Hierarchical spatiotemporal modeling of human visceral leishmaniasis in Rio Grande do Norte, Brazil.

Visceral leishmaniasis (VL) is a neglected tropical disease that is globally distributed and has the potential to cause very serious illness. Prior literature highlights the emergence and spread of VL is influenced by multiple factors, such as socioeconomic status, sanitation levels or animal and human reservoirs. The study aimed to retrospectively investigate the presence and infectiousness of VL in Rio Grande do Norte (RN), Brazil between 2007 and 2020. We applied a hierarchical Bayesian approach to estimate municipality-specific relative risk of VL across space and time. The results show evidence that lower socioeconomic status is connected to higher municipality-specific VL risk. Overall, estimates reveal spatially heterogeneous VL risks in RN, with a high probability that VL risk for municipalities within the West Potiguar mesoregion are more than double the expected VL risk. Additionally, given the data available, results indicate there is a high probability of increasing VL risk in the municipalities of Natal, Patu and Pau dos Ferros. These findings demonstrate opportunities for municipality-specific public health policy interventions and warrant future research on identifying epidemiological drivers in at-risk regions.

D-penicillamine-induced angiopathy in rats. Changes in aortic collagen, glycosaminoglycans, DNA and RNA in rats treated with D-penicillamine.

Male Sprague-Dawley rats were treated with D-penicillamine (D-pen) in doses of 100, 250 or 500 mg/kg per day for 10, 32, 42 or 70 days. In addition animals were examined 28 days after withdrawal from 42 day's treatment with D-pen at 100 or 500 mg/kg per day. Pair-fed rats served as controls. The changes in aortic collagen, glycosaminoglycans (GAGs), DNA and RNA were studied. D-Pen had a dose- and time-related solubilizing effect on aortic collagen, which regained normal resistance to extraction within 28 days after cessation of the treatment. In contrast, D-pen caused a progressive accumulation of hydroxyproline (Hyp) in the aortic wall during and after treatment, probably mediated by an increased number of matrix synthesizing cells, as judged by augmentation of the DNA content in the presence of unaltered Hyp/DNA and RNA/DNA ratios. The relative amount of type III collagen was increased after 500 mg/kg per day D-pen for 10 and 42 days. High doses of D-pen increased the percentage of water in the aortic wall and reduced the ratio of Hyp to total tissue protein, suggesting an increased content of water-binding substances. This was confirmed by GAG accumulation. Hyaluronic acid (HA) and chondroitin 4,6-sulphate (CHS) were predominant after 32 and 42 days, whereas CHS, heparan sulphate (HS) and dermatan sulphate (DS) prevailed after 70 days of treatment. These observations suggest that processes of repair and regeneration are elicited secondary to the inhibitory effect of D-pen on aortic collagen and elastin crosslinking. Hypertrophy of the vessel wall may imply an increased rigidity, resulting in further increase of the susceptibility to haemodynamic injury.

Doc Holliday's dental chair.

John Henry Holliday, DDS, was one of the best-known dentists of the United States. However, little is known about his actual practice of dentistry. This article discusses a dental chair that was used by Doc and shows where it fits into his dental life.

Effect of different doses of D-penicillamine and combined administration of D-penicillamine and methylprednisolone on collagen, glycosaminoglycans, DNA and RNA of granulation tissue, skin, bone and aorta in rats.

D-penicillamine (D-pen) in doses of 20, 100 and 500 mg/kg/day or D-pen 100 mg/kg/day plus methylprednisolone (MP) 2.0 mg/kg/day was administered daily for 42 days to rats implanted with viscose-cellulose sponges. Operated, pairfed rats served as controls. D-pen increased the DNA content of granulation tissue, but had no effect on the amount of tissue produced. In contrast, high dose D-pen reduced the content of DNA and collagen in skin. A dose related inhibition of collagen crosslink formation occurred in all tissues, particularly in skin, as indicated by increased proportions of extractable collagen with increased alpha/beta chain ratio and aldehyde content. Moreover, low doses of D-pen increased the hydroxyproline/proline ratio of acid soluble skin collagen, presumably due to solubilization of type III collagen as demonstrated by SDS-polyacrylamide gel electrophoresis in the presence of 3.6 M urea. These changes were associated with increased skin fragility and edema plus excess elastin deposition in the aorta after high dose D-pen treatment. Low dose D-pen stimulated the 35S-sulphate uptake into the sulphated glycosaminoglycans (GAGs) of granulation tissue without altering their relative amounts, whereas high dose D-pen reduced the concentration of chondroitin-4/6-sulphate in skin. MP antagonized the solubilizing effect of D-pen on collagen, probably by inhibition of the collagen synthesis. In addition, MP inhibited the cell proliferation and GAG metabolism. Food restriction reduced the DNA content of granulation tissue. The inhibitory effect of D-pen on the formation of granuloma collagen crosslinks in the presence of unaltered rate of collagen biosynthesis may diminish the amount of fibrotic tissue due to increased degradability of crosslink deficient collagen. Simultaneous administration of MP may facilitate this effect by inhibiting the biosynthesis of collagen. However, long-term D-pen treatment seems to increase the susceptibility of normal tissues to mechanical injury.

Effect of D-penicillamine on collagen, glycosaminoglycans, DNA and RNA of granulation tissue and connective tissue of skin, bone and aorta in rats.

Granulation tissue was produced by subcutaneous implantation of viscose-cellulose sponges on rats. The effect of D-penicillamine 500 mg/kg/day for 10 days on granulation tissue and the connective tissue of skin, bone and aorta was studied ny comparison of treated animals with operated and unoperated controls. In addition, the effect of sponge implantation on intact tissues was studied by comparison between the control groups. The amount of granulation tissue was not affected by D-penicillamine, and the granulomas-DNA content even increased. D-penicillamine increased the amount of salt soluble collagen in all tissues consistent with an inhibition of collagen crosslinking as reflected by increased aldehyde content and alpha/beta chain ratio in soluble skin collagen. Skin appeared to be most sensitive. The content of free hydroxyproline and RNA and the RNA/DNA ratio in skin decreased suggesting a decreased collagen biosynthesis. The hydroxylation of proline and lysine was not affected by the treatment. The water percentage of aorta increased during D-penicillamine treatment, and the 35S-sulphate uptake in the sulphated glycosaminoglycans was stimulated in all tissues, in granulation tissue mainly in the chondroitin-4/6-sulphate fraction. No quantitative glycosaminoglycan changes occurred in granulation tissue. Sponge implantation caused an increase in the amount of salt soluble skin collagen without any change in alpha/beta chain ratio and aldehyde content of purified, soluble collagen. D-penicillamine plus operation reduced the collagen content of aorta. The effects of D-penicillamine on connective tissue compounds may be of importance for its antirheumatic efficacy, but the accompanying effect on normal tissues may imply side effects.

Effect of D-penicillamine pre- and post-implantation treatment on formation of sponge-induced granulation tissue in rats.

DNA, collagen and sulfated glycosaminoglycans (GAGs) of rat sponge granulation tissue were studied after 42 days of D-penicillamine (D-pen) treatment at 100, 250 or 500 mg/kg/day, starting 10 days before or 28 days after induction of granulation tissue formation. The effects were compared with those observed when the same dosage was started at the onset of the granulation tissue formation and with pair-fed controls. D-pen stimulated the cell invasion into the sponge implants, as manifested by an increased DNA content, particularly with pre-treatment. Pre-treatment reduced the net deposition of of collagen per cell as assessed by the lower hydroxyproline/DNA ratio, at the lower dose leading to reduced collagen concentration. The total amount of granulation tissue collagen remained essentially unaffected within the observation period. Salt-soluble collagen was augmented in a dose-dependent manner, irrespective of treatment protocol, signifying decreased collagen cross-linking. Both pre- and post-implantation treatment enhanced the radiosulfate incorporation into sulfated GAGs, regardless of dose, whereas treatment from the day of sponge implantation had no effect. It is concluded that D-pen enhances the early connective tissue response to injury. Reduction of collagen cross-linking and net collagen deposition, concomitant with stimulation of the proteoglycan metabolism, may pertain to the antirheumatoid activity of D-pen. The observations suggest that long-term administration of D-pen, starting before new attacks of arthritis, may be most effective in controlling developing articular fibrosis.

Vascular injury compared to ageing of normal rabbit aorta. Biochemical and histochemical studies on time-dependent alterations of vascular connective tissue.

Male albino rabbits of the Danish country strain, 5 months of age, were divided into two groups. One group of animals was killed 180 days after a single mechanical dilatation injury of the thoracic aorta. A second group of untreated controls was killed at ages of 150, 165, 180, 210, 330, and 450 days. Glycosaminoglycans, uptake of 35S-sulphate, collagen, uptake of 125I-albumin, and vascular histochemistry and morphology were analyzed in the thoracic aorta. In the injured aortae the dry weight and the total amounts of hexosamine, hyaluronic acid, chondroitin-4,6-sulphate, dermatan sulphate, heparan sulphate, and hydroxyproline were increased. The concentration of hyaluronic acid decreased, whereas the concentration of dermatan sulphate increased. The concentrations of chondroitin-4,6-sulphate and heparan sulphate were unchanged. The total uptake of 35S-sulphate into the sulphated proteoglycans as well as the uptake of 125I-albumin were increased. The light microscopical examination showed thickening of the intima, medial changes with fibrosis, accumulations of proteoglycans, calcifications, formation of cartilage, and ossified tissue with haematopoiesis. In the uninjured thoracic aorta the only significant change during ageing was an increase in the total amount of hyaluronic acid and a decrease of the 35S-sulphate incorporation into the chondroitin-4,6-sulphate in the aorta. No morphological or histochemical alterations were observed during ageing. Spontaneous lesions were observed in 2 out of 55 aortas. It may be concluded that injury and ageing are reflected quite differently in the thoracic aorta of the rabbits. The observations may be of relevance to the interpretation of the alterations in human arterial diseases involving processes of injury and repair as well as ageing.

Proteoglycans, DNA, and RNA in rat granulation tissue, skin, and aorta. Biochemical and histological studies.

Proteoglycans in skin and aorta and nucleic acids in skin were studied in rats with subcutaneous sponge implants and in unoperated rats and compared with the sponge induced granulation tissue during a 42 day period. In rat aorta there was a predominance of the sulphated glycosaminoglycans, in particular heparan sulphate, while in skin there was a predominance of hyaluronic acid and dermatan sulphate. The subcutaneous sponge implantation caused a decrease in the dry weights of skin and aorta but did not influence the concentrations of the measured variables. In aorta the concentrations of chondroitin sulphate and dermatan sulphate decreased with age while in skin there was a slight fall in the concentrations of hyaluronic acid and heparan sulphate with age. The rate of biosynthesis of proteoglycans as estimated from the 35S-sulphate uptake was higher in skin than in aorta. A sequential development was noticed in granulation tissue with an initial high content of hyaluronic acid followed by increasing amounts of chondroitin sulphate and dermatan sulphate in older granulation tissue. The RNA/DNA ratio reached a maximum in 14 day old granulation tissue, but was unchanged in skin throughout the 42 day period. It is concluded that the distribution of proteoglycans and nucleic acids differs from tissue to tissue. This may be of relevance for tissue differences in susceptibility to diseases and to the effects - and side-effects - of drugs. The morphological and biochemical development of sponge induced granulation tissue from rats was similar to other types of granulation tissue during the first 4 weeks.

Acid glycosaminoglycans in myxoedema.

Acid glycosaminoglycans were measured in the tissues of a virtually untreated 83-year-old woman with myxoedema. Intercellular oedema was demonstrated histologically in the tongue, myocardium, striated muscles, and in the skin. Tissue oedema was absent in two female control patients. All tissues from the patient with myxoedema, apart from the stomach, showed high concentrations of hyaluronic acid, but there was no consistent elevation of chondroitin-4,6-sulphate, heparan sulphate or dermatan sulphate. The accumulation of hyaluronic acid might contribute to the oedema formation in myxoedema.