A strange case of Transthyretin Cardiac Amyloidosis in the Elderly: a diagnostic challenge.

Abstract: Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. We here report the case of a 83-year-old woman, which has rapresented an unique case of transthyretin-related cardiac amyloidosis, as a patient with an initial diagnosis of hypertensive heart disease later develops an infiltrative cardiomyopathy due to amyloid deposits.

Isoflavones improve collagen I and glycosaminoglycans and prevent bone loss in type 1 diabetic rats.

Objective: The objective of this study was to evaluate the action of soy isoflavones (ISO) and 17ß-estradiol on collagen I (CollI) and sulfated glycosaminoglycans (GAGs) in the bone matrix of diabetic rats.Methods: Sixty adult female rats (Rattus norvegicus albinus) underwent ovariectomy, and then were randomized into six groups of 10 animals each: GI, sham control ovariectomized animals; GII, sham control diabetic (DM) ovariectomized animals; GIII, control ovariectomized animals receiving propylene glycol vehicle; GIV, control ovariectomized DM animals receiving propylene glycol vehicle; GV, ovariectomized DM animals treated with ISO (150 mg/kg by gavage); and GVI, ovariectomized DM animals treated with estrogen (17ß-estradiol, 10 mg/kg, subcutaneously). 17ß-Estradiol was used as a positive control when compared with ISO. To obtain significant depletion of the estrogen levels and subsequent bone loss, a postsurgical period of 90 days was observed. Treatments occurred during 30 consecutive days. After euthanasia, shafts of the animals' femurs were immersed in liquid nitrogen for molecular biology analysis, and the distal femurs were removed and processed for paraffin embedding.Results: ISO (GV) and 17ß-estradiol (GVI) improved bone formation, increasing GAGs and CollI formation when compared to the control group (GIV) (p < 0.05).Conclusions: ISO and 17ß-estradiol contribute to the decrease of bone loss in diabetic rats.

Soy isoflavones protect against oxidative stress and diminish apoptosis in ovary of middle-aged female rats.

Ovarian aging is characterized by declines in follicular reserve and oocyte quality due, in part, to increased oxidative stress and apoptosis. Soy isoflavones (ISOs) have been shown to improve ovarian lifespan by acting as antioxidant and antiapoptotic agents. We aimed at evaluating whether ISOs could modulate oxidative stress and reduce apoptosis and improve ovarian follicle survival in middle-aged female rats. Twelve ovary-intact female Wistar rats (12-month-old) were divided into groups: control (CTRL) and ISO, daily treated by gavage with vehicle or soy-ISO extract (150 mg/kg b.w), respectively. After 8 weeks, rats were euthanized and their ovaries removed for histomorphometric (% follicles) and apoptosis (cleaved-caspase-3/BCL2 immunostaining) evaluations, or subjected to biochemical assays to survey reactive oxygen species (ROS) and lipid peroxidation levels and total antioxidant capacity (TAC). The frequency of atretic follicles and number of cleaved-caspase-3-positive cells, as well as the ROS and lipid peroxidation levels, were significantly lower in ISO group compared to CTRL. A significantly higher number of BCL2-positive cells and TAC levels were also observed in ISO group. In conclusion, soy ISOs could decrease follicular atresia, apoptosis and oxidative stress, as well as increase the TAC in ovaries of female rats.

Combined effects of ovariectomy and streptozotocin-induced diabetes in the articular cartilage of rats.

AIM: To evaluate the combined effects of streptozotocin-induced diabetes (Di) and ovariectomy in the articular cartilage of rats. METHODS: Forty adult female Wistar rats were ovariectomized (OVX) or sham-operated. After recovery from surgery, the animals were assigned randomly into four groups: OVX control (OVX-C); OVX treated with 10 µg/kg/day of 17ß-estradiol (OVX-E); sham-operated subjected to Di (Sham-Di); and OVX subjected to Di (OVX-Di). After 60 days of treatment, the animals were euthanized and the distal femurs with articular cartilage were processed for paraffin-embedding. Sections were stained with hematoxylin and eosin for histomorphometry, Picro-Sirius Red for collagen, or Alcian Blue for glycosaminoglycan (GAG) content. To detect apoptosis, sections were stained with an antibody to cleaved caspase-3 (casp-3). RESULTS: Articular cartilage thickness and GAG content were significantly lower (p < 0.05) in the OVX-Di group, which also showed a higher number of casp-3-positive chondrocytes than the other groups. Interestingly, the higher percentage (p < 0.05) of mature collagen fibers was seen in the OVX-Di group, may be as a result of a reduced extracellular matrix remodeling of the articular cartilage. CONCLUSION: Our results indicate that the combination of ovariectomy and streptozotocin-induced diabetes produces more deleterious effects in articular cartilage of rats than either condition alone.

Humidification mitigates acute mucosal toxicity during radiotherapy when factoring volumetric parameters. Trans Tasman Radiation Oncology Group (TROG) RadioHUM 07.03 substudy.

PURPOSE/OBJECTIVE(S): To model in a subset of patients from TROG 07.03 managed at a single site the association between domiciliary based humidification use and mucositis symptom burden during radiotherapy (RT) for head and neck cancer (HNC) when factoring in volumetric radiotherapy parameters derived from tumour and normal tissue regions of interest. MATERIALS/METHODS: From June 2008 through June 2011, 210 patients with HNC receiving RT were randomised to either a control arm or humidification using the Fisher & Paykel Healthcare MR880 humidifier. This subset analysis involves patients recruited from Auckland City Hospital treated with a prescribed dose of ≥70 Gy. Regression models included control variables for Planning Target Volume 70 GY (PTV70Gy); Equivalent Uniform Dose (EUD) MOIST and TSV (surrogates of total mucosal and total swallowing volumes respectively). RESULTS: The analysis included 39 patients (humidification 20, control 19). There was a significant odds reduction in CTCAE v3.0 functional mucositis score of 0.29 associated with the use of humidification (p<.001). Within the parameters of the model therefore, the risk of a humidification patient being scored as experiencing a one-step increase in functional mucositis was 3.45 times lower (1/0.29) than for control patients. A control patient was 4.17 times more likely to receive an unfavourable nutritional mode score (p<.001). The risk of being admitted to hospital decreased by a factor of 11.11 for humidification patients (p=.013). CONCLUSION: The results support the hypothesis that humidification can help mitigate mucositis symptom burden. Radiotherapy dosimetric parameters assist in the evaluation of toxicity interventions.

Effects of soy isoflavones on the concentration of hyaluronic acid in the vagina of type 1 diabetic rats.

OBJECTIVE: To assess the effects of isoflavones and 17ß-estradiol on the vaginal epithelium extracellular matrix and hyaluronic acid (HA) in the diabetic rat model. METHODS: Sixty adult, virgin, female rats underwent ovariectomy, then randomization into six groups of ten animals each: GI, sham ovariectomized control animals; GII, sham ovariectomized control diabetic animals; GIII, control ovariectomized rats receiving propylene glycol vehicle; GIV, control ovariectomized diabetic animals receiving propylene glycol vehicle; GV, diabetic ovariectomized animals treated with soy isoflavones (150 mg/kg by gavage); GVI, ovariectomized diabetic rats treated with estrogen (17ß-estradiol, 10 mg/kg, subcutaneously). Treatment took place over 30 consecutive days. After euthanasia, a portion of the vagina was immersed in liquid nitrogen for RT-qPCR and Western blotting. Another portion was processed for paraffin embedding. Sections were stained with hematoxylin & eosin for histomorphometry and Picro Sirius Red for collagen quantification. RESULTS: Vaginal epithelium histomorphometry in GIII (15.3 ± 1.1 µm) and GIV (14.5 ± 1.8 µm) was thinner than in GV (41.3 ± 1.5 µm) and GVI (74.3 ± 1.6 µm). There was an increase in collagen content in GV (84.1 ± 1.2 µm) and GVI (88.2 ± 1.7 µm). HA quantification was higher in GV (0.38 ± 1.1 µg/mg) and GVI (0.49 ± 1.4 µg/mg) when compared with GIII (0.12 ± 1.1 µg/mg) and GIV (0.10 ± 1.2 µg/mg), p < 0.05. CONCLUSIONS: Soy isoflavones increase hyaluronic acid concentration in the vagina of diabetic ovariectomized rats. Such findings might help to attenuate the effects of vulvovaginal atrophy in women.

Effects of early and late treatment with soy isoflavones in the mammary gland of ovariectomized rats.

INTRODUCTION: Soy isoflavones have been shown to be an alternative to hormone therapy at menopause, without causing side-effects such as breast cancer. However, the effects of early and late treatment with isoflavones on the mammary gland remain controversial. OBJECTIVE: To investigate the effects of early and late treatment with soy isoflavones on the mammary gland of ovariectomized rats. METHODS: Thirty 3-month-old rats were ovariectomized and divided equally into groups: Control, treated with vehicle solution; or with 150 mg/kg/body weight of isoflavones by gavage; or subcutaneously treated with 10 µg/kg/body weight with 17ß-estradiol. Treatments started 3 days (early treatment) or 30 days (late treatment) after ovariectomy and lasted for 30 consecutive days. Thereafter, the animals were euthanized and the mammary glands were removed and processed for paraffin embedding. Sections were stained with hematoxylin and eosin for histomorphometry or subjected to immunohistochemical detection of Ki-67 and VEGF-A. RESULTS: The ductal, lobular and total epithelial fractions were similar between controls and the early/late isoflavone groups, but they were significantly higher in the groups treated with estradiol. In both epithelial and stromal regions, the immunoreactivity of VEGF-A and the percentage of Ki-67-positive cells were significantly higher in the groups treated with estradiol, while they were similar in the early/late isoflavone groups and control groups. CONCLUSION: Our results indicate that early and late treatment with soy isoflavones at the dose of 150 mg/kg/body weight does not show proliferative and angiogenic effects on the mammary gland of ovariectomized rats.

Soybean isoflavones attenuate the expression of genes related to endometrial cancer risk.

OBJECTIVE: We evaluated whether genistein or estrogen treatment has the same effect when administered immediately or late to rats induced with menopause using ovariectomy. METHODS: Sixty adult female rats were divided into six treatment groups: GI = vehicle immediately after ovariectomy; GII = vehicle 30 days after ovariectomy; GIII = genistein immediately after ovariectomy; GIV = genistein 30 days after ovariectomy; GV = estrogen immediately after ovariectomy; and GVI = estrogen 30 days after ovariectomy. All animals were treated for 30 consecutive days. At the end of the treatment, part of the uteri was removed for subsequent histological studies and another part was used to evaluate estrogen receptors 1 and 2, cell proliferation (cyclin A1 and A2, cyclin D1, cyclin-dependent kinase inhibitors 1, 1B and 2, antigen identified by the monoclonal antibody Ki67) and angiogenesis (vascular endothelial growth factor, VEGF-A) gene expression. RESULTS: Late treatment after castration in rats resulted in more developed endometrium, enhanced cell proliferation and estrogen-signalling pathways, particularly the cyclin-related genes Ki67 and VEGF-A, compared to early treatment. Interestingly, these same effects were less intense with genistein compared to those induced by estrogen, especially when genistein was administered late. CONCLUSION: Our data show that isoflavone renders a lower risk of cancer when compared to estrogen in treatments.

An historical perspective on how advances in microscopic imaging contributed to understanding the Leishmania Spp. and Trypanosoma cruzi host-parasite relationship.

The literature has identified complex aspects of intracellular host-parasite relationships, which require systematic, nonreductionist approaches and spatial/temporal information. Increasing and integrating temporal and spatial dimensions in host cell imaging have contributed to elucidating several conceptual gaps in the biology of intracellular parasites. To access and investigate complex and emergent dynamic events, it is mandatory to follow them in the context of living cells and organs, constructing scientific images with integrated high quality spatiotemporal data. This review discusses examples of how advances in microscopy have challenged established conceptual models of the intracellular life cycles of Leishmania spp. and Trypanosoma cruzi protozoan parasites.

Effects of different doses of soy isoflavones on bone tissue of ovariectomized rats.

AIM: Studies report that hormone replacement prevents osteoporosis, but there are doubts whether isoflavones are really efficient in this process. The aim of this study was to evaluate the effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. METHODS: Forty female rats at the age of 6 months were ovariectomized and, after 3 months, the animals were divided into four groups: GI - Control (treated with drug vehicle); GII - treated with isoflavones (80 mg/kg per day); GIII - treated with isoflavones (200 mg/kg per day) and GIV - treated with isoflavones (350 mg/kg per day). Soy isoflavones were administered by gavage for 90 consecutive days. After treatment, the rats were euthanized and their distal femurs were removed for histological routine, histochemistry and biochemical study. Histological sections were stained with hematoxylin-eosin or subjected to picrosirius red and alcian blue methods. Shafts of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. RESULTS: In distal femurs, the trabecular bone volume was higher in the groups treated with isoflavones, being higher in GIV, while the cortical bone width and the presence of mature type I collagen fibers were higher in GII. At the trabecular bone region, the percentage of total glycosaminoglycans (GAGs) was higher in GII and the percentage of only sulfated GAGs was higher in GIII, while the higher content of chondroitin sulfate in shafts of femurs was seen in GIV. Biophysical and biomechanical tests in tibias did not differ among the groups. CONCLUSION: Our data indicate that soy isoflavones improve bone quality in femurs of rats by increasing histomorphometric parameters, the content of GAGs and mature type I collagen fibers. These positive effects are dose-dependent and it was different in cortical and trabecular bone.

p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription.

Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38alpha activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38alpha sustains the expression of HIF1alpha target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38alpha triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38alpha inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc(Min) mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38alpha affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.

A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells.

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38alpha/beta kinases. We report that p38alpha is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38alpha activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38alpha pathway in the treatment of colorectal cancer.

Pharmacokinetics and mammary elimination of imidocarb in sheep and goats.

The pharmacokinetics and mammary excretion of imidocarb dipropionate, a therapeutic/prophylactic agent against a variety of tick-borne hemoparasitic diseases in domestic animals, have been investigated in sheep and goats. A commercial formulation of imidocarb di-propionate was injected i.m. at a single dose of 3 mg/kg of body weight in 7 mature lactating ewes and 8 lactating does in good health. Blood samples were collected for 48 h after administration and milk samples were collected every 12 h for 10 d. A weak cation-exchange solid-phase procedure was used to remove imidocarb from plasma. A hexane/isoamyl alcohol liquid-liquid procedure was adopted to extract the drug from the milk of sheep. The same method was used for goat milk after exposing the matrices to enzymatic digestion. The extracted samples were analyzed by HPLC. The i.m. disposition kinetics of imidocarb in the 2 species showed significant differences in the rate of elimination (0.0075 +/- 0.002 and 0.025 +/- 0.004 L/h in sheep and goats, respectively), being faster in ewes than in does. Nevertheless, a smaller area under the concentration-time curve (12.21 +/- 0.76 and 9.49 +/- 0.54 microg/mL per h in sheep and goats, respectively), a larger volume of distribution (4.18 +/- 0.44 and 7.68 +/- 0.57 L/kg in sheep and goats, respectively), and a longer mean residence time (9.07 +/- 0.77 and 14.75 +/- 2.20 h in sheep and goats, respectively) were found in goats, suggesting a more rapid and effective drug storage in tissues during the first 48 h after the injection. The concentrations of imidocarb in milk of both species were higher than in plasma. However, a fast passage through the blood-milk barrier and a high storage of imidocarb were observed in the milk of ewes, whereas the drug concentrations were not as high nor was the extent of drug penetration from blood to milk as great in the milk of goats (AUC(milk 0-48)/AUC(plasma 0-48) = 2.5 +/- 0.45 and 1.26 +/- 0.27 in sheep and goat, respectively). Despite the differences in pharmacokinetic behavior, and considering the sensitivity of pathogens to imidocarb, the same dosage regimen can be used for clinical efficacy against Babesia spp. infection in both species. In contrast, the differences in depletion of imidocarb residue in milk and the large variability in mammary drug elimination found in goats suggests that great care should be taken in defining the withdrawal time in small ruminant dairy species.

Hypertension in early alcohol withdrawal in chronic alcoholics.

AIMS: Hypertension is an established risk factor in chronic alcoholics, but little is known about the relationship between blood pressure (BP), severity of their alcohol abuse, and severity of alcohol withdrawal syndrome (AWS). METHOD: BP was assessed daily for 18 days in a series of chronic alcoholics on early alcohol withdrawal (AW), while also assessing the severity of their AWS on the CIWA-Ar scale. RESULTS: A sharp and sustained decrease in BP was observed after AW; at T0, BP had increased in 55% of patients, and at T18 in 21%. The variation of BP is partially explained by years of at-risk drinking and AWS severity, but other factors may play a role in hypertension in alcoholics, as a large amount of BP variation was not explained by the alcohol-abuse-related parameters that we studied. BP values were not correlated with cigarette smoking, anxiety, or depression. Hypertension found in 'detoxified' alcoholics (approximately 20%) may be related to alcohol-independent hypertension or to a long-lasting alcohol-induced derangement of the BP regulating mechanisms. Further research is needed in these patients to elucidate the mechanisms of persistent hypertension and to set up a treatment protocol. At present, careful monitoring is advisable, as well as pharmacological treatment for moderate or severe hypertension; often a modification of life-style is needed which includes physical activity and possibly sodium (Na) restriction, since hypertension in detoxified alcoholics seems to be Na sensitive. CONCLUSION: Complete alcohol abstinence must be recommended to all hypertensive alcoholics, as AW-induced transient hypertension was found to be harmless in all our subjects, and abstinence leads to a complete recovery from hypertension in most cases.

Erythrocyte thiamine (Th) esters: a major factor of the alcohol withdrawal syndrome or a candidate marker for alcoholism itself?

AIMS: Thiamine (Th) deficiency is a major problem in alcoholics. In this study, the relationship of alcohol withdrawal syndrome (AWS) to Th and its esters, as well as the diagnostic power of Th and its esters were investigated. PATIENTS AND METHODS: Th and its esters were assessed in a series of chronic alcoholics (and in controls) using an improved method. RESULTS: No association was found between AWS severity and Th and its esters, while the diagnostic power of thiamine diphosphate (TDP) and Th was very high. TDP was the most significant among the parameters under study, confirming that erythrocyte TDP is a suitable marker of alcoholism: TDP sensitivity across subjects was 84.1%, specificity 85.4%, positive predictive value 82.4%, and negative predictive value 88.0%.

[Case report Brown-Vialetto-Van laere syndrome]. / Un caso clinico. Sindrome di Brown-Vialetto-Van Laere.

A case of a young man (36 years old) suffering from a progressive bulbo-pontine palsy, bilateral central deafness and respiratory failure, clinically known as Brown-Vialetto-Van Laere syndrome (BVVL) is reported. The illness occurred at 24 years and, after a period of quiescence of 12 years, led to a serious dependence from mechanical ventilation. In tyhis report the most important points of view about resuscitation and intensive treatment, such as neuromuscular failure and locked-in condition, are discussed.

Recent Developments in IMRT: Therascan, a new Prototype of Linear Accelerator dedicated to Intensity Modulated Radiotherapy

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Pulsed dose rate perioperative brachytherapy for soft tissues sarcomas

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Pharmacological and dietary prophylaxis and treatment of acute actinic esophagitis during mediastinal radiotherapy.

Our purpose was to evaluate a pharmacological and dietary protocol of prophylaxis and treatment of acute actinic esophagitis during mediastinal radiotherapy. This phase II study was conducted on 29 patients affected by cancer not directly involving the esophagus. The irradiated volume included at least 10 cm of esophagus with a median dose of 46 Gy and the incidence of clinical acute esophagitis was scored with RTOG-EORTC tables. During the entire course of radiation therapy all patients were subjected to prophylaxis pharmacological therapy in addition to dietetic rules commonly used. All patients were evaluable, 9 (31%) had no acute esophageal toxicity, 20 (69%) had toxicity of degree 1, and no patient showed a toxicity of degree 2, 3, or 4, there were no toxicity-related related interruptions of the radiotherapy course. In conclusion, this low cost protocol seems to reduce the incidence and degree of acute radiation esophagitis (without added morbidity), compared with literature reports.

Dermoscopic criteria for melanoma in situ are similar to those for early invasive melanoma.

BACKGROUND: Dermoscopy is a noninvasive technique that increases the diagnostic accuracy of pigmented skin lesions, particularly improving the diagnosis of patients with cutaneous melanoma in situ (CMIS) and early invasive melanoma. To establish reliable and reproducible dermoscopic criteria for the diagnosis of CMIS, the authors conducted a retrospective clinical study of 37 patients with CMIS and 53 patients with invasive cutaneous melanomas (ICM). METHODS: The 37 patients with CMIS were divided into three groups: those with CMIS lesions measuring < or = 5 mm in greatest dimension (8 patients), those with CMIS lesions measuring from > 5 mm to < or = 10 mm in greatest dimension (20 patients), and those with CMIS lesions measuring > 10 mm in greatest dimension (9 patients). The 53 patients with ICM were divided into two groups according to Breslow index: those with ICM lesions measuring < or = 0.75 mm in tumor thickness (19 patients) and those with ICM lesions measuring > 0.75 mm in tumor thickness (34 patients). Lesions were examined with a dermatoscope and were photographed at a magnification of x10. Dermoscopic criteria were evaluated from examination of the photomicrographs. RESULTS: Blue-whitish veil, gray-blue areas, black dots, and irregular extensions and branched streaks were the most relevant dermoscopic criteria for CMIS and were present in 78%, 76%, 73%, and 62% of lesions, respectively. Brown globules, irregular pigment network, pseudopods, and depigmentation were present in 57%, 54%, 54%, and 51% of CMIS lesions, respectively. White scar-like areas and linear and/or dotted vascular patterns, two criteria that are associated frequently with ICM, were not found in our patients with CMIS. No clinically significant differences were observed between the three groups of CMIS patients. CONCLUSIONS: Dermoscopic criteria for CMIS were similar to those for ICM, although white scar-like areas and linear and/or dotted vascular patterns were observed only in patients with ICM. Dermoscopic criteria appeared to be independent of CMIS lesions size.