Development and chemical characterization of biodegradable polymeric implants containing sirolimus for the treatment of malignant solid tumors.

The use of sirolimus and its analogs has been evaluated in studies aimed at combating several types of cancer; however, because of the limited bioavailability of the drug, the search for new forms of administration is required. Biodegradable polymeric implants containing sirolimus were developed and assessed as an alternative method of drug administration. Implants containing 25 % (w/w) sirolimus were prepared employing the polymer matrices chitosan, polycaprolactone and poly(lactic-co-glycolic acid) (PLGA) in two proportions: PLGA 50:50 and PLGA 75:25. Thermal analysis techniques such as thermogravimetry and differential scanning calorimetry, combined with x-ray diffraction were used to characterize and evaluate the compatibility of the constituents of the formulation. No incompatibilities were found between the components, but drug amorphization was observed in all samples. Implants made from the polymers chitosan and PCL may accelerate the degradation of SRL when these polymers are dissolved in methanol at 50 °C. HPLC analysis showed that the implant prepared with PLGA 75:25 did not present degradation products and maintained its appropriate drug content, even when dissolved in methanol and heated to 50 °C. Therefore, it represents the most suitable biodegradable polymer for use in implants developed for the treatment of malignant solid tumors. However, it is still necessary to further study the drug effects after amorphization of the crystal and also to perform stability and solubility analysis.

Comparison of cytotoxicity, genotoxicity and immunological inflammatory biomarker activity of several endodontic sealers against immortalized human pulp cells.

AIM: To establish an SV40 T-Ag-transfected cell line of human pulp-derived cells in order to compare the cytotoxicity, genotoxicity and to investigate the activities of immunological biomarkers of several endodontic sealers. METHODOLOGY: Primary human pulp cells and transfected cells were cultured. Cell morphology and proliferation were analysed, and the expression of cell-specific gene transcripts and proteins was detected by RT-PCR and immunohistochemistry. Transfection of human pulp-derived cells resulted in an immortalized cell line retaining phenotypic characteristics from the primarily cells tested. The SV40 T-Ag-transfected cells were cultured and stimulated by sealers (Apexit Plus, Real Seal, AH Plus, and EndoREZ) to evaluate the cytotoxicity and genotoxicity by MTT and MTN assays, respectively. Immunological inflammatory biomarkers (IL6, IL8 and TNF-α) were determined by ELISA assay. The differences between median values were statistically analysed using Kruskal-Wallis and Dunn's tests at 5% significance level. RESULTS: The cytotoxicity assay revealed that multimethacrylate (Real Seal) was the most cytotoxic sealer (P < 0.05) and exhibited the highest inflammatory potential against the SV40 T-Ag-transfected cells (P < 0.05). All root canal sealers tested were able to stimulate the immortalized pulp cells to produce IL-6, IL-8 and TNF-α, with differences in relation to the control group (P < 0.05). Higher levels of IL-6, IL-8 and TNF-α were found in cell supernatant after stimulation with multimethacrylate (Real Seal) compared to all other sealers tested (P < 0.05). No differences were found comparing epoxy resin-based sealer (AHPlus), single-methacrylate sealer (EndoREZ) and calcium hydroxide-based sealer (Apexit Plus), regardless of the cytokine investigated (all P > 0.05). CONCLUSIONS: A SV40 T-Ag-transfected cell line of human pulp-derived cells was established. The methacrylate resin-based sealer (Real Seal) exhibited the greatest cytoxicity and inflammatory potential against immortalized pulp cells compared to an epoxy resin-based sealer (AH Plus), a methacrylate-based sealer (EndoRez) and a calcium hydroxide-based sealer (Apexit).

Public resource usage in health systems: a data envelopment analysis of the efficiency of health systems of autonomous communities in Spain.

OBJECTIVES: The efficiency in the management of public resources is one of the main pillars of the welfare state. The objective of this work is to analyze the efficiency of the public resources that regional governments in Spain (Autonomous Communities (AC)) invest in health systems (HS). STUDY DESIGN: A dataset from of the Ministry of Health, Social Services and Equality of Spain has been used, which contains the most important indicators from the National HS. The following variables have been chosen in this study: the health care expenses per resident, the percentage of this investment that is forwarded to labour expenses, frequency of hospital care services, frequency of specialized external health care services and, primary health care services in medicine and nursing per resident. METHODS: To this end, Data Envelopment Analysis (DEA) is applied, which enables researchers and managers to obtain measurements of efficiency of the analyzed regions, and to propose corrective steps to achieve efficiency for inefficient HS. Moreover, the super-efficiency measurement is shown for a constant and a variable scale. RESULTS: The results show that there are three groups of AC, first a group composed by six HS that are globally efficient, a second group composed by eight HS that are globally inefficient, and a third group composed by three HS that are efficient in some terms and their efficiency can be improved. CONCLUSIONS: It is concluded that DEA is an appropriate method for evaluating efficiencies of health systems and giving the adjustments for the application of economic, social and organizational policies to improve their efficiencies.

[Neuropsychiatric symptomatology in post-COVID syndrome. Intervention proposal and referral from primary care]. / Sintomatología neuropsiquiátrica en el síndrome post-COVID. Propuesta de manejo y derivación desde atención primaria.

SARS-CoV-2 infection is a multiorgan disease with a wide spectrum of clinical manifestations, including neurological and psychiatric, which are expressed in all stages of the disease and often has long-term symptoms, called post-COVID syndrome. Among the neuropsychiatric symptoms derived from this syndrome, in this article we focus on headache, cognitive impairment, taste and smell alterations, depression, anxiety and sleep disorders. Intervention algorithms for these symptoms in primary care establishing criteria for referral to specialized care are proposed.

Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders.

BACKGROUND: There is a lack of consistent evidence regarding associations of neurological soft signs (NSS) with illness-related variables in schizophrenia. This study examined NSS in first-episode psychotic patients with respect to their factor structure and associations with risk factors, pre-morbid characteristics, psychopathology and spontaneous extrapyramidal syndromes. METHOD: First-episode, drug-naive patients with schizophrenia-spectrum disorders (n=177) were assessed for NSS using the Neurological Evaluation Scale, and its 26 constituting items were factor analysed. The identified neurological dimensions were then entered into hierarchical regression models as outcome dependent variables of a set of predictors including risk factors (familial loading for schizophrenia, obstetric complications), pre-morbid characteristics (neurodevelopmental delay, symptoms of attention deficit-hyperactivity disorder, pre-morbid functioning), psychopathological domains (reality distortion, disorganization, negative symptoms, mania, depression, catatonia) and spontaneous extrapyramidal syndromes (parkinsonism, dyskinesia, akathisia). RESULTS: Five neurological domains were identified: sequencing, release signs, sensory integration, abnormal movements and coordination. Multivariate analyses showed independent associations (p<0.01) of sequencing with familial liability to schizophrenia, deterioration of pre-morbid adjustment and parkinsonism; release signs with obstetric complications, catatonic symptoms and parkinsonism; sensory integration with familial liability to schizophrenia; abnormal movements with familial liability to schizophrenia, obstetric complications, parkinsonism and dyskinesia; and coordination with neurodevelopmental delay. The empirically derived factors explained additional variance over and above that explained by subscale scores across the examined variables. CONCLUSIONS: Familial liability to schizophrenia, obstetric complications, neurodevelopmental delay, deterioration in pre-morbid functioning and observable motor disorders appear to contribute independently to domains of neurological dysfunction. The findings support a neurodevelopmental model of NSS in schizophrenia.

Goat milk during iron repletion improves bone turnover impaired by severe iron deficiency.

The effect of goat or cow milk-based diets, with either normal Fe content or an Fe overload, on bone turnover and the mineralization process was studied in control and anemic rats during chronic Fe repletion. One hundred eighty male Wistar rats were studied during a pre-experimental period of 40 d in which they were randomly divided into 2 groups, a control group receiving the AIN-93G diet with normal Fe content (45 mg/kg of diet) and the Fe-deficient group receiving the AIN-93G diet with low Fe content (5mg/kg of diet) for 40 d. After the pre-experimental period, the rats were fed for 10, 30, or 50 d with goat or cow milk-based diets with a normal Fe content (45 mg/kg of diet) or an Fe overload (450 mg/kg of diet). In anemic rats, goat milk with normal Fe content increased levels of the biomarker of bone formation N-terminal propeptides of type I procollagen and diminished parathyroid hormone levels after only 10 d of supplying this diet, indicating the beginning of restoration of the bone demineralization induced by the anemia, which was not observed with cow milk. After 30 d of supplying the milk-based diets with normal Fe content or an Fe overload, biomarkers of bone formation and bone resorption were not different between control and anemic rats, indicating that the bone demineralization induced by the Fe-deficiency anemia had recovered, although the process of stabilization of bone turnover began earlier in the animals fed goat milk. In addition, a higher Ca deposit was observed in femur, which positively affects bone mineralization, as well as an increase of Fe in sternum, which indicates that the hematopoietic process essentially recovered earlier on the goat milk diet compared with the cow milk diet.

Biofilm microbial communities of denture stomatitis.

INTRODUCTION: Denture stomatitis is a common lesion that affects denture wearers. Its multifactorial etiology seems to depend on a complex and poorly characterized biofilm. The purpose of this study was to assess the composition of the microbial biofilm obtained from complete denture wearers with and without denture stomatitis using culture-independent methods. METHODS: Samples were collected from healthy denture wearers and from patients with denture stomatitis. Libraries comprising about 600 cloned 16S ribosomal DNA (rDNA) bacterial sequences and 192 cloned eukaryotic internal transcribed spacer (ITS) region sequences, obtained by polymerase chain reactions, were analyzed. RESULTS: The partial 16S rDNA sequences revealed a total of 82 bacterial species identified in healthy subjects and patients with denture stomatitis. Twenty-seven bacterial species were detected in both biofilms, 29 species were exclusively present in patients with denture stomatitis, and 26 were found only in healthy subjects. Analysis of the ITS region revealed the presence of Candida sp. in both biofilms. CONCLUSION: The results revealed the extent of the microbial flora, suggesting the existence of distinct biofilms in healthy subjects and in patients with denture stomatitis.

Sintomatología neuropsiquiátrica en el síndrome post-COVID. Propuesta de manejo y derivación desde atención primaria / Neuropsychiatric symptomatology in post-COVID syndrome. Intervention proposal and referral from primary care

La infección por SARS-CoV-2 es una enfermedad multiorgánica. Tiene un amplio espectro de manifestaciones clínicas, entre ellas neurológicas y psiquiátricas, que se expresan en todos los estadios evolutivos de la enfermedad. En muchas ocasiones presenta sintomatología a largo plazo que se ha denominado síndrome post-COVID. Entre la sintomatología neuropsiquiátrica derivada del mencionado síndrome, nos centramos en este manuscrito, por su prevalencia, en la cefalea, el deterioro cognitivo, las alteraciones del gusto y olfato, la depresión, los trastornos de ansiedad y el insomnio. En este documento se revisa esta sintomatología y se proponen algoritmos de manejo y criterios de derivación de atención primaria (AP) a otros especialistas (AU)

SARS-CoV-2 infection is a multiorgan disease with a wide spectrum of clinical manifestations, including neurological and psychiatric, which are expressed in all stages of the disease and often has long-term symptoms, called post-COVID syndrome. Among the neuropsychiatric symptoms derived from this syndrome, in this article we focus on headache, cognitive impairment, taste and smell alterations, depression, anxiety and sleep disorders. Intervention algorithms for these symptoms in primary care establishing criteria for referral to specialized care are proposed (AU)

Brush border calcium uptake in short-bowel syndrome in rats.

Resection of distal small intestine causes calcium malabsorption in humans and in a rat model of 50% distal resection. We tested the hypothesis that this calcium malabsorption is caused in the rat model by a brush border defect. We compared brush border membrane vesicles from the proximal small intestine of control (transection and anastomosis at mid-small intestine) with distally resected rats. Mucosal protein was 25% greater in the resected group and the vesicles were enriched 37-fold in sucrase activity when compared with homogenate. Kinetic constants Vmax (maximal initial rate of saturable calcium uptake at infinite concentration), kT (calcium concentration for saturable calcium uptake rate at half Vmax), and KD (rate constant for nonsaturable calcium uptake per unit concentration) were slightly but not significantly greater in the resected as compared with the transected group, ruling out the brush border as the cause for decreased transmucosal calcium transport.

Effect of epithelial debridement on glycosaminoglycan synthesis by human corneal explants.

The purpose of the present work was to investigate the effects of mechanical epithelial debridement upon glycosaminoglycan synthesis by human corneal explants. Corneal explants were maintained under tissue culture conditions for 2-72 days and the glycosaminoglycans synthesized in 24 h were metabolically labeled by addition of 35S-sulfate to the culture medium. These compounds were isolated from the tissue explants and analyzed by a combination of agarose gel electrophoresis and enzymatic degradation with specific mucopolysaccharidases. The glycosaminoglycans synthesized by isolated epithelial cells and by corneas previously submitted to epithelial cell debridement were compared to controls. Keratan sulfate (26 kDa) and dermatan sulfate (43 kDa) were the main corneal glycosaminoglycans, each one corresponding to about 50% of the total. Nevertheless, the main 35S-labeled glycosaminoglycan was 35S-dermatan sulfate (73%), with smaller amounts of 35S-keratan sulfate (15%) and 35S-heparan sulfate (12%), suggesting a lower synthesis rate for keratan sulfate. The main glycosaminoglycan synthesized by isolated epithelial cells was heparan sulfate. The removal of epithelial layer caused a decrease in heparan sulfate labeling and induced the synthesis of dermatan sulfate by stromal cells. This increased synthesis of dermatan sulfate suggests a relationship between epithelium and stroma and could be related to the corneal opacity that may appear after epithelial cell debridement.

Beneficial effect of pollen and/or propolis on the metabolism of iron, calcium, phosphorus, and magnesium in rats with nutritional ferropenic anemia.

There has been considerable debate regarding the nutritional benefits of pollen and the propolis produced by bees, although most contributions have lacked scientific soundness. This paper describes the possible beneficial effect of their use in pharmacological products in cases of anemic syndrome. We studied the effect of these two natural products on the digestive utilization of iron, calcium, phosphorus, and magnesium, using control rats and rats with nutritional ferropenic anemia. The addition of these products to the diet produced a positive effect on weight gain; this fact could constitute a scientific basis for the application of pollen and propolis as fortifiers. They improve the digestive utilization of iron and the regeneration efficiency of hemoglobin, especially during recovery from an anemic syndrome. They also have a positive effect on phosphocalcic metabolism and maintain an appropiate level of magnesium metabolism. Furthermore, in iron-deficient rats, these natural products palliate, to a large extent, the adverse effects of iron deficiency on calcium and magnesium metabolism as a result of the improvement in the digestive utilization of these minerals.

The importance of the proportion of heme/nonheme iron in the diet to minimize the interference with calcium, phosphorus, and magnesium metabolism on recovery from nutritional ferropenic anemia.

The digestive utilization of Fe and its nutritive interaction with Ca, P, and Mg were studied in rats with nutritional ferropenic anemia. The diet contained 80% ferric citrate and 20% heme iron (80/20 diet). The weight gain, digestive utilization of Fe, and regeneration efficiency of hemoglobin and seric Fe were higher in iron-deficient rats (ID) fed the 80/20 diet than in iron-deficient rats fed the 50/50 diet (Campos et al., 1996). The phospho-calcic metabolism, which is adversely affected in ferropenic anemia, returned to normal values when iron was added to the diet. The digestive utilization of Mg, which fell with the 50/50 diet (Campos et al., 1996), returned to normal values when the ferropenic anemia was reversed with the 80/20 diet. In a state of iron deficiency, certain parameters related to the glucose and lipid metabolism are affected; the glucose and triglycerides values return to a normal range with the 80/20 diet.

Effect of epithelial debridement on human cornea proteoglycans.

Corneal transparency is attributed to the regular spacing and diameter of collagen fibrils, and proteoglycans may play a role in fibrillogenesis and matrix assembly. Corneal scar tissue is opaque and this opacity is explained by decreased ultrastructural order that may be related to proteoglycan composition. Thus, the objectives of the present study were to characterize the proteoglycans synthesized by human corneal explants and to investigate the effect of mechanical epithelial debridement. Human corneas unsuitable for transplants were immersed in F-12 culture medium and maintained under tissue culture conditions. The proteoglycans synthesized in 24 h were labeled metabolically by the addition of (35)S-sulfate to the medium. These compounds were extracted by 4 M GuHCl and identified by a combination of agarose gel electrophoresis, enzymatic degradation with protease and mucopolysaccharidases, and immunoblotting. Decorin was identified as the main dermatan sulfate proteoglycan and keratan sulfate proteoglycans were also prominent components. When the glycosaminoglycan side chains were analyzed, only keratan sulfate and dermatan sulfate were detected (approximately 50% each). Nevertheless, when these compounds were (35)S-labeled metabolically, the label in dermatan sulfate was greater than in keratan sulfate, suggesting a lower synthesis rate for keratan sulfate. (35)S-Heparan sulfate also appeared. The removal of the epithelial layer caused a decrease in heparan sulfate labeling and induced the synthesis of dermatan sulfate by the stroma. The increased deposit of dermatan sulfate proteoglycans in the stroma suggests a functional relationship between epithelium and stroma that could be related to the corneal opacity that may appear after epithelial cell debridement.

Beneficial effect of goat milk on bioavailability of copper, zinc and selenium in rats.

We studied the effects of dietary inclusion of freeze-dried goat and cow milk on the utilization of copper, zinc and selenium, and on the metabolic fate of copper and zinc, in rats using a standard (non-milk) control diet recommended by the American Institute of Nutrition and diets based on goat or cow milk. For animals given the goat milk diet, the apparent digestibility coefficient (ADC) of copper is similar to that obtained with the standard diet and higher than that in animals given the cow milk diet. The copper balance was higher among the rats given the goat milk and the standard diets than among those given cow milk. The ADC and retention of zinc and selenium were higher for the goat milk diet than for the other two diets. The copper content in the kidneys and in the femur was greater when the animals consumed a goat milk diet than a cow milk diet. Zn deposits in femur, testes, liver, kidney, heart and longissimus dorsi muscle were greatest with the goat-milk diet, followed by the standard diet and were lowest for the rats given cow-milk diet. This study shows that the goat-milk has an important and beneficial effect on the bioavailability of copper, zinc and selenium.

Influence of goat and cow milk on the digestive and metabolic utilization of calcium and iron.

The effects of goat and cow milk on the digestive and metabolic utilization of calcium and iron were studied in rats using a standard (non-milk) control diet. The digestive utilization of calcium is greater when the animals consume the goat-milk-based diet rather than that based on cow milk or the standard diet. The digestive utilization of iron, however, is similar for the goat-milk diet and the standard diet, and in both cases superior to that based on cow milk. The calcium content in the femur, sternum and Longissimus dorsi muscle (L.D. muscle) provides an indication of what happens during the utilization of the mineral; more is deposited when the rats consume a milk-based diet, particularly one based on goat milk. The iron content in the reserve organs, namely the liver and the spleen, is greater with the standard diet and the goat milk diet than with that containing cow milk. There is an obviously beneficial effect of goat milk on the metabolism of calcium and iron, which minimizes any interaction between the two minerals.

Nutritive utilization of calcium in rats: effects of dietary fat components and vitamin D3 on intestinal resected rats.

The nutritive utilization of calcium was studied in adult rats in which 50% of the distal small intestine (DSI) had been resected and in sham-operated controls one month and three months after the operation. Resection of half the DSI reduced the digestive utilization of Ca as reflected by mineral content in bone. Three months after resection, nutritive utilization of Ca had still not recovered. Feeding the resected rats with a diet in which fat content consisted of equal parts of medium-chain triglycerides (MCT), sunflower seed oil, and olive oil failed to improve nutritive utilization of Ca after one or three months in comparison with a diet containing olive oil as the only source of lipids. Supplementation with vitamin D3 (0.04 mg/100 g diet) enhanced nutritive utilization of Ca in resected rats after one month, the beneficial effect becoming much more patent after three months. At the dose used, vitamin D3 favored calcium deposition in bone tissue. Serum levels of Ca remained unchanged under all experimental conditions, both one month and three months after 50% DSI resection.

Nutritive utilization of phosphorus in the rat: influence of intestinal resection and dietary medium chain triglycerides and vitamin D3.

The effects of intestinal resection and diet on the digestive and metabolic utilization of phosphorus were studied in adult rats from which 50% of the distal small intestine had been removed and in sham-operated controls. Metabolic parameters were measured both 1 and 3 months after surgery. The loss of half of the distal small intestine led to a decline in digestive utilization of phosphorus 1 month after surgery as reflected in bone mineral content. Digestive efficiency had improved by 3 months after surgery. One month's feeding with a diet in which fat was provided as equal parts of medium chain triglycerides, sunflower seed oil and olive oil instead of 100% olive oil enhanced phosphorus absorption and retention, although this improvement was less evident after 3 months. The negative effects of distal small intestine resection on the nutritive utilization of phosphorus were not only palliated but significantly enhanced by supplementing the diet with vitamin D3 at a rate of 0.08 mg/100 g diet. This dose is within physiological limits, and favors phosphorus deposition in bone tissue.

Influence of intestinal resection and type of diet on digestive utilization and metabolism of magnesium in rats.

The influence of intestinal resection and type of diet on nutritive utilization of magnesium was studied in rats in which 50% of the distal small intestine was removed and in sham-operated controls. Nutritive parameters were analyzed after feeding the rats different diets for one or three months after surgery. Loss of 50% of the distal small intestine reduced digestive utilization of Mg as reflected in the mineral content of bone, however digestive and metabolic utilization of Mg were seen to recover by three months postsurgery. When dietary fat was supplied as equal parts of medium chain triglycerides, sunflower seed oil and olive oil instead of 100% olive oil, Mg absorption and retention were enhanced in resected rats after one month with the beneficial effects on Mg metabolism becoming even more marked after three months. One month after resection, dietary supplementation with vitamin D3 clearly stimulated digestive utilization of Mg. Although this effect was less notable at three months, nutritive utilization of Mg remained higher than in resected rats fed a diet lacking vitamin D3 supplementation. Dietary levels of vitamin D3 favored the deposition of Mg in bone tissue.

Influence of dietary fat components and intestinal resection on iron, zinc and copper metabolism in rats.

The effect of resecting 50% of the distal small intestine (DSI) on iron, zinc and copper nutritive utilization was studied in rats fed two different types of diet: a standard diet containing 4% olive oil (A) and a diet containing different sources of fat (1/3 olive oil, 1/3 sunflower oil and 1/3 medium chain triglycerides) (B). One month and 7 days after surgery, intestinal resection led to a deterioration in digestive (ADC) and metabolic (balance) utilization of iron, zinc and copper. To assess trace metal postresectional homeostasis, we also measured these mineral concentrations in whole blood, plasma and several organs (liver, femur, sternum, longissimus dorsi muscle and testes). Our findings showed no significant differences in iron, zinc and copper concentrations between the organs, suggesting that the observed decrease in digestive and metabolic efficiency of these minerals was not markedly reflected at the postabsorptive level, since the distribution of the trace elements in the whole organism remained unchanged. We conclude that one month and 7 days after this surgical intervention, adaptive mechanisms are well developed in resected rats fed a diet with an adequate mineral supplement.

Effects of type of dietary fat and cholecalciferol on magnesium absorption in rats with intestinal resection.

We studied the effect of type of dietary fat and supplementation with cholecalciferol on magnesium absorption in the duodenum, jejunum and proximal colon in rats with resection of 50% of the distal small intestine. Magnesium transport against the concentration gradient was found to occur in all three intestinal segments, although transport increased significantly only in the proximal colon of intestinally resected rats fed a diet supplemented with cholecalciferol at a rate of 0.425 mg/kg diet and mixture of equal parts of medium chain triglycerides, sunflower oil and olive oil as the source of dietary fat (diet B), in comparison with magnesium absorption in control rats subjected to intestinal transection and fed diet B, and in resected rats fed a diet without cholecalciferol supplementation and in which olive oil was the sole source of dietary fat (diet A). Magnesium absorption due to active and passive transport together, was greater in resected than in transected rats in all three intestinal segments, although the difference was significant only in the jejunum (the segment closest to the anastomosis), because of the greater increase in mucosal mass in resected animals. When the three intestinal segments were compared, magnesium absorption in favour of and against the concentration gradient in the proximal colon was significantly greater than in the duodenum or the jejunum, in resected and transected animals fed diet A or diet B. These findings show that the colon is the segment that most efficiently absorbs magnesium in rats with intestinal resection, especially when diet B is given.