women on HRT supplemented their therapy with palliative drugs to a larger extent than other women.     

Bioavailability in the human eye of a fixed combination of latanoprost and timolol compared to monotherapy.

The ocular pharmacokinetics of a single topical administration of a fixed combination (FC) of latanoprost 0.005% and timolol 0.5% was compared to the monotherapies of latanoprost and timolol in cataract surgery patients. The absorption rate of latanoprost and timolol into the aqueous humor was similar after administration of the FC compared to the two drugs given separately. The aqueous humor concentration of the acid of latanoprost tended to be higher 1-4 hours after administration of FC compared to latanoprost monotherapy. This resulted in an increased AUC. The Tmax and elimination half-life of both latanoprost and timolol were similar after administration of either FC or the two drugs given as monotherapy. Latanoprost did not have any influence on the ocular pharmacokinetics of timolol. The bioavailability of latanoprost and timolol into human aqueous humor, after FC, was at least as good as for the two drugs administered separately.     

Autoradiography of l–Methyl–4–phenyl–l,2,3,6–tetrahydropyridine (MPTP): Uptake in the Monoaminergic Pathways and in Melanin Containing Tissues

Abstract: A recently discovered neurotoxic compound, l–methyl–4–phenyl–l,2,3,6–tetrahydropyridine, has been found to cause a parkinsonian–like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP–induced lesions. By means of whole–body autoradiography of ³H–MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin–containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP–induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be due to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites     

Ki-67 (clone MIB-1) proliferation index in recurrent glial neoplasms: no prognostic significance

Background To determine if the Ki-67 (MIB-1 clone) proliferative index (PI) has prognostic potential in patients with recurrent astroglial neoplasms.

Methods We conducted a retrospective review of 27 patients whose initial and recurrent specimens were available. Histopathology was determined according to the World Health Organization classification. Proliferation index was calculated on formalin-fixed tissue using the Ki-67 (MIB-1 clone) antibody. Morphometric data were analyzed in conjunction with clinical data and Cox Proportionate Hazards Analysis, Spearman’s correlation co-efficient and Mann-Whitney Test.

Results Initial histopathology included 14 glioblastoma multiforme, 7 anaplastic astrocytoma, 3 oligoastrocytoma, and 3 astrocytoma. Recurrent specimens showed changes consistent with treatment. While univariate analysis shows initial histology correlated with survival (p < 0.036), PI did not correlate with survival after either initial (p = 0.86) or recurrent (p = 0.46) surgery for any tumor type. PI difference between specimens also did not correlate with survival (p = 0.91). Initial PI did not correlate with recurrent PI either (p = 0.43).

Conclusions Ki-67 PI does not confer additional prognostic information for patients with recurrent astroglial neoplasms. One possible explanation for this observation is that treatment may alter the PI independent of its effect on tumor growth.     

Mutations in Escherichia coli K-12 Decreasing the Rate of Streptomycin Uptake: Synergism with R-Factor-Mediated Capacity to Inactivate Streptomycin

Escherichia coli K-12 carrying the R-factor R1 or R6K is resistant to streptomycin. The resistance is due to R-factor-coded enzymes that metabolize the drug. Streptomycin can be inactivated in two ways, either by adenylylation or by phosphorylation; both reactions require adenosine 5'-triphosphate. In this work we show that the R-factor R1 codes for an enzyme that adenylylates streptomycin and that the enzyme activity is located in the periplasmic volume, whereas the R-factor R6K codes for a streptomycin phosphorylase, which is mainly cytoplasmic. From a strain without any R-factor or carrying different R-factors, mutants were isolated that are 10 times more resistant to streptomycin than the parent strains. This increased resistance is not due to increased amounts of metabolizing enzymes. The mutants have a decreased rate of uptake of streptomycin and an altered response to other antibacterial agents as well. The mutations are located on the chromosome and not on the plasmid. It is likely that the mutations cause changes in the outer layers of the cell envelope and that the increased resistance is due to the synergistic effect of an efficient penetration barrier and a low activity of inactivating enzyme.     

Endodontic follow-up practices,sources of knowledge,and self-assessed treatment outcome among general dental practitioners in Sweden and Norway

Abstract

Objective: To reduce the gap between what can be achieved in endodontic treatments and the observed treatment outcome among general dental practitioners, the present study set out to assess the status of the endodontic practices as regards to knowledge and self-assessed skills among general dental practitioners in Sweden and Norway.

Material and method: The questionnaire was sent to 1384 general dental practitioners. It contained questions regarding access to continuing education in endodontics, sources of knowledge for clinical management of patients, post-operative follow-ups, self-assessed success-rate, and the initial diagnosis impact on the outcome of endodontic treatments.

Results: The response rate was 61.4%. Almost half estimated their endodontic success-rate to be 90%. About two-thirds of the respondents did not know, or did not believe, that the initial diagnosis could affect the outcome of their endodontic treatments. Respondents who did not believe the diagnosis could impact the outcome were more likely to estimate their success rate as the highest (p<.001). Less than half performed post-operative follow-ups a year after treatment. A third of the respondents had not attended any continuing endodontic education.

Conclusion: Dentists who do not receive regular feedback on their treatments may lack insight into their own shortcomings. If this is combined with insufficient knowledge and understanding it may result in sub-par endodontic treatments being performed. It is important to have reliable ways to communicate current endodontic knowledge and to establish robust methods that may help dentists accurately assess their own performance in endodontics.