Moderate-to-severe atopic dermatitis in adolescents treated with dupilumab: A multicentre Italian real-world experience.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) in the adolescence is a high burden disease, and its treatment can be very challenging due to paucity of approved systemic drugs for this age and their side-effects. Dupilumab was recently approved for treatment of adolescent AD. OBJECTIVES: A multicentre, prospective, real-world study on the effectiveness and safety of dupilumab in adolescents (aged from ≥12 to <18 years) with moderate-to-severe AD was conducted. The main AD clinical phenotypes were also examined. METHODS: Data of adolescents with moderate-to-severe AD treated with dupilumab at label dosage for 16 weeks were collected. Treatment outcome was assessed by EASI, NRS itch, NRS sleep loss and CDLQI scores at baseline and after 16 weeks of treatment. The clinical scores were also evaluated according to clinical phenotypes. RESULTS: One hundred and thirty-nine adolescents were enrolled in the study. Flexural eczema and head and neck eczema were the most frequent clinical phenotypes, followed by hand eczema and portrait-like dermatitis. Coexistence of more than 1 phenotype was documented in 126/139 (88.5%) adolescents. Three patients (2.1%) contracted asymptomatic SARS-CoV-2 infection and 1 of the discontinued dupilumab treatment before the target treatment period. A significant improvement in EASI, NRS itch, NRS sleep loss and CDLQI was observed after 16 weeks of treatment with dupilumab. This outcome was better than that observed in clinical trials. Dupilumab resulted effective in all AD phenotypes, especially in diffuse eczema. Twenty-eight (20.1%) patients reported adverse events, conjunctivitis and flushing being the most frequent. None of patients discontinued dupilumab due to adverse event. CONCLUSIONS: Dupilumab in adolescent AD showed excellent effectiveness at week 16 with consistent improvement of all clinical scores. Moreover, dupilumab showed a good safety profile also in this COVID-19 pandemic era.

Abnormal gut motility in inflammatory bowel disease: an update.

BACKGROUND: There is substantial evidence linking disturbed gastrointestinal motility to inflammation. Thus, it is not surprising that abnormalities of gastrointestinal motility play a role in inflammatory bowel disease (IBD), affecting patient outcomes. We performed a review of the literature to investigate the relationship between abnormal gut motility and IBD. METHODS: With an extensive literature search, we retrieved the pertinent articles linking disturbed gut motility to IBD in various anatomical districts. RESULTS: The evidence in the literature suggests that abnormal gastrointestinal motility plays a role in the clinical setting of IBD and may confuse the clinical picture. CONCLUSIONS: Abnormal gut motility may be important in the clinical setting of IBD. However, additional data obtained with modern techniques (e.g., magnetic resonance imaging) are needed to individuate in a more precise manner gastrointestinal motor dysfunctions, to understand the nature of clinical manifestations and properly tailor the treatment of patients.

A long-term follow-up in conservative management of unilateral ureteropelvic junction obstruction with poor drainage and good renal function.

The aim of the study was to retrospectively review the outcome of neonatal ureteropelvic junction obstruction with a good renal function and a poor drainage at a first diuretic renal scan, in cases where surgery was recommended on the basis of a loss of renal function, worsening of hydronephrosis or occurrence of clinical symptoms. Hydronephrosis was graded from 1 to 4 or as ureteral tract dilatation (UTD) P1 to UTD P3. During follow-up, 15 out of 38 patients (34.2%) required surgery while 25 out of 38 (65.8%) could have been managed conservatively. In patients with grade 2, 3, and 4 hydronephrosis, the ureteropelvic junction obstruction resolved or improved spontaneously in 100%, 63%, and 33% of cases (in 100% of UTD P1, 67% of UTD P2, and 50% of UTD P3), respectively. The median of follow-up was 14 years. Chi-square test showed a significant relationship between initial grade of hydronephrosis or UTD and the possibility of an efficient conservative management (p = 0.0088 and p = 0.0460).Conclusion: Conservative management can be safely achieved in ureteropelvic junction obstruction with poor drainage. Scheduled controls are needed for early discovery of functional renal deterioration. High-grade hydronephrosis is unlikely to resolve spontaneously and is often accompanied by a loss of renal function during the first years of life. What is Known: • There is controversy about which management should be adopted in infants with unilateral ureteropelvic junction obstruction with poor drainage but good differential renal function. What is New: • Long-term follow-up suggests that conservative management can be safely achieved also in unilateral ureteropelvic junction obstruction with poor drainage in more than 60% of cases, even if high-grade hydronephrosis is unlikely to resolve spontaneously and it is often accompanied by a loss of renal function during the first years of life. In our experience, surgical intervention was required in more than 50% of cases before 1 year of life and in all cases before 3 years of life.

Symptomatic sensorineural hearing loss in patients with ulcerative colitis.

BACKGROUND: Sensorineural hearing loss has been reported as an extraintestinal manifestation of inflammatory bowel disease, especially in adult patients with ulcerative colitis. However, to date only a few series have been reported in the literature, and none from Italy. The aim of the present investigation was to assess the prevalence of symptomatic sensorineural hearing loss in Italian patients with ulcerative colitis. METHODS: We retrospectively assessed the charts of all patients with ulcerative colitis who underwent otolaryngologic investigation in a 10-year period. RESULTS: Complete charts of 57 patients were available for the observation period. Reasons for head and neck investigation were transient, mild hearing loss and sporadic vertigo. Clinical and instrumental head and neck examination was unremarkable in all but one woman who complained of mild hearing loss without vertigo or tinnitus, in whom sensorineural hearing loss was diagnosed. CONCLUSIONS: In our series, sensorineural hearing loss was found in less than 2 % of adult patients with ulcerative colitis evaluated in a department of otolaryngology. Systematic evaluation for this extraintestinal manifestation should not be carried out unless hearing loss is present.

Hyperhomocysteinemia in patients with Crohn's disease.

BACKGROUND: Thromboembolic complications have been reported in patients with Crohn's disease. Among the contributing factors, hyperhomocysteinemia has been described, although controversial data exist. The aim of our study was to assess the incidence of hyperhomocysteinemia in a nonselected group of patients with Crohn's disease and to determine whether it might represent a risk marker for thrombosis in such patients. METHODS: Fifty consecutive patients were recruited, and clinical and laboratory variables were compared between those without and those with hyperhomocysteinemia. In the latter, gene mutations in N5-N10-methyltetrahydrofolate reductase were searched for, and clinical and laboratory variables were related to hyperhomocysteinemia. The presence/absence of thrombotic episodes in both groups was determined. RESULTS: Both groups had similar clinically active disease, with higher C-reactive protein values found in those with hyperhomocysteinemia. Hyperhomocysteinemia was found in 46 % of patients. Of these, 74 % had moderate, 13 % intermediate, and 13 % severe increase in serum homocysteine levels. No relationship was found between homocysteine levels, and age, vitamin B12 levels, folic acid levels, Crohn's Disease Activity Index score, and CRP values. Gene mutations were found in 5 (22 %) patients, 2 homozygotes and 3 heterozygotes. None of the patients with or without hyperhomocysteinemia had episodes of venous or arterial thrombosis, or stroke. CONCLUSIONS: Hyperhomocysteinemia is frequent in patients with Crohn's disease, and it could be a cofactor for the pathogenesis of thrombotic episodes.

D-dimer levels during delivery and the postpartum.

BACKGROUND: D-dimer (DD) measurement has proved to be very useful to exclude venous thromboembolism (VTE) in outpatients. However, during pregnancy, the progressive increase as well as the interindividual variations of DD means that in this instance they are of poor value to rule out VTE. Only a few studies have reported measurements of DD levels in the postpartum. OBJECTIVES: To measure DD sequentially in the puerperium in order to determine when DD levels return to values obtained in non-pregnant women and can again be used in the exclusion of VTE. PATIENTS AND METHODS: After uncomplicated pregnancies, 150 women delivering at term either vaginally (n = 100) or by cesarean section (n = 50) were included. DD levels were measured immediately following delivery and next at days 1, 3, 10, 30 and 45. RESULTS: There was a marked elevation of DD at delivery, especially when instrumental. All DD measurements were above 500 ng mL(-1) at delivery, at day 1 and at day 3 postpartum. A sharp decrease in DD was observed between day 1 and day 3, followed by a slight increase at day 10. At day 30 and day 45, respectively, 79% and 93% of women in the vaginal delivery group and 70% and 83% in the cesarean group had levels below 500 ng mL(-1). Bleeding, breastfeeding and heparin prophylaxis did not modify DD levels significantly. CONCLUSION: Using the Vidas DD new assay, our study provides reference intervals for DD in the postpartum period. Using a cut-off at 500 ng mL(-1), DD measurement for ruling out VTE was found to be useful again 4 weeks after delivery.

The giant umbilical cord.

The giant umbilical cord is a rare malformation of the umbilical cord that can easily be diagnosed on prenatal scans and is unmistakable postnatally. We report a case to highlight issues of this rare finding. Visual diagnosis is easy and surgical repair is usually required.

[Gynaecology-obstetrics. Invasive prenatal diagnosis and in utero surgical treatments: what is new?]. / Gynécologie-obstétrique. Nouveautés concernant le diagnostic prénatal invasif et les traitements chirurgicaux in utero.

Early ultrasonographic antenatal diagnosis permits to perform intrauterine treatment to improve the prognosis of the fetus. These interventions are, however, invasive and associated with risks. In 2004, the results of the randomized trial comparing treatment options in the case of twin-to-twin transfusion syndrome were published. We summarize in this article the current knowledge on invasive fetal therapy.

Celiac disease, non-celiac gluten sensitivity and inflammatory bowel disease.

Celiac disease (CD) and inflammatory bowel disease (IBD), such as Crohn's disease (CrD) and ulcerative colitis (UC), are chronic inflammatory condition of the gastro-intestinal tract. The prevalence of IBD in celiac patients has been reported as 5-10 times higher than in the general population. The possibility of the presence of CD in IBD should be considered in IBD patients with long-term iron deficiency anemia (IDA) not responsive to iron supplementation. Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra intestinal symptoms due to the ingestion of gluten-containing food in subject without CD and/or wheat allergy. Patients with Crohn's disease and SR-NCGS were more significantly affected by joint pains compared to UC patients (50% versus 11.1%). In Crohn's patients, a higher percentage of fatigue (50% versus 38.9%) and headache (27.3% versus 22.2%) was evident. For the association between NCGS and IBD new studies are warranted and, at this moment, a gluten free diet (GFD) may be useful more in CrD than in UC.

TNFalpha processing enzyme inhibitors prevent aspirin-induced TNFalpha release and protect against gastric mucosal injury in rats.

BACKGROUND: Although previous studies indicate that prevention of tumour necrosis factor alpha (TNFalpha) release protects against NSAID-induced gastric mucosal injury, intracellular pathways by which aspirin causes TNFalpha release are unknown. TNFalpha is synthesized as a precursor which is proteolytically cleaved by a specific converting enzyme, TACE, to release the mature cytokine. TACE inhibitors prevent TNFalpha release and protect against TNFalpha-mediated disease. AIM: To investigate: (i) molecular events that regulate TNFalpha secretion in response to aspirin in vivo and in vitro; (ii) whether TNFalpha secretion inhibitors prevent aspirin-induced TNFalpha release and protect against gastric mucosal damage; and (iii) whether TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells. METHODS: In vitro studies were carried out on mouse macrophages and rat gastric mucosal cells. Gastric mucosal damage was induced in rats by oral administration of 300 mg/kg aspirin. TNFalpha cytotoxicity on gastric mucosal cells was examined by treating rats with lipopolysaccharide to release TNFalpha or by incubating dispersed gastric mucosal cells with increasing concentrations of TNFalpha. RESULTS: Aspirin increases intracellular calcium (Ca2+) levels and causes a time and concentration dependent increase in macrophage TNFalpha mRNA accumulation and cytokine release. Agents that cause Ca2+ mobilization with a receptor-independent mechanism, such as ionomycin and thapsigargin, stimulate TNFalpha release. Incubating the macrophages in a Ca2+ free medium inhibited TNFalpha secretion. Agents that prevent TNFalpha mRNA transcription, e.g. lisophylline, PGE2, interleukin-10 and 8-BrcAMP, or TACE inhibitors, e.g. EDTA, TAPI-2 and BB-3103, inhibit TNFalpha release and protect rats against gastric mucosal injury induced by oral administration of aspirin. TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells as demonstrated by the reduced viability observed in gastric mucosal cells prepared from rats treated with lipopolysaccharide, or directly incubated with increasing concentrations of TNFalpha. CONCLUSIONS: (i) Aspirin directly stimulates TNFalpha gene transcription; (ii) TACE inhibitors protect against aspirin-induced gastric mucosal injury; and (iii) TNFalpha exerts a direct cytotoxic effect on gastric epithelial cells.

Nitric oxide-releasing NSAIDs inhibit interleukin-1beta converting enzyme-like cysteine proteases and protect endothelial cells from apoptosis induced by TNFalpha.

BACKGROUND: Nitric oxide (NO)-releasing NSAIDs are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. Although it has been demonstrated that NO-NSAIDs spare gastric mucosal blood flow, molecular determinants involved in this effect are unknown. AIM: To investigate the effect of aspirin, naproxen and flurbiprofen, and their NO-derivatives, on gastric apoptosis and endothelial cell damage induced by tumour necrosis factor-alpha (TNFalpha). In other systems, TNFalpha-induced apoptosis is mediated by caspases, a growing family of cysteine proteases similar to the IL-1beta converting enzyme (ICE), and so we have investigated whether NO-NSAIDs modulate ICE-like endopeptidases. METHODS: Rats were treated orally with aspirin, naproxen and flurbiprofen, or their NO-releasing derivatives in equimolar doses, and were killed 3 h later to assess mucosal damage and caspase activity. Endothelial cells (HUVECs) were obtained from human umbilical cord by enzymatic digestion. Caspase 1 and 3 activities were measured by a fluorimetric assay using selective peptides as substrates and inhibitors. Apoptosis was quantified by ELISA specific for histone-associated DNA fragments and by the terminal transferase nick-end translation method (TUNEL). RESULTS: In vivo NSAID administration caused a time-dependent increase in gastric mucosal damage and caspase activity. NCX-4016, NO-naproxen and NO-flurbiprofen did not cause any mucosal damage and prevented cysteine protease activation. NSAIDs and NO-NSAIDs stimulated TNFalpha release. Exposure to TNFalpha resulted in a time- and concentration-dependent HUVEC apoptosis, an effect that was prevented by pretreating the cells with NCX-4016, NO-naproxen, NO-flurbiprofen, SNP or Z-VAD.FMK, a pan-caspase inhibitor. The activation of ICE-like cysteine proteases was required to mediate TNFalpha-induced apoptosis of HUVECs. Exogenous NO donors inhibited TNFalpha-induced cysteine protease activation. Inhibition of caspase activity was due to S-nitrosylation of ICE/CPP32-like proteases. NO-NSAIDs prevented IL-1beta release from endotoxin-stimulated macrophages. CONCLUSIONS: NO-releasing NSAIDs are a new class of non-peptide caspase inhibitors. Inhibition of ICE-like cysteine proteases prevents endothelial cell damage induced by pro-inflammatory agents and might contribute to the gastro-protective effects of NO-NSAIDs.

Nitric oxide-releasing NSAIDs: a review of their current status.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide owing to their anti-inflammatory, antipyretic and analgesic properties. However, their use is hampered by gastrointestinal (GI) toxicity, the most common drug-related serious adverse event in industrialised nations. Nitric oxide (NO)-releasing NSAIDs, a recently described class of drugs, are generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NO-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in animals, thus the abbreviation NO-NSAIDs used here refers to the latter group of NSAID derivatives. NO-NSAIDs retain the anti-inflammatory and antipyretic activity of original NSAIDs, although they exhibit markedly reduced gastrointestinal toxicity. NO-NSAIDs are nonselective cyclo-oxygenase (COX) inhibitors, and they also exert COX-independent activities that are NO-dependent. Indeed, NO-NSAIDs suppress production of the cytokines interleukin (IL)-1beta, IL-18 and interferon-gamma by causing the S-nitrosilation/inhibition of caspase-1. In acute and chronic animal models of inflammation, it has been demonstrated that NO-NSAIDs abrogated prostaglandin E2 as well as thromboxane B2 generation. In a murine model, NO-naproxen was approximately 10-fold more potent than naproxen in reducing animal writhing after intraperitoneal injection of acetic acid. Similar data have been obtained in chronic models of pain such as rat adjuvant arthritis. In vivo and in vitro studies suggest that NO-aspirin (acetylsalicylic acid) exerts more potent antithrombotic action than aspirin, probably by coupling the ability to inhibit COX-1 with the anti-adhesive effect of NO. Moreover, in a model of renal injury NO-flurbiprofen not only has been demonstrated to be devoid of nephrotoxicity but also to ameliorate renal function. Finally, in an animal model of chronic neurodegenerative disease, NO-flurbiprofen and NO-aspirin attenuated the brain inflammatory response. The GI toxicity of NO-flurbiprofen and NO-naproxen is currently being investigated in healthy individuals.

Cyclo-oxygenase isoenzymes. Structural basis for selective inhibition of cyclo-oxygenases by anti-inflammatory agents.

Cyclo-oxygenase (prostaglandin endoperoxide synthase) is the enzyme which metabolizes the conversion of arachidonic acid to prostaglandin. It exists in at least two isoforms: the constitutive (cyclo-oxygenase-1) and the inducible (cyclo-oxygenase-2) which is controlled by a number of factors, including cytokines and intracellular messengers. These enzymes are the therapeutic targets of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen. The cyclo-oxygenase active site is a long, hydrophobic, channel where the substrate arachidonic acid gains access to the active site. Cyclo-oxygenase-2 differs form cyclo-oxygenase-1 in certain key characteristics, particularly important is the valine/leucine substitution at position 523 that creates a defect in the inner shell of the cyclo-oxygenase-2 enzyme channel leaving a side pocket by which drugs selective for cyclo-oxygenase-2 gain access. Although cyclo-oxygenase-1 seems to be expressed in physiological conditions and cyclo-oxygenase-2 in inflammatory conditions, it is not yet possible to identify all their different roles. Cyclo-oxygenase-2 may be expressed constitutively, whereas the generation of prostaglandin by cyclo-oxygenase-2 may replace that by cyclo-oxygenase-1 in some situations (or vice-versa). Both cyclo-oxygenase isoenzymes contribute to mucosal defence and the inhibition of the two isoforms contributes to the pathogenesis of non-steroidal anti-inflammatory drug-induced gastric damage.

Nitric oxide and portal hypertension: a nitric oxide-releasing derivative of ursodeoxycholic acid that selectively releases nitric oxide in the liver.

Portal hypertension, a common consequence of chronic liver diseases, is directly responsible for most complications of cirrhosis. In liver microcirculation, nitric oxide is considered a major fine tuner of vascular tone by counterbalancing vasoconstrictors (sympathetic nervous activity, the renin-angiotensin system, and endothelin-1) in normal and cirrhotic livers. The deficiency of endothelial nitric oxide release is a key factor in the hemodynamic abnormalities associated with the dynamic component of portal hypertension. Conventional nitric oxide donors release nitric oxide into the blood stream, causing systemic hypotension and progression of vasodilatory syndrome in cirrhotic patients. NCX1000 is a nitric oxide-releasing derivative of ursodeoxycholic acid-derived compounds, being capable of selectively releasing nitric oxide into the liver circulation. Administration of NCX1000 to portal hypertensive rats decreases intrahepatic resistance providing a novel therapy for the treatment of portal hypertension.

Analgesia and cyclo-oxygenase inhibitors.

Non-steroidal anti-inflammatory drugs are among the most commonly used medications and they are a mainstay in the treatment of inflammatory diseases. Non-steroidal anti-inflammatory drugs are widely used to reduce pain associated with acute or chronic inflammation. Recently, a new class of inhibitors of the inducible enzyme cyclo-oxygenase-2 have become available. These inhibitors selectively target the inducible enzyme and have been shown to spare the gastrointestinal tract. While a role of cyclo-oxygenase-2 in the development of chronic inflammation has been well established, its role in pain perception is still unclear. Recent experimental data led to the hypothesis that cyclo-oxygenase-1 plays an important role in pain perception. This short review addresses some recent preclinical data as well as some clinical evidence showing that cyclo-oxygenase-1 is an important component of inflammatory pain.

Mechanism of non-steroidal anti-inflammatory drug-gastropathy.

Non-steroidal anti-inflammatory drugs are recognized to cause gastrointestinal damage impairing the defense ability of gastric mucosal barrier. A variety of mechanisms due to non-steroidal anti-inflammatory drugs direct irritant (topical) action and to their main pharmacological (systemic) effect, is involved in the pathogenesis of non-steroidal anti-inflammatory drugs induced gastropathy. The systemic activity comprises the inhibition of cyclo-oxygenase, but an increasing body of evidence suggests that cyclo-oxygenase-independent mechanisms are involved in the development of gastric injury. In line with this concept, neither cyclo-oxygenase-1 nor cyclo-oxygenase-2 deficient mice develop spontaneous gastrointestinal ulcers and pharmacological inhibition of cyclo-oxygenase-1 or cyclo-oxygenase-2 with selective inhibitors doesn't elicit gastrointestinal damage; suggesting that both isoforms of cyclo-oxygenase enzymes have to be inhibited to induce ulcers. Moreover non-steroidal anti-inflammatory drugs administration in rats, induces the systemic release of tumor necrosis factor-alpha and drives gastric epithelial cells to apoptosis activating the pro-apoptotic cascade of caspases. In response to non-steroidal anti-inflammatory drugs, neutrophils are recruited into the gastric microcirculation through a process that requires activation of adhesion molecules. Although there is virtually no information regarding the regulation of expression of gastric endothelial cell adhesion molecules in response to non steroidal anti-inflammatory drugs, the nuclear factor-kB may represent a potential modulator. Supporting this view, selective proteasome inhibitors inhibit nuclear translocation of nuclear factor-kB induced by tumor necrosis factor-alpha in human endothelial cells in vitro and reduce indomethacin-induced gastric mucosal injury in vivo.

Low-amplitude propagated contractile waves: a relevant propulsive mechanism of human colon.

BACKGROUND: Human colonic motility is still poorly understood, especially as far as concerns its propulsive function. Available data refer almost exclusively to the forceful propulsive activity, which is recognized as high-amplitude propagated contractions, the manometric equivalent of mass movements. By contrast, information on less vigorous propulsive contractions is still lacking. AIMS: To investigate the presence and behaviour of low-amplitude propagated contractile waves (less than 50 mmHg in amplitude) in the colon of healthy humans during a 24-hour study period. SUBJECTS AND METHODS: A series of 16 healthy volunteers of both sexes entered the study, and were investigated by a standard technique involving a colonoscopically-positioned manometric catheter. During the study, two standard 1,000 kcal mixed meal and a 450 kcal breakfast were served. The recordings were, therefore, scanned for the presence of low-amplitude propagated contractile waves (waves of less than 50 mmHg in amplitude, propagated over at least three consecutive recording ports), their daily distribution, and their relationship with physiological events. RESULTS: Low-amplitude propagated contractile waves were constantly present in all the tracings, with an average of about 61 events/subject/day and a mean amplitude of about 20 mmHg. More than 80% of these events appeared during the day, with a significant (p<0.05) increase after meals and after morning awakening. In 25% of subjects, these waves were accompanied by emission of flatus. CONCLUSIONS: In the human colon, low-amplitude propagated contractile waves are a constant physiological propulsive pattern, which is generally related to sleep-wake cycles and meal ingestion.