Chronic constipation diagnosis and treatment evaluation: The "CHRO.CO.DI.T.E." study

Background: According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy. Methods: During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded. Results: Eight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC. Conclusions: Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the "first line" diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a "second line" approach. Diagnostic tests and prescribed therapies increased by increasing CC severity

Astrocytes and Microglia-Mediated Immune Response in Maladaptive Plasticity is Differently Modulated by NGF in the Ventral Horn of the Spinal Cord Following Peripheral Nerve Injury

Reactive astrocytes and activated microglia are the key players in several pathophysiologic modifications of the central nervous system. We used the spared nerve injury (SNI) of the sciatic nerve to induce glial maladaptive response in the ventral horn of lumbar spinal cord and examine its role in the remodeling of the tripartite synapse plasticity. Imaging the ventral horn revealed that SNI was associated with both an early microglial and astrocytic activation, assessed, respectively, by analysis of Iba1 and GFAP expression. Microglia, in particular, localized peculiarly surrounding the motor neurons somata. Perineuronal astrocytes, which play a key role in maintaining the homeostasis of neuronal circuitry, underwent a substantial phenotypic change following peripheral axotomy, producing reactive gliosis. The gliosis was associated with the reduction of glial aminoacid transporters (GLT1 and GlyT1) and increase of neuronal glutamate transporter EAAC1. Although the expression of GABAergic neuronal marker GAD65/67 showed no change, glutamate increase, as demonstrated by HPLC analysis, shifted the excitatory/inhibitory balance as showed by the net increase of the glutamate/GABA ratio. Moreover, endogenous NGF levels were altered in SNI animals and not restored by the intrathecal NGF administration. This treatment reverted phenotypic changes associated with reactive astrocytosis, but failed to modify microglia activation. These findings on one hand confirm the correlation between gliopathy and maladaptive plasticity of the spinal synaptic circuitry, on the other hand add new data concerning the complex peculiar behavior of different glial cells in neuronal degenerative processes, defining a special role of microglia in sustaining the inflammatory response

Modulation of Matrix Metalloproteinases Activity in the Ventral Horn of the Spinal Cord Re-stores Neuroglial Synaptic Homeostasis and Neurotrophic Support following Peripheral Nerve Injury - Fig 1

<p>Low (A) and high (B-C) magnification of spinal cord sections stained for glial markers. A) Low magnification (5x) sections show the entire spinal cord in SHAM and SNI rats treated with ACSF. Note, in SNI-ACSF sections, the significant asymmetry of the glial markers expression (indicative of the injured side) and the selective reaction in the dorsal and ventral horn. Scale bar: 200 μm. B) Magnifications (20x) of the ventral horn showing reactive gliosis. Scale bar: 50 μm. C) High magnification (40x) morphological details of reactive microglia and astrocytes. Scale bar: 50 μm.</p

Endogenous NGF expression in the ventral horn.

<p>(A) Sections of lumbar spinal cord prepared from SHAM and SNI rats treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained with NGF antibody. Scale bar: 50 μm. (B) Densitometric quantitation of NGF levels. Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.</p

Expression of spinal glial and neuronal aminoacid transporters.

<p>Sections of ventral horn of lumbar spinal cord from SHAM and SNI animals treated for 7 days with ACSF (vehicle), BB14 (0.9 mg/kg b.w.), or GM6001 (100 mg/kg. b.w.) and immunostained for glial glutamate (A–B) or glycine (C–D) transporters, or the neuronal glutamate transporter EAAC1 (E–F). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.</p

Evaluation of glial markers in the ventral horn of spinal cord.

<p>Sections (A and C) and densitometric quantitation (B and D) of ventral horn of lumbar spinal cords from SHAM and SNI-operated animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle) and immunostained for GFAP (A–B) or Iba1 (C–D). Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test). Scale bar: 50 μm.</p

HPLC analysis of Glutamate/GABA ratio.

<p>Amino acid levels were measured by HPLC in the ventral horn of lumbar spinal cord dissected from SHAM and SNI animals treated for 7 days with BB14 (0.9 mg/kg b.w.), GM6001 (100 mg/kg. b.w.) or ACSF (vehicle). The Glutamate/GABA ratio was calculated as described in M&M. Data are the mean±SEM (**p≤0.001, ACSF vs. SHAM/BB14/GM6001; ANOVA and Holm–Sidak test).</p