Amelioration of Neurosensory Structure and Function in Animal and Cellular Models of a Congenital Blindness

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Anticoagulant treatment in COVID-19: a narrative review

Journal of Thrombosis and Thrombolysis - The actual Coronavirus Disease (COVID 19) pandemic is due to Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the coronavirus...     

Coronary microcirculation in essential hypertension: a quantitative myocardial contrast echocardiographic approach.

AIMS: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls. METHODS AND RESULTS: Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole. CONCLUSION: The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected.     

Probability of cure in elderly Hodgkin's disease patients

BACKGROUND: Elderly Hodgkin's disease patients have a poor prognosis. The question arises whether these patients need aggressive treatment or a palliative strategy. So far, as a consequence of the scarcity of trials designed for them, useful information can be obtained only by retrospective analyses. METHODS: We retrospectively studied clinical data from 567 patients recorded from 1982 to 1989 in the Piemonte Hodgkin's Disease Register (PHDR). The 65 patients over 65 years of age were compared to younger ones. We analyzed the role of disease independently of confounding variables, mainly inadequacy of staging and/or treatment, comorbidity and toxicity. RESULTS: In the elderly comorbidity was as high as 35%. Forty elderly patients (60%) entered a suboptimal plan with a low degree of aggressivity, which was different from the usual PHDR protocol. Elderly patients also had a high proportion of subsequent protocol interruptions (25%). Chemotherapy dose intensity was negatively affected by advanced age (p < 0.01 after both 3 and 6 courses of chemotherapy). Toxic deaths were significantly higher in elderly patients than in younger ones (14% vs 1%; p < 0.05). CR rates, overall survival (OS), disease-specific survival (DSS) and event free survival (EFS) were all significantly influenced by age (p < 0.01). Relapse-free survival (RFS) in patients achieving CR did not differ according to age class (77% vs 60%; p = ns). RFS was better in elderly patients entering the PHDR protocols than in those following an alternative plan (75% vs 54%; p = 0.04); however, elderly patients treated according to PHDR guidelines showed a higher incidence of toxic deaths than those treated less aggressively (23% vs 8%). The two groups had similar EFS (36% vs 24%; p = ns). CONCLUSIONS: Elderly patients who achieve CR can have good RFS and cure is possible, but the toxic cost of conventional strategies is unacceptable and selected strategies still must be found.     

Phagocytosis of Hemozoin (Native and Synthetic Malaria Pigment), and Plasmodium falciparum Intraerythrocyte-Stage Parasites by Human and Mouse Phagocytes

Hemozoin, the detoxification product of hemoglobin heme, piles up as electron-dense material in the food vacuole (FV) of intraerythrocytic malaria parasites (malaria pigment). In infected individuals, pigment is internalized by both circulating and resident phagocytes, thus modulating their functions. Synthetic beta-hematin, prepared in vitro from hematin (ferriprotoporphyrin IX hydroxide) in acidic condition, is spectroscopically identical to hemozoin. In this electron microscopy study, native and synthetic hemozoin also prove to be morphologically indistinguishable (large polygonal crystals with apparent transverse banding) and to undergo the same process when internalized by phagocytes (primarily a direct uptake of crystals, similar to what is described for asbestos fibers). On the contrary,whole parasites appear to follow a classical endocytic pathway. This suggests that there may be differences between the ingestion of free particles and whole parasites in terms of modulation of phagocytes' functions.     

Spontaneous and pronase‐induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines

A subgroup of HER2‐overexpressing breast tumours co‐expresses p95 $^{{\rm{HER2}}}$ , a truncated HER2 receptor that retains a functional HER2 kinase domain but lacks the extracellular domain, thus impairing trastuzumab binding. We evaluated p95 $^{{\rm{HER2}}}$ expression in 99 frozen breast carcinoma samples by western blot analysis. The HER2‐positive cell line BT474 treated with pervanadate or pronase was used as a positive control for p95 $^{{\rm{HER2}}}$ expression. Immunohistochemistry was performed on parallel formalin‐fixed, paraffin‐embedded sections of the same case series using antibodies directed against either the intra‐ or extra‐cellular binding domain of HER2. In particular, biotinylated trastuzumab (BiotHER) was used to evaluate the binding capacity of the humanized antibody. To avoid a subjective evaluation of the score values and the percentage of immunostained cells, the slides were scanned and automatically analysed. The number of cases with HER2 overexpression (score 3+) and HER2 gene amplification was higher in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐positive samples than in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐negative group. Automated analysis confirmed a significantly higher percentage of 3+ scored cells in p95 $^{{\rm{HER2}}}$ ‐positive cases. Conversely, the percentage of 2+ scored cells was higher in p95 $^{{\rm{HER2}}}$ ‐negative cases. The status of the HER2 extracellular domain was then studied using flow cytometry on BT474 cells after pronase enzymatic digestion using trastuzumab and pertuzumab, while the presence of HER2‐HER3 dimers was studied using a proximity‐ligation assay. In vitro experiments showed that short‐term pronase digestion of BT474 cells produced two HER2 fragments (of 95 and 150 kDa, detectable in tissue specimens as well), increased the binding affinity of trastuzumab, reduced the rate of HER2–HER3 dimers, and did not interfere with pertuzumab‐binding capacity. In conclusion, the presence of p95 $^{{\rm{HER2}}}$ as detected by western blot analysis does not compromise the immunohistochemical detection of HER2. Our data suggest that a reduction of the receptor steric hindrance as induced by enzymatic shedding may facilitate the binding capacity of trastuzumab. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.