Nanoporous silica nanoparticles functionalized with a fluorescent turn-on spirorhodamineamide as pH indicators.

We prepared water soluble, biocompatible fluorescent turn-on pH nanosensors and characterized their behavior as a function of changes in pH. The response relies on a halochromic reaction of a spirorhodamineamide derived from the bright and highly chemically and photo-stable rhodamine 6G, encapsulated in core/nanoporous shell silica nanoparticles. The fluorescent sensors displayed a fast response in the pH range of intracellular compartments. The encapsulation conferred solubility in aqueous environments and biocompatibility. We assessed the two main properties of the sensor, namely the useful pH range and the kinetics of the response, and compared them to those of the free probe. We found that such properties are strongly dependent on the functionalization and position in the silica matrix relative to the core/shell structure. Finally, we demonstrated the cellular uptake of the nanosensors, and their localization in lysosomes of living cells, by fluorescence confocal microscopy.

Exercise tolerance in systemic sclerosis patients without pulmonary impairment: correlation with clinical variables.

OBJECTIVES: In systemic sclerosis (SSc) patients pulmonary vasculopathy (PV) is present in the early stage of disease and impairs dilation of affected pulmonary blood vessels, impeding pulmonary blood flow during exercise. Abnormal gas exchange findings were early investigated by cardiopulmonary exercise test (CPET). METHODS: A total of 34 female and 6 male [median age 49 (20-63) years] SSc patients with normal chest imaging and pulmonary function tests were enrolled. Twenty healthy controls age and sex matched [16 female and 4 male; median age 51 (35-73) years] were also recruited. All subjects underwent a full clinical examination, including a nailfold video capillaros copy (NVC). An incremental symptom-limited CPET was performed with estimation of minute ventilation (VE), workload (WR), peak oxygen uptake (pVO22), and ventilatory efficiency (VE/VCO2 slope). RESULTS: A reduced exercise tolerance (pVO2<80% of predicted) was documented in 18 out of 40 subjects (45%). Six out of 18 patients with a reduced exercise tolerance showed indirect signs of ventilation perfusion mismatch (VE/ VCO2 slope >34). Patients with digital ulcers (DUs) history showed VE/VCO2slope values significantly higher [31.4 (18-39.6)] than in patients without DUs history [26.9 (22-29.4)] (p<0.0001). VE/VCO2slope values also significantly differed between the three capillaroscopic groups: early [26.3 (18-29.4)], active [28 (26.8-39.6)], and late [32.9 (22.4-39)] (p<0.0001). A positive correlation was found between the VE/ VCO2slope and both Disease Activity Index (p<0.0001, r=0.59) and Disease Severity Scale (p<0.0001, r=0.73). CONCLUSIONS: In SSc patients without evidence of pulmonary and cardiac involvement, CPET might be useful in disclosing an early PV.

Fat overload syndrome following intravenous lipid emulsion administration as antidote in suspected anesthetic intoxication: insights from a clinical and forensic case experience.

Abstract: Medication errors pose significant risks to patients' health, representing a relevant social and economic issue for the healthcare system. This study focuses on the life-threatening consequences of an overdose of intravenous lipid emulsion (ILE), used as an antidote for suspected bupivacaine intoxication in a young woman undergoing hip surgery. Shortly after administration of the local anesthetic, the woman experienced cardiac arrest and was admitted to the intensive care unit with severe respiratory failure, metabolic acidosis and deep coma. Despite medical intervention, her condition worsened, leading the medical team to administer ILE for suspected bupivacaine intoxication. The patient's condition did not improve and ultimately resulted in death. The autopsy highlighted a widespread presence of oily material in the vascular system, compatible with an overdose of ILE. At a checking, medical records reported a dose of ILE that was 4-fold higher than the recommended dose in this off-label indication. This case report highlights the important need for healthcare professionals to understand the risks of using ILE as an antidote. Adequate monitoring of these "sentinel events" and their critical evaluation can lead to the implementation of specific clinical risk management protocols to reduce the risk for the patient and contain healthcare costs.

3D printing and 3D bioprinting technology in medicine: ethical and legal issues.

Abstract: There has been a surge of interest in new technologies in medicine because of their promising clinical applications. Extensive research on additive manufacturing and its applications in the medical field has been carried out with good results and very high expectations. Due to their disruptive nature and potential, 3D printing and even more 3D bioprinting raise many ethical and safety concerns that need to be adequately addressed to provide good regulation before entering clinical practice. This article aims to highlight the general ethical concerns associated with the use of additive manufacturing in medicine and the lack of current international regulatory directives to guide these experiments. Transparency about how these new medical devices are regulated and approved is a fundamental requirement to promote and improve public trust, efficiency, safety and quality.

Four cases of sodium nitrite suicidal ingestion: A new trend and a relevant Forensic Pathology and Toxicology challenge.

Sodium nitrite (NaNO2) is an inorganic compound commonly used as a food additive, antifreeze admixture, and fertilizer. Its toxicity mechanism is mainly represented by the oxidation of ferrous iron to ferric iron of one of the four heme structures in haemoglobin with the onset of methaemoglobin. The mechanism of death by sodium nitrite toxicity is severe hypoxia. We present four cases of suicidal sodium nitrite ingestion that closely occurred within a two months-period. Self-poisoning with sodium nitrite actually represents an increasing trend in nitrates' related deaths. In order to reach a precise diagnosis of NaNO2 intoxication, a complete toxicological analysis should be carried out including not only MetHb blood levels but also nitrites and nitrites in standard or alternative matrices as a routine procedure. Autopsy should be carefully performed to detect common indicators of hypoxia or more rarely evident typical by themselves-non specific signs of sodium nitrite toxicity. Suicidal manner of death should be carefully considered when circumstantial data support that ingestion of large amounts of NaNO2 occurred as a consequence of a self-injurious behaviour. Relevant informations include victim's previous Internet or book researches about paths to follow to commit suicide with sodium nitrate, employment and past medical history, with strong regard to psychiatric diseases as well as eventual taking psycotropic drugs. Finally, an accurate integration of autoptic and toxicological results with circumstantial data is necessary to make correct diagnosis of death due to acute respiratory failure secondary to suicidal sodium nitrite ingestion.

Death occurred due to undiagnosed systemic amyloidosis: a case report.

Abstract: Amyloidosis is a disorder related to errors in protein folding. We present a clinical case of systemic amyloidosis manifesting as hypotension, tachycardia, pain, weight loss, asthenia, anorexia, dysphagia, and mood deflection in a 49-year-old-year-old woman with a previous clinical history of articular and muscular pain, correlated to suspected seronegative arthritis. The blood test revealed kidney insufficiency, an electrocardiogram identified low voltages of the peripheral leads and T waves anomalies. A serum protein electrophoresis revealed the presence of high levels of monoclonal kappa free chains. The woman started to have a sense of suffocation, and after one week she was found dead in her bed. After the autopsy, the results of Congo red staining of the myocardium were characteristic of amyloid. According to the autoptic and the histological examination, death occurred due to acute cardiac and respiratory arrest secondary to amyloid cardiomyopathy in a patient with undiagnosed systemic amyloidosis.

Vitamin D status of inmates: the experience of penitentiaries prisons in the province of Salerno in Southern Italy.

Introduction: Prisoners are at risk of developing vitamin D deficiency due to their lacking exposure to sunlight. So far, there are no published studies evaluating blood levels of vitamin D in relation to the health status of inmates and the quality of the Italian prison system. Aim: To investigate vitamin D status and its determinants in a cohort of prisoners. Subject and Methods: One hundred and seventy-two (172) pri-son inmates (males, n=159, age 47± 11.3 years; females, n=13, age 43.91±12.18 years) of three penitentiaries in the province of Salerno. Vitamin D deficiency, insufficiency and sufficiency were respectively defined as a 25(OH)D level <20 ng/mL; from 20 to 30 ng/mL, >30 ng/mL. Results: In our group, Vitamin D deficiency occurs in 77.32% of the prisoners with 32.55% of the cases having severe insufficiency. Prisoners with higher BMI show lower circulating vitamin D levels (p<0.001). No significant relationship was found with the duration of detention (Pearson R: 0.01). Conclusion: In this cohort of inmates the vitamin D status is determined by BMI, but not by the duration of the detention.

Physician-Patient Relationship, Assisted Suicide and the Italian Constitutional Court.

In 2017, Italy passed a law that provides for a systematic discipline on informed consent, advance directives, and advance care planning. It ranges from decisions contextual to clinical necessity through the tool of consent/refusal to decisions anticipating future events through the tools of shared care planning and advance directives. Nothing is said in the law regarding the issue of physician assisted suicide. Following the DJ Fabo case, the Italian Constitutional Court declared the constitutional illegitimacy of article 580 of the criminal code in the part in which it does not exclude the punishment of those who facilitate the suicide when the decision has been freely and autonomously made by a person kept alive by life-support treatments and suffering from an irreversible pathology, the source of physical or psychological suffering that he/she considers intolerable, but fully capable of making free and conscious decisions. Such conditions and methods of execution must be verified by a public structure of the national health service, after consulting the territorially competent ethics committee. This statement admits, within strict and regulated bounds, physician assisted suicide, so widening the range of end-of-life decisions for Italian patients. Future application and critical topics will be called into question by the Italian legislator.

A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

BACKGROUND: Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide. OBJECTIVES: In this retrospective study we analysed the 'real-world' TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance. METHODS: All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015-17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing. RESULTS: 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence. CONCLUSIONS: Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.

Bleeding varicose veins' ulcer as a cause of death: a case report and review of the current literature.

ABSTRACT: Chronic venous insufficiency (CVI) and varicose veins (VVs) of the lower limbs are very frequent vascular diseases in Western countri-es. One possible complication of these conditions is skin ulceration and its consequent rupture, which can be spontaneous or due to mild or trivial trauma. In some cases, the resulting hemorrhage is fatal. When the victim is found dead, a large amount of blood around the body might lead to the hypothesis of violent death. The Forensic Pa-thologist needs to be very careful in the corpse's examination, in order to exclude any alternative cause of death. Herein, an illustrative case is reported, as well as a literature review of the literature concerning sudden hemorrhages from VVs. We found 27 scientific papers, the total reported cases of VVs rupture with profuse hemorrhages were 36, 32 of which were fatal. The main characteristics of such forensic scenario have been collected. Corpse examination of the victims showed pallor of the skin and mucous membranes, as well as marked pallor of organs as a sign of hemorrhagic shock, but these pathological findings are unspecific. Usually, the skin near the ulcer presented color alteration (discoloration and atrophy or pigmentation and hyperemia). Besides, the histological examination of the skin could be a valid instrument to demonstrate the presence of the ulcer, even if it could be very difficult to sample, because of its small size. An important limit of our study is the small number of collected cases. More studies in this field are needed to improve evidence concerning death due to VVs rupture.

Erratum to: A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.

[This corrects the article DOI: 10.1093/jacamr/dlab026.].

Claims in total hip arthroplasty: analysis of the instigating factors, costs and possible solution.

PURPOSE: Over the years, the number of total hip replacements has been steadily increasing. Despite the improvement in surgical results, the number of claims for malpractice is higher. The primary endpoint of this work is to provide an analysis of litigation after hip replacement, to outline what are the instigating causes and costs. The secondary endpoint is to propose a possible preventive strategy for an improved care and a reduction in legal proceedings. MATERIALS AND METHODS: The data of this study were collected from medical and legal files and from professional liability insurance of our institution from January 2005 to December 2016. RESULTS: Out of a total of 4770 THA, 40 claims were received. Peripheral nerve injuries represent the first cause of litigation (37%), followed by infectious complications, leg length discrepancy, metallosis, dislocations of the implant and a case of deep vein thrombosis. From the analysis of the past trial judgment, complications such as nerve lesions and infections are almost always recognized, as a medical error, with a high percentage of claims settled. CONCLUSION: This study shows the necessity of preventive strategies to reduce the higher number of claims for malpractice in total hip arthroplasty. Some complications such as nerve injuries and infection are frequently considered directly dependent on physician's errors. Litigations can be reduced providing evidence of a diligent execution of the surgical procedure and of a proper postoperative management: the correct compilation of a specific informed consent and adequate doctor-patient communication.

Role of post mortem CT (PMCT) in high energy traumatic deaths.

BACKGROUND: Post Mortem Computed Tomography (PMCT) is being increasingly implemented in forensic field and could be an adjuvant to classic autopsies. In this study we evaluated the feasibility of complementation of conventional autopsy in trauma victims with PMCT. MATERIALS AND METHODS: A total of 21 subjects, who had sustained various types of blunt high-energy trauma, were selected from the casuistry of the Section of Legal Medicine at University of Pisa: before autopsy, a PMCT examination (Toshiba Aquilion 16 CT scanner) was performed, and after the acquisition of the raw images, MPR and VR reconstructions were performed with dedicated software. RESULTS: PMCT is more sensitive than conventional autopsy in detecting skeletal injuries, whilst autopsy constitutes the method of choice for the detection of thoracic and abdominal visceral injuries. CONCLUSIONS: PMCT should be considered a useful tool in addition to conventional autopsy in evaluating trauma victims: it detects further bone fractures in body parts difficult to investigate during autopsy (i.e. posterior regions), facilitating the pathologist in the reconstruction of events and in determining the cause of death.

Unexpected delayed death after manual strangulation: need for careful examination in the emergency room.

The aim of this case report was to demonstrate the importance of detailed clinical assessment in victims of attempted manual strangulation, to prevent the occurrence of delayed death due to an airway collapse; and to provide an update on clinical management of these patients. An elderly male patient presented with a sore throat and speech impairment after attempting manual strangulation. Physical examination showed reddish skin of the neck, an extensive haematoma of the hard palate and anterior tongue. Flexible laryngoscopy failed to show any swelling of the hypopharynx or larynx. A few hours after presentation, the patient developed acute dyspnoea and died. Autopsy and post-mortem CT scan showed a haematoma in the thyro-epiglottal space. In conclusion, victims of manual strangulation can survive despite internal neck injury which can lead to delayed fatal airway collapse. This is because often there are few or no signs of assault, therefore medical evaluation should be thorough and timely. Sometimes immediate tracheotomy can be life saving.

Resistant hypertension and obstructive sleep apnea syndrome in therapy with continuous positive airway pressure: evaluation of blood pressure, cardiovascular risk markers and exercise tolerance.

OBJECTIVE: Resistant hypertension (RH) may be associated with Obstructive Sleep Apnea (OSA), determining a remarkable increase in cardiovascular risk. The aim of the study was to assess the effect of six months with continuous positive airway pressure (CPAP) treatment on blood pressure (BP) values, cardiovascular risk markers, and exercise tolerance in patients with RH and OSA. PATIENTS AND METHODS: Twenty-four patients with RH and OSA were recruited and 24-hour ambulatory BP, intima-media thickness (IMT), flow mediated dilation (FMD), renal resistive index (RRI), and endurance cardiopulmonary exercise testing (CPET) were obtained at enrollment and after 6-month treatment. RESULTS: Significant reduction in clinic systolic and diastolic BP, IMT, and RRI (p = 0.003, p = 0.009, p = 0.020, p = 0.04, respectively) and increase in the left ventricular ejection fraction (p = 0.035) were observed after a 6-month therapy with CPAP. Moreover, improvement in all polysomnographic parameters (number of apneas/hypopneas per hour (p < 0.001), number of episodes of night-time hemoglobin desaturation (ODI) (p = 0.010)), an improvement in Epworth Sleepiness Scale (p < 0.001), as well as in endurance time during constant workload CPET (p = 0.017) were observed too. CONCLUSIONS: CPAP treatment for six months reduces BP and improves cardiovascular risk and exercise tolerance in patients with RH and OSA. An extended cardiovascular assessment, including exercise testing, might be helpful in this population, given the possible reversibility of some endothelial dysfunction and atherosclerotic markers with CPAP treatment, as reported in our study.

Aedes albopictus and Culex pipiens implicated as natural vectors of Dirofilaria repens in central Italy.

To identify the natural vectors of Dirofilaria repens Railliet et Henry, entomological samplings were carried out in four sites within the Lazio region, foci of canine subcutaneous dirofilariasis. Collections were made in 2002-2003 by means of dog-baited and miniature Centers for Disease Control and Prevention traps as well as on humans. Microscopy identified 1576 attracted mosquito females as belonging to six species, but molecular diagnostics detected filarial DNA only in Culex pipiens L. and Aedes albopictus (Skuse, 1894). Dirofilaria immitis Leidy DNA, D. repens DNA, or both were found in the head and thorax of both mosquitoes. The simultaneous presence of vectors showing diurnal and nocturnal activity patterns is of concern for animal and human health. The finding of D. immitis DNA in mosquitoes in areas where only D. repens was been recovered in dogs also demonstrates that this filarial parasite circulates among carnivores (wild or domesticated pets).