Sjögren syndrome successfully treated with oxygen-ozone auto-hemotherapy (O2-O3-AHT). a case report.

OBJECTIVE: Sjögren syndrome (SS) is an autoimmune disorder, affecting about 16,000 individuals in Italy, yet lacking a standardized therapy protocol and a plain inclusion in the reimbursed healthcare services. This raises many controversial issues about how managing the SS patient, to relief pain and discomfort and improve patients' health and social life. The ozone therapy resulted successful in previous reports, and therefore, it was used in this case report. CASE PRESENTATION: A 69-years old female outpatient, showing positivity to Schirmer's test, was previously diagnosed as a primary Sjögren syndrome, who later developed an autoimmune thyroiditis and showed the presence of rheumatoid factors. The patient suffered from a marked ocular dryness, subsequently to a purported endothelitis, alongside with fatigue and pain. Laboratory tests showed a positive ANA 1:320 in a speckled pattern with negative anti-SSA and anti-SSB tests. From December 2020 to January 2021 she underwent 2 routes of three sessions of oxygen-ozone autohemotherapy (O2-O3 AHT), as described below and improved, with only 2 sessions, her symptomatology and clinical outcome, as ocular dryness, fatigue and pain, rapidly disappeared. CONCLUSIONS: The use of ozone in the therapy of SS is a straightforward, affordable and feasible approach to treat primary Sjögren syndrome without significant side effects.

Prevalence and impact of self-reported irritable bowel symptoms in the general population.

Background and aims: The symptom-based diagnostic criteria for irritable bowel syndrome (IBS) have recently been revised in the Rome IV consensus. On the other hand, with rising public awareness of IBS, self-diagnosis and self-management is also increasing. We compared the prevalence and impact of Rome IV-based IBS vs self-diagnosed IBS in the general population. Methods: An internet panel filled out an online survey on bowel symptoms and their impact on health care utilization and daily activities. Results: A representative internet panel of 1012 individuals completed the online survey. Bowel symptoms were present in 68.6% of the population. Of these, 21% consulted a physician for these symptoms in the last year and 42% earlier. Rome IV IBS criteria were fulfilled by 5.5%, and these were younger and more likely to be female. In this subset, 37% had consulted a physician for IBS symptoms in the preceding year and 29% had done so earlier. A colonoscopy had been performed in 22%. Based on a brief description, 17.6% of the population self-identified as suffering from IBS (p < 0.001 compared to Rome IV IBS prevalence), and these were more likely to be female. Concordance with the Rome IV criteria was only 25%, but except for a lower reporting of pain, the symptom pattern, severity, impact on daily life, inability to work and health care utilization were similar to the Rome IV group. A total of 134 days of absence from work were attributed to bowel symptoms in those self-reporting with IBS. Conclusion: In the general population, bowel symptoms are highly prevalent, and the self-reported "IBS" is three times more prevalent than according to Rome IV criteria. Self-reported IBS is associated with a similar impact on health care utilization and quality of life but a higher impact on absence from work.

An atypical occurrence of Aspergillosis in leukemic patient: Brief description of a clinical case.

Herein we describe a 43 year-old Caucasian female patient with acute myeloid leukemia that developed an unconventional form of invasive Aspergillosis. For therapeutic reasons, a Groshong-type central venous catheter was positioned. Monitoring the patient's clinical conditions, positive values for C-reactive protein and galactomannan were correlated with a probably Aspergillosis. Surprisingly no pulmonary evidences were observed. Due to worsening conditions, she was re-hospitalized and a blood culture was performed, whom positivity resulted as the first clinical evidence of Aspergillus fumigatus. Further evidence about species identification was obtained by sequencing the fungal ITS region. We support the clinical value of blood culture as a decisive factor to improve the diagnosis of catheter-related Aspergillosis.

Opioid receptors in the GI tract: targets for treatment of both diarrhea and constipation in functional bowel disorders?

Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation.

When all seems lost: management of refractory constipation-Surgery, rectal irrigation, percutaneous endoscopic colostomy, and more.

While the pharmacological armamentarium for chronic constipation has expanded over the past few years, a substantial proportion of constipated patients do not respond to these medications. This review summarizes the pharmacological and behavioral options for managing constipation and details the management of refractory constipation. Refractory constipation is defined as an inadequate improvement in constipation symptoms evaluated with an objective scale despite adequate therapy (ie, pharmacological and/or behavioral) that is based on the underlying pathophysiology of constipation. Minimally invasive (ie, rectal irrigation and percutaneous endoscopic colostomy) and surgical therapies are used to manage refractory constipation. This review appraises these options, and in particular, percutaneous endoscopic colostomy, which as detailed by an article in this issue, is a less invasive option for managing refractory constipation than surgery. While these options benefit some patients, the evidence of the risk: benefit profile for these therapies is limited.

Intragastric infusion of the bitter tastant quinine suppresses hormone release and antral motility during the fasting state in healthy female volunteers.

BACKGROUND: Intragastric administration of the bitter tastant denatonium benzoate inhibits the increase of motilin plasma levels and antral contractility. While these findings suggest that gastrointestinal bitter taste receptors could be new targets to modulate gastrointestinal motility and hormone release, they need confirmation with other bitter receptor agonists. The primary aim was to evaluate the effect of intragastric administration of the bitter tastant quinine-hydrochloride (QHCl) on motilin and ghrelin plasma levels. Secondly, we studied the effect on interdigestive motility. METHODS: Ten healthy female volunteers were recruited (33±4 y; 22±0.5 kg/m²). Placebo or QHCl (10 µmol/kg) was administered intragastrically through a nasogastric feeding tube after an overnight fast in a single-blind randomized fashion. Administration started 20 min after the first phase III of the migrating motor complex. The measurement continued for another 2 h after the administration. Blood samples were collected every 10 min with the baseline sample taken 10 min prior to administration. KEY RESULTS: The increase in plasma levels of motilin (administration; P=.04) and total ghrelin (administration; P=.02) was significantly lower after QHCl. The fluctuation of octanoylated ghrelin was reduced after QHCl (time by administration; P=.03). Duodenal motility did not differ. The fluctuation of antral activity differed over time between placebo and QHCl (time by administration; P=.03). CONCLUSIONS AND INFERENCES: QHCl suppresses the increase of both motilin and ghrelin plasma levels. Moreover, QHCl reduced the fluctuation of antral motility. These findings confirm the potential of bitter taste receptors as targets for modifying interdigestive motility in man.

Development, content validity, and cross-cultural adaptation of a patient-reported outcome measure for real-time symptom assessment in irritable bowel syndrome.

BACKGROUND: End-of-day questionnaires, which are considered the gold standard for assessing abdominal pain and other gastrointestinal (GI) symptoms in irritable bowel syndrome (IBS), are influenced by recall and ecological bias. The experience sampling method (ESM) is characterized by random and repeated assessments in the natural state and environment of a subject, and herewith overcomes these limitations. This report describes the development of a patient-reported outcome measure (PROM) based on the ESM principle, taking into account content validity and cross-cultural adaptation. METHODS: Focus group interviews with IBS patients and expert meetings with international experts in the fields of neurogastroenterology & motility and pain were performed in order to select the items for the PROM. Forward-and-back translation and cognitive interviews were performed to adapt the instrument for the use in different countries and to assure on patients' understanding with the final items. KEY RESULTS: Focus group interviews revealed 42 items, categorized into five domains: physical status, defecation, mood and psychological factors, context and environment, and nutrition and drug use. Experts reduced the number of items to 32 and cognitive interviewing after translation resulted in a few slight adjustments regarding linguistic issues, but not regarding content of the items. CONCLUSIONS AND INFERENCES: An ESM-based PROM, suitable for momentary assessment of IBS symptom patterns was developed, taking into account content validity and cross-cultural adaptation. This PROM will be implemented in a specifically designed smartphone application and further validation in a multicenter setting will follow.

Naloxegol: the first orally administered, peripherally acting, mu opioid receptor antagonist, approved for the treatment of opioid-induced constipation.

Treatment of opioid-induced constipation (OIC) is becoming a relevant clinical challenge as most of the treatments demonstrated to be more effective than placebo in treating OIC have safety issues limiting a broad clinical application. Naloxegol is the first orally administered, peripherally acting, µ opioid receptor antagonist approved by the FDA and EMA specifically for the treatment of noncancer patients with OIC. This review summarizes the results of the studies regarding the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions. Phase II and phase III studies in patients with noncancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25-mg dose once daily. Side effects were mainly gastrointestinal in origin (and usually transient and mild) and there were no signs of opioid withdrawal in the studies. Safety and tolerability were shown in a long-term safety study. Considering its efficacy, safety, route of administration and the limitations of most of the other available treatments, naloxegol has the potential to become the first-line treatment for noncancer patients with OIC.

Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome.

BACKGROUND: Tachykinins (TKs) are a family of endogenous peptides widely expressed in the central and in the peripheral nervous systems as well as in the gastrointestinal (GI) tract. They act as full agonists at three different membrane receptors neurokinin (NK) 1, NK2, and NK3, which are G protein-coupled receptors and in the GI tract are expressed both on neurons and effector cells. PURPOSE: This article reviews the literature concerning the role of TKs in the GI tract function in physiological and pathological conditions and their potential relevance in the treatment of functional GI disorders with particular reference to irritable bowel syndrome (IBS). The efficacy of NK1 antagonists in chemotherapy-induced and postoperative nausea and vomiting is well established. While pharmacodynamic studies have reported conflicting and negative results concerning the effects of NK1 and of NK3 antagonists, respectively, on the GI tract function in humans, clinical studies applying the NK3 antagonist talnetant in IBS-D were negative. Pharmacodynamic studies applying NK2 antagonists have suggested a role for antagonism of NK2 receptors in modulation of GI chemical-induced altered motility and of stress-induced altered bowel habits. Clinical studies and in particular a recently completed Phase 2 study have reported that the NK2 antagonist ibodutant is effective and safe in treating symptoms of D-IBS, especially in females.

Endogenous motilin, but not ghrelin plasma levels fluctuate in accordance with gastric phase III activity of the migrating motor complex in man.

BACKGROUND: Fluctuations in motilin plasma levels have been implicated in the control of the migrating motor complex (MMC). A plasma peak of motilin is present before a gastric phase III. Furthermore, not only exogenous administration of motilin but also ghrelin induces a gastric phase III in man. Aim of this study was to investigate the role of endogenous ghrelin in the regulation of the MMC. METHODS: Plasma samples for motilin and ghrelin were taken in between two consecutive phases III of either origin measured using high-resolution manometry. KEY RESULTS: The duration of 1 complete MMC cycle was on average 95 ± 12 min. Sixty percent of the first phases III and 40% of the second phases III had a gastric origin (p = 0.0574). Motilin (p < 0.05) plasma levels differed significantly between the phases of the MMC but total and octanoylated ghrelin did not. The percentage change in motilin during the MMC was dependent on the origin of phase III (p < 0.05). Motilin levels increased on average with 35 ± 10% right before a gastric phase III and with 3 ± 4% before a duodenal phase III (p < 0.05). The percentage change in total and octanoylated ghrelin plasma levels was not affected by the origin of phase III. CONCLUSIONS & INFERENCES: These results confirm the role of motilin but not of ghrelin as an endogenous physiological regulator of the MMC with a gastric phase III.

The quest for biomarkers in IBS-where should it lead us?

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder which represents a major cost to health-care services. The diagnosis of IBS is currently performed by means of symptom-based diagnostic criteria, but there has been an ongoing interest in developing biomarkers which could simplify the diagnosis and/or evaluating the effect of treatments. This article reviews the current literature concerning the proposed biomarkers including those of altered gut motility, of visceral hypersensitivity, of abnormal brain mechanisms, of serum, fecal and mucosal inflammation and of increased intestinal permeability.

FDA and EMA end points: which outcome end points should we use in clinical trials in patients with irritable bowel syndrome?

Trial design and endpoints for the evaluation of drug efficacy in irritable bowel syndrome (IBS) underwent major changes over the last two decades. A systematic review in the early 1990s concluded that there were few well-designed and well-executed treatment trials in IBS. Over the next decade, the so-called binary endpoints were used in several clinical trials in IBS in the US, Europe and other parts of the world. In 2006, the Food and Drug Administration (FDA) published a general guidance for the evaluation of symptom benefit in clinical trials based on patient-reported outcome (PRO) measures, which had a major impact on trial design in IBS. In May 2012, the FDA recommended to use as provisional endpoint the quantification of two major IBS aspects, abdominal pain and disordered defecation, to assess the efficacy of pharmacological treatments in IBS. In the present issue of Neurogastroenterology & Motility, the performance of the FDA Responder Endpoint for clinical trials in irritable bowel syndrome with constipation was evaluated using data from two large Phase III clinical trials of linaclotide. The FDA interim endpoints are clinically relevant as they are also able to capture the smallest patient-reported difference in the domain of Abdominal Pain intensity and Abnormal Defecation with good diagnostic accuracy. The FDA responder definition and the European Medicines Agency responder definitions generate similar response rates, while binary endpoints generate higher responder rates. The implications for optimalization and harmonisation are discussed.

Influence of nitric oxide synthase inhibition on the motility and sensitivity of distal colon in man.

BACKGROUND: Alterations of nitrergic innervation have been implicated in the pathophysiology of motor-sensory abnormalities of post infectious functional dyspepsia and could be involved in the pathophysiology of post infectious irritable bowel syndrome. The role of nitrergic neurons in the control of distal colonic sensorimotor function in man is not known. The aim of this study is to evaluate the motility and sensitivity of distal colon in healthy subjects before and after a nitric oxide synthase inhibitor (L-NMMA). METHODS: A 700-mL balloon connected with a barostat-manometry assembly was placed in the descending colon of 10 healthy subjects and distension (4 mmHg/2 min) was performed. Intra-balloon pressure was then set at minimal distending pressure + 2 mmHg for 30 min, placebo or L-NMMA (8 mg kg(-1) h(-1)) was administered i.v. in double-blind, randomized, cross-over design and distensions were repeated. KEY RESULTS: Placebo and L-NMMA did not influence colonic compliance, motility index, and tone. Placebo did not affect thresholds for first perception and discomfort and the areas under the pressure-perception curve. L-NMMA did not alter thresholds for first perception, but significantly decreased the pressure thresholds for discomfort (P = 0.008) and increased the areas under the pressure-perception score (P = 0.01). CONCLUSIONS & INFERENCES: In man, inhibition of nitric oxide synthase sensitizes the distal colon to distension. Impaired nitrergic innervation is a mechanism that may be involved in the pathogenesis of hypersensitivity to colonic distension.

Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C.

The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has been shown to be active on acute myeloid leukemia (AML) and refractory anemia with excess of blasts (RAEB). Thirty-one elderly AML/RAEB patients (AML n=25; RAEB n=6) with a high rate of comorbidity were entered in a phase II study with low-dose cytarabine (Ara-C) and VPA. Fitness was evaluated by means of the Comprehensive Geriatric Assessment (CGA), including the Cumulative Illness Rating Scale (CIRS) score, the self-sufficiency scores of Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL). Eight patients obtained a lasting complete remission and 3 other patients obtained hematologic improvement for a total response rate of 35%. Five of 11 responding patients were relapsed or resistant after a previous treatment with Ara-C. Seven of 11 responding patients were assessed as frail at enrollment and/or had IADL impairment. Grades 3 and 4 toxicities were mainly hematological. Low-dose Ara-C and VPA is a relatively non-toxic combination with good therapeutic activity in elderly patients with AML/RAEB. This therapeutic approach represents an alternative treatment for patients who cannot undergo standard induction therapy.

Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man.

BACKGROUND: It is unclear whether decreased serotonin transporter function contributes to sensorimotor abnormalities in irritable bowel syndrome. AIM: To study the influence of acute serotonin transporter inhibition on colonic sensorimotor function in man. METHODS: Ten healthy subjects (five men, aged 20-29 years) underwent a combined manometry/barostat study of the descending colon on two occasions. Stepwise distentions by 2 mmHg increments were performed until discomfort. Subsequently, placebo or citalopram 20 mg were administered i.v. over 20 min and distentions were repeated. Afterwards, isobaric tone measurements were performed 30 min before and 90 min after ingestion of a meal. High-amplitude propagated contractions, colonic motility index, colonic compliance, sensitivity and colonic response to a meal after placebo or citalopram were compared by t-test and two-way ANOVA. RESULTS: Citalopram induced a significant increase in colonic motility index (5.6 +/- 0.9 to 0.8 +/- 1.9 mL*min, P < 0.005) and high-amplitude propagated contractions (32 after citalopram vs. 2 after placebo, P < 0.05), which were associated with abdominal cramping. Administration of citalopram increased colonic compliance (10.3 +/- 1.5 vs. 14.5 +/- 2.2 mL/mmHg, P < 0.01) and inhibited colonic response to a meal (volume decrease 48 +/- 12 vs. 16 +/- 12 mL, P < 0.01). CONCLUSIONS: Acute serotonin transporter inhibition in man increases colonic phasic contractility and the occurrence of high-amplitude propagated contractions, increases colonic compliance and suppresses the colonic tonic response to a meal. These data suggest that both release and elimination of 5-hydroxytryptamine by serotonin transporter are involved in the control of colonic motility in man.

Perceptual sensitivity and response bias during rectal distension in patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) report an increased frequency of sensations during rectal distension in comparison with healthy subjects. This alteration might be due to a psychological response bias leading patients to over report their sensations. The aim of this study was to measure perceptual sensitivity and response bias during rectal distension in healthy subjects and IBS patients using the sensory decision theory (SDT). Thirteen healthy subjects and 22 IBS patients underwent five rectal distensions up to 100 mL, five up to 200 mL and five sham distensions. They were asked to identify the distension by means of an electronic marker. Perceptual sensitivity and response bias were calculated according to the SDT. The patients identified a more 100 mL distensions than the healthy subjects (P = 0.02), whereas there was no difference in the number of identified 200 mL and sham distensions between the two groups. The perceptual sensitivity of IBS patients was significantly greater during 100 mL (P = 0.01), but not during 200 mL distensions. The response bias was not significantly different between the two groups. These data suggest that the increased frequency of sensations reported by IBS patients is not due to a psychological response bias.

The role of tension receptors in colonic mechanosensitivity in humans.

BACKGROUND: Perception of colonic distension, which is enhanced in a subset of patients with irritable bowel syndrome, requires activation of mechanoreceptors. In animal studies, distension activates both in series ("tension") and in parallel ("elongation") mechanoreceptors. During active contractions against a fixed volume balloon, tension receptors are activated without elongation of receptor activation. AIM: To evaluate the role of tension receptors in the perception of mechanical stimuli from the colon in healthy subjects. METHODS: A 700 ml balloon connected to a barostat-manometer assembly was placed in the descending colon of 10 healthy subjects. After volume controlled distension (50 ml/2 minutes) to assess the first perception threshold, fixed volume subthreshold distension (122 (16) ml) was maintained for a 30 minute period before and after administration of neostigmine 0.5 mg intravenously. Mean intraballoon pressure, number, amplitude, and duration of contractions, and frequency of sensations were analysed. The period after neostigmine was divided into 10 second intervals and evaluated for the occurrence of contractions and onset of sensations. Fisher's exact test was applied to calculate the sensation-contraction association probability (SAP) as (1.0-p)x100%. RESULTS: Neostigmine increased intraballoon pressure (p<0.01), number of contractions (p<0.01), and number of sensations (p<0.01) per minute in all subjects. In seven of 10 subjects a significant association (SAP >95%) was found between sensations and contractions. In the remaining subjects, contractions were not associated with sensations and had lower amplitude (p<0.05) and duration (p<0.01) compared with contractions in the other seven subjects. CONCLUSION: In humans, tension receptors are involved in mediating colonic mechanosensitivity.