Kinetic and mechanistic study of ultrasonic inactivation of Kunitz (KTI) and Bowman-Birk (BBI) inhibitors in relation to process-relevant parameters.

In this study, quantitative monitoring of low-frequency (20 kHz) and high-frequency (355 kHz) ultrasound-induced inactivation of Kunitz (KTI) and Bowman-Birk inhibitor (BBI) using RP-HPLC was achieved, and its consistency with a traditional TI activity assay was verified. The effect of TI concentration, ultrasonic frequency, power density and pH on inactivation kinetics of KTI and BBI was explored. Results showed that the pseudo-first-order kinetic rate constants of KTI and BBI were decreased by over 60% when the initial TI concentration was increased from 100 mg/L to 1000 mg/L. Also, the amounts of inactivated KTI and BBI were increased by around 4-fold at the higher TI concentration of 1000 mg/L (20 kHz, 1.71 W/mL and pH 4). The colloidal environment and ultrasonic conditions influenced the secondary and tertiary structure and particle size of TIs in LF-induced inactivation. In comparison, the abovementioned conditions affected the oxidation of methionine and the conformational change of TIs in HF-induced inactivation.

Is There any Link between Madelung Disease and Ischemic Stroke? A Case Report.

A 70-year-old man presented to the Emergency Department with left hemiparesis, slurred speech, and elevated blood pressure. A brain computed tomography scan revealed an ischemic lesion in the right frontal and parietal lobes. At clinical examination bilateral pseudo gynecomastia was detected together with the presence of multiple elastic, adipose bulging masses on the neck, trunk, and upper limbs. A type I-II Lanois-Bensaude syndrome was diagnosed. Ultrasonography confirmed their adipose nature. Multiple symmetric lipomatosis, also known as Lanois-Bensaude syndrome or Madelung disease, is a very rare condition with extreme variability in its clinical presentation. The simultaneous occurrence of ischemic stroke and lipomatosis in the same patient might be due to a mitochondrial function impairment, which could lead to abnormal fat tissue distribution and defective cellular energy production, thus resulting in neuronal sufferance and death. The possibility that, in our case, lipomatosis could have represented a further risk factor in promoting the stroke occurrence is discussed. In our opinion, multiple symmetric lipomatosis must be carefully evaluated to improve the patients' quality of life.

[The relationship between physical exercise and gut microbiota in the human being: a systematic review]. / Relazione tra esercizio fisico e microbiota intestinale nell'essere umano: revisione sistematica.

BACKGROUND: the relationship between physical exercise and gut microbiota has opened new therapeutic frontiers for many inflammatory diseases. However, there is still a lot of uncertainty about how to administer exercise. OBJECTIVES: to review the literature to bridge this gap and examine the relationship between cardiorespiratory fitness (CRF) and microbiota. DESIGN: systematic review. SETTING AND PARTICIPANTS: studies involving humans who undergoing exercise programmes of any lengths, intensities, and types were included. The research was carried out through PubMed, Scopus, and Web of Science. MAIN OUTCOME MEASURES: the primary outcome was change in gut microbiota composition (α and ß-diversity), while the secondary outcome was the CRF level. RESULTS: the 15 studies included (all with PEDro scale <=5) used aerobic training alone or combined with resistance exercises. In general, exercise has shown positive effects on the microbiota, influencing the faecal count of some bacterial phyla (in particular Bacteroidetes, Firmicutes, and Proteobacteria), with a weak tendency towards proportionality in relation to training duration and intensity. However, the evidence supporting the exercise effects on the gut microbiota and the relationship with CRF are of low quality. CONCLUSIONS: despite the weak evidence in favour of the effects of the practice of physical exercise on the intestinal microbiota, there are still many aspects that need to be explored. In particular, future studies shall have higher quality and methodological rigour, standardize the methods for outcome assessment, and determine type and thresholds of interventions intensity and duration.

The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort.

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.

Remdesivir Use in Patients Requiring Mechanical Ventilation due to COVID-19.

BACKGROUND: Remdesivir has been associated with accelerated recovery of severe coronavirus disease 2019 (COVID-19). However, whether it is also beneficial in patients requiring mechanical ventilation is uncertain. METHODS: All consecutive intensive care unit (ICU) patients requiring mechanical ventilation due to COVID-19 were enrolled. Univariate and multivariable Cox models were used to explore the possible association between in-hospital death or hospital discharge, considered competing-risk events, and baseline or treatment-related factors, including the use of remdesivir. The rate of extubation and the number of ventilator-free days were also calculated and compared between treatment groups. RESULTS: One hundred thirteen patients requiring mechanical ventilation were observed for a median of 31 days of follow-up; 32% died, 69% were extubated, and 66% were discharged alive from the hospital. Among 33 treated with remdesivir (RDV), lower mortality (15.2% vs 38.8%) and higher rates of extubation (88% vs 60%), ventilator-free days (median [interquartile range], 11 [0-16] vs 5 [0-14.5]), and hospital discharge (85% vs 59%) were observed. Using multivariable analysis, RDV was significantly associated with hospital discharge (hazard ratio [HR], 2.25; 95% CI, 1.27-3.97; P = .005) and with a nonsignificantly lower mortality (HR, 0.73; 95% CI, 0.26-2.1; P = .560). RDV was also independently associated with extubation (HR, 2.10; 95% CI, 1.19-3.73; P = .011), which was considered a competing risk to death in the ICU in an additional survival model. CONCLUSIONS: In our cohort of mechanically ventilated patients, RDV was not associated with a significant reduction of mortality, but it was consistently associated with shorter duration of mechanical ventilation and higher probability of hospital discharge, independent of other risk factors.

Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome.

OBJECTIVES: The outbreak of COVID-19 posed the issue of urgently identifying treatment strategies. Colchicine was considered for this purpose based on well-recognised anti-inflammatory effects and potential antiviral properties. In the present study, colchicine was proposed to patients with COVID-19, and its effects compared with 'standard-of-care' (SoC). METHODS: In the public hospital of Esine, northern Italy, 140 consecutive inpatients, with virologically and radiographically confirmed COVID-19 admitted in the period 5-19 March 2020, were treated with 'SoC' (hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir). They were compared with 122 consecutive inpatients, admitted between 19 March and 5 April 2020, treated with colchicine (1 mg/day) and SoC (antiviral drugs were stopped before colchicine, due to potential interaction). RESULTS: Patients treated with colchicine had a better survival rate as compared with SoC at 21 days of follow-up (84.2% (SE=3.3%) vs 63.6% (SE=4.1%), p=0.001). Cox proportional hazards regression survival analysis showed that a lower risk of death was independently associated with colchicine treatment (HR=0.151 (95% CI 0.062 to 0.368), p<0.0001), whereas older age, worse PaO2/FiO2, and higher serum levels of ferritin at entry were associated with a higher risk. CONCLUSION: This proof-of-concept study may support the rationale of use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.

Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders: First Report of Multilocus Syndrome in Piebaldism.

Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.

Reactive arthritis secondary to Hafnia alvei enterocolitis.

Diagnosis of postenteritic reactive arthritis (ReA) is a challenge and might have a broad range of differential diagnoses. A 50-year-old man was referred to our attention because of persistent inflammatory low back pain and asymmetric oligoarthritis. The clinical history was positive for diarrhoea in the previous 3 months. Inflammatory bowel disease, Whipple and celiac diseases were carefully excluded. In addition, serology, stool cultures, biopsies from the upper gastrointestinal tract yielded negative results for infections. A presumptive diagnosis of ReA was done and a non-steroidal anti-inflammatory drug trial prescribed. Persistence of symptoms prompted us for a second look of the colon. Biopsy collected from the terminal ileum were cultured and surprisingly colonies of Hafnia alvei, a rod-shaped Enterobacteriaceae, were detected. Treatment with ciprofloxacin leads to fast symptoms resolution. Although enterocolitis from H. alvei has been rarely reported, the culture of intestinal specimens might be recommended in the work-up of patients with suspected postenteritic ReA.

Congenital Hypopigmentary Disorders with Multiorgan Impairment: A Case Report and an Overview on Gray Hair Syndromes.

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.

A Modified Translaryngeal Tracheostomy Technique in the Neurointensive Care Unit. Rationale and Single-center Experience on 199 Acute Brain-damaged Patients.

BACKGROUND: Brain-injured patients frequently require tracheostomy, but no technique has been shown to be the gold standard for these patients. We developed and introduced into standard clinical practice an innovative bedside translaryngeal tracheostomy (TLT) technique aided by suspension laryngoscopy (modified TLT). During this procedure, the endotracheal tube is left in place until the airway is secured with the new tracheostomy. This study assessed the clinical impact of this technique in brain-injured patients. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data from adult brain-injured patients who had undergone modified TLT during the period spanning from January 2010 to December 2016 at the Neurointensive care unit, San Gerardo Hospital (Monza, Italy). The incidence of intraprocedural complications, including episodes of intracranial hypertension (intracranial pressure [ICP] >20 mm Hg), was documented. Neurological, ventilatory, and hemodynamic parameters were retrieved before, during, and after the procedure. Risk factors for complications and intracranial hypertension were assessed by univariate logistic analysis. Data are presented as n (%) and median (interquartile range) for categorical and continuous variables, respectively. RESULTS: A total of 199 consecutive brain-injured patients receiving modified TLT were included. An overall 52% male individuals who were 66 (54 to 74) years old and who had an admission Glasgow Coma Scale of 7 (6 to 10) were included in the cohort. Intracerebral hemorrhage (30%) was the most frequent diagnosis. Neurointensivists performed 130 (65%) of the procedures. Patients underwent tracheostomy 10 (7 to 13) days after intensive care unit admission. Short (ie, <2 min) and clinically uneventful increases in ICP>20 mm Hg were observed in 11 cases. Overall, the procedure was associated with an increase in ICP from 7 (4 to 10) to 12 (7 to 18) mm Hg (P<0.001). Compared with baseline, cerebral perfusion pressure (CPP), respiratory variables, and hemodynamics were unchanged during the procedure (P-value, not significant). Higher baseline ICP and core temperature were associated with an increased risk of complications and intracranial hypertension. Complication rates were low: 1 procedure had to be converted to a surgical tracheostomy, and 1 (0.5%) episode of minor bleeding and 5 (2.5%) of minor non-neurological complications were recorded. Procedures performed by intensivists did not have a higher risk of complications compared with those performed by ear, nose, and throat specialists. CONCLUSIONS: A modified TLT (by means of suspension laryngoscopy) performed by neurointensivists is feasible in brain-injured patients and does not adversely impact ICP and CPP.

Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers.

Germline mutations on the CDKN2A gene, the most important known genetic factors associated with cutaneous melanomas (CMs), predispose carriers to multiple primary CMs (MPMs) with higher frequency and younger onset compared to non-carriers. Most of the largest published studies concerning clinical and histological characteristics of CMs with CDKN2A mutation carriers did not specify if the described CMs are first or subsequent to the first, and they used sporadic CMs from non-genotyped patients as controls. We conducted a single-centre observational study to compare clinical and histological CM features of 32 unrelated carriers (MUT) of 5 germline CDKN2A mutations (one of which was never previously described) compared to 100 genotyped wild-type (WT) patients. We stratified the data based on time of diagnosis, anatomical site and histological subtype of CMs, demonstrating several significant unreported differences between the two groups. MUT developed a higher number of dysplastic nevi and MPMs. We proved for the first time that anatomical distribution of CMs in MUT was independent of gender, unlike WTs. MUTs developed in situ and superficial spreading melanomas (SSMs) more frequently, with significantly higher number of SSMs on the head/neck. In MUTs, Breslow thickness was significantly lower for all invasive CMs. When CMs were stratified on the basis of the time of occurrence, statistical significance was maintained only for SSMs subsequent to the first. In WTs, Clark level was significantly higher, and ulceration was more prevalent than in MUTs. Significant differences in ulceration were observed only in SSMs. In nodular CMs, we did not find differences in terms of Breslow thickness or ulceration between WTs and MUTs. In situ CMs developed 10 years earlier in MUTs with respect to WTs, whereas no significant differences were observed in invasive CMs. In contrast to those reported previously by other authors, we did not find a difference in skin phototype.