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.

Abuse and misuse of prescription opioids: is it only an Ameri- can problem? An observational study on an Italian casuistry.

ABSTRACT: Medical use of prescription opioids has steadily increased since the 1990s, particularly in the U.S.A. and Canada, along with abuse of these substances and significant increases in rates of addiction and death related to prescription opioids. The American authorities speak of an "addiction epidemic" and are launching a series of countermeasures to better address the problem. In Europe, there is an increasing use of prescription opioids and related problems, but the European context is much less dramatic than the American and Canadian ones. Never-theless, based on the data, it cannot be ruled out that a similar crisis will occur on the Old Continent. The aim of this study is to analyze the Italian context to better understand whether there is a possibility of an addiction epidemic. Twenty-four cases of death of people under treatment with pre-scription opioids have been retrospectively analyzed. Toxicological samples were collected with routine methods during the autopsy, followed by systematic screening for substances by diverse methods. Volatile compounds were identified using gas chromatography-flame ionization detection (GC-FID). Medical drugs and drugs of abuse were identified via the use of gas chromatography-mass spectrome-try (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS). Of a total of 24 subjects, 14 died due to an overdose of Tramadol, while 7 died due to an overdose of Buprenorphine and 3 dues to a Fentanyl overdose. The most used drug was Tramadol. Histological examination was performed with hematoxylin/eosin staining, though no significant findings emerged apart from widespread edema and focal sclerosis of the myocardium, and interstitial and alveolar edema of the lungs. Our data show that attention must be paid to prescription opioids. European institutions, as soon as possible, must implement preventive measures that avoid the recurrence of the North American situation.

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.

Post-mortem diagnosis of sepsis: when it's too late.

Post-mortem diagnosis of sepsis is often very difficult to make, especially in the elderly affected by multiple comorbidities. However, clinical evaluation following histology, immunohistochemistry, microbiological tests, immunoassays and proteomics can improve reliability of this post-mortem diagnosis.

Different prevalence and degree of nonspecific bronchial hyperreactivity between seasonal and perennial rhinitis.

From the patients observed at our respiratory allergology service, we selected patients with rhinitis only, without any past or present respiratory symptoms, for our study. All these patients had normal pulmonary function, were administered carbachol or methacholine bronchial challenges, and had one or more skin reactions to perennial or seasonal allergens. Patients were allocated to three groups: group A, patients with seasonal rhinitis who were administered nonspecific challenges out of season; group B, patients with seasonal rhinitis tested during the season; and group C, patients with perennial rhinitis. The three groups were divided into subgroups according to the duration in years of rhinitis and to the degree of nonspecific bronchial responsiveness. The distribution into four groups of reactivity, arbitrarily defined as normal and mildly, moderately, and severely increased reactivity, was as follows: group A, 124, 21, 30, 22; group B, 75, 15, 7, and 21: and group C, 69, 17, 39, and 72, respectively. The patients of group C (perennial rhinitis) demonstrated a distribution significantly (p less than 0.001) different from subjects with seasonal rhinitis, both group A and group B. Our results are consistent with the hypothesis that perennial rhinitis is much more important than seasonal rhinitis as a risk factor for developing nonspecific bronchial hyperresponsiveness.

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.

Effect of nisoldipine (BAY k 5552) on methacholine-induced bronchoconstriction in patients with nonspecific bronchial hyperreactivity.

The purpose of this study was to determine whether a new calcium antagonist, nisoldipine (BAY k5552), exerted protection against methacholine-induced bronchoconstriction in subjects with hyperreactive airways. Twelve symptomless rhinitic and/or asthmatic patients with previously demonstrated bronchial hyperreactivity to methacholine were treated with placebo or nisoldipine (10 mg) according to a randomized, double-blind, crossover, placebo-controlled study design. Airway reactivity was examined through changes in response to methacholine challenge three hours after drug or placebo administration. Nisoldipine, in comparison to placebo, produced a weak but significant rise of provocative dose of methacholine responsible for a 15% fall in FEV1 (P less than .01). The data suggest that a single dose of 10 mg of nisoldipine is able partially to counteract methacholine-induced bronchoconstriction in atopic subjects with nonspecific airway hyperresponsiveness.

Renal effects of enalapril in hypertensive patients with glomerulonephritis.

Renal effects of enalapril maleate in ten hypertensive patients with glomerulonephritis were evaluated after 1 and 16 weeks of therapy. Systemic blood pressure decreased, glomerular filtration rate was not significantly changed, and sodium fractional excretion and renal plasma flow increased, whereas renal vascular resistances and filtration fraction decreased acutely at the end of the study. Proteinuria diminished, but no variations in qualitative pattern were observed. ACE inhibitors, promoting efferent rather than afferent arteriolar vasodilatation and reduction of glomerular permeability coefficient, may reduce glomerular capillary hypertension and the development of proteinuria.

Famotidine effects on theophylline pharmacokinetics in subjects affected by COPD. Comparison with cimetidine and placebo.

The effect of a new H2-antagonist, famotidine, on theophylline pharmacokinetics was compared with placebo and cimetidine in 26 patients affected by COPD. Cimetidine, placebo, and famotidine were administered, four days each drug at random, to all the subjects. Results suggest that famotidine, contrary to cimetidine, does not influence theophylline metabolism in man.

Procaterol metered aerosol in patients with chronic obstructive pulmonary disease.

The activity and tolerability of procaterol, a recently introduced beta 2-adrenergic drug, were evaluated in comparison with fenoterol and a placebo in a single blind, cross-over study, using a metered aerosol formulation. Twelve patients suffering from chronic obstructive pulmonary disease with reversible bronchial obstruction were enrolled. Before and 30, 120, 240, 360, 480 min after drug administration, forced vital capacity (FVC), forced expiratory volume at the first second, forced expiratory flow at 25-75% and 75-85% respectively of the FVC, thoracic gas volume and the specific airways conductance were calculated. Procaterol 20 mcg showed a significant bronchodilating activity as well as fenoterol 400 mcg. This activity was already significant within 30 min, achieved its maximum after two hours and lasted more than eight hours. Side-effects were complained of by 41% of patients treated with procaterol and by 50% treated with fenoterol; procaterol showed less cardiovascular effects than fenoterol.

Comparison of bronchodilator effects of Duovent and Reproterol in patients with chronic reversible airway obstruction.

The bronchodilator effect of Duovent (a combination of a beta-2-agonist, fenoterol, and an anticholinergic, ipratropium bromide) was compared with that of Reproterol (a pharmacological hybrid which presents both resorcinol and theophylline portions) in 16 patients suffering from chronic reversible airway obstruction. Each of the 16 patients (14 males and 2 females, mean age 65.8 years) had a baseline FEV1 ranging from 30 to 70% of their predicted values (CECA values) (mean value +/- SE of the group: 1,238 +/- 78 ml), which increased at least 15% after the inhalation of two puffs of 400 micrograms fenoterol (percent increase of the group: 26.5 +/- 2%, mean +/- SE). This single-blind study was carried out on 3 different days, between 8:30 a.m. and 4:30 p.m. After measurement of the baseline functional parameters [FVC (forced vital capacity), FEV1 (1-second forced expiratory volume), and FEF25-75 (forced expiratory flow between 25 and 75% of vital capacity)], each patient was given two puffs of placebo the 2nd day, and either of Duovent (200 micrograms of fenoterol and 80 micrograms of ipratropium bromide) or of Reproterol (1 mg) the 1st or the 3rd day, at random. The measurements of functional parameters were repeated after 30, 120, 240, 360 and 480 min. Blood pressure, heart rate and possible side effects were recorded at the same time. Both Duovent and Reproterol, at all times, produced a statistically significant increase in FEV1 and FEF25-75.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison between inhaled clenbuterol and salbutamol in chronic bronchitis with reversible airway obstruction.

Twenty-one patients with chronic bronchitis and reversible airway obstruction participated in two single-blind, cross-over, placebo-controlled studies in inhaled clenbuterol - a new bronchodilator - and salbutamol. Nine patients participated in a dose-response study. Clenbuterol 10 microgram/puff, salbutamol 100 microgram/puff and placebo, were given by pressurized aerosol in cumulative doses of 1, 2, 4, 8, and 16 inhalations of each drug and placebo. The mean peak % FEV1 increases above the baseline were similar after all doses of clenbuterol and salbutamol and were significantly greater than after placebo. No cardiovascular effects were observed. Tremors were noted in two patients after 160 microgram clenbuterol and in one patient after 1600 microgram salbutamol. In a second study, clenbuterol (20 microgram), salbutamol (200 microgram) - two equieffective doses - and placebo were compared in a 6 h period in 12 patients. Clenbuterol and salbutamol produced bronchodilation of comparable magnitude, onset of action (15 min) and duration (4-6 h). Clenbuterol is an effective bronchodilator and, on the basis of molecular weight, about ten times more potent than salbutamol when given by aerosol.

Oral NAB 365 (clenbuterol) and terbutaline in chronic obstructive lung disease: a double-blind, two-week study.

The bronchodilator effects of large oral doses of clenbuterol (30 micrograms, t.i.d.) and terbutaline sulfate (5 mg, t.i.d.) were compared using the forced expiratory volume in one second (FEV1), the specific airway resistance (sRaw) and the maximum expiratory flow at 50% of vital capacity (V50% VC) in a double-blind, two-week study, with groups of 12 patients each. The patients suffered from chronic obstructive lung disease with partially reversible airway obstruction. The bronchodilator actions of the two medications were significant between 30 and 240 minutes after the first administration on day 1 and between 30 and 60 minutes after the first administration on day 14. The administration of hydroxyphenylorciprenaline at 60 min on day 14 produced a significant additional bronchodilating effect over the bronchodilating effects of clenbuterol and terbutaline. The basal values recorded on days 7 and 14 demonstrated a significant improvement of pulmonary function over the basal values on day 1, similar in both groups. No tachyphylaxis to the bronchodilator effect to either drug occurred over the two-week study period. Neither the incidence nor the nature of side effects differed in the two treated groups. No changes in heart rate or blood pressure were noted. No abnormal effects on blood gas tension or laboratory results were observed. It was concluded that oral clenbuterol is about 170 times more potent than oral terbutaline.

[A comparative trial of bronchodilator effects of fenoteral and sch 1000 in chronic bronchitis (author's transl)]. / Etude comparative des effets bronchodilatateurs du fénotérol et du sch 1000 dans la bronchite chronique

In a group of 20 patients with chronic bronchitis, bronchodilator effects of fenoterol (400 mug), SCH 1000 (40 mug), and their combination (fenoterol 400 mug msch 1000 40 mug) have been evaluated and compared by measuring total pulmonary capacity (CPT), intrthoracic gas volume (VGT), forced expiratory volume in one second (VEMS), specific airways resistance (SRva) and maximun expiratory flow at a lung volume for which the initial flow was 0.1 l/s (Vo.iv). Measurements have been made before and 30, 60, 120 and 180 min after administration of the drug. With each of the three drugs, the improvement of the five functional parameters is statistically significant at all time intervals. Changes in CPT, VGT, VEMS and SRva are not statistically different when using the different drugs, whereas the Vo.1v changes suggest a lesser bronchodilator effect of SCH 1000 than fenoterol (p less than 0.05 at 180 min), and especially than fenoterol-SCH 1000 combination (p less than 0.05 at all time intervals). The combination is lightly but not significantly better than fenoterol only. On account of these results and the very high tolerance for the two drugs, a new medication combining SCH 1000 and fenoterol is desirable. The authors emphasize the sensitivity of maximum expiratory flow measurements at low lung volumes for trials on bronchodilators and the necessity to consider the possible reduction in CPT for flows comparison at an identical absolute lung volume.