Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study

Objective  This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients.
Methods  Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled.
Results  Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant ( P =  0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71% vs. 27%), hepatobiliary (41% vs. 8%) and respiratory (5% vs. 28%).
Conclusion  This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.     

Italian Guidelines for the Diagnosis and Infectious Disease Management of Osteomyelitis and Prosthetic Joint Infections in Adults

Bone and joint infections are recognized as difficult-to-treat infections that result in significant morbidity and mortality among patients and increased healthcare costs. This article presents the recommendations for the diagnosis and management of osteomyelitis and prosthetic joint infections in adults developed by Bone and Joint Infections Committee for the Italian Society of Infectious and Tropical Diseases. It contains data published through to November 2007. An evidence-based scoring system that is used by the Infectious Diseases Society of America was applied to treatment recommendations.     

Clinical Operational Tolerance After Solid Organ Transplantation

Clinical operational tolerance (COT) is a clinical condition obtainable with difficulty after solid organ transplantation (SOT). It is characterized by perfectly normal graft function in the total absence of maintenance immunosuppression. Major benefits deriving from the onset of COT are the reduction of risk for immunosuppression-related side effects and the improved quality of life. Currently, COT can be safely achieved in stable liver transplant recipients; it remains a challenge after renal transplantation. Only 1 case of COT has been reported after lung transplantation; no cases have been described after other types of SOT. Overall, mechanisms of COT are unclear and strategies to induce COT cannot be applied on a regular base to a large cohort of SOT recipients. Due to the failure of molecularly based tolerogenic protocols, great hope relies in the adoption of cell-based strategies.     

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.     

Constitutive activation of MAPK cascade in acute quadriplegic myopathy

Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.     

Balance exercise in patients with chronic sensory ataxic neuropathy: a pilot study

Although exercise therapy is considered part of the treatment of neuropathic patients, and somatosensory input is essential for motor learning, performance and neural plasticity, rehabilitation of patients with sensory ataxia has received little attention so far. The aim of this prospective pilot study was to explore the short‐ and medium‐term efficacy of a 3‐week intensive balance and treadmill exercise program in chronic ataxic neuropathy patients; 20 consecutive patients with leg overall disability sum score (ODSS‐leg) ≥2, absent/mild motor signs, clinical and therapeutic stability ≥4 months were enrolled. Evaluations were done at baseline, at the end of treatment and at 3‐ and 6‐month follow‐up. Outcome measurements included: ODSS‐leg, Berg balance scale, 6‐min walk distance, and the functional independence measure (FIM) scale. The short‐form‐36 health status scale (SF‐36) was used to measure health‐related quality of life (HRQoL). ODSS‐leg improved significantly compared with baseline, 3 weeks, 3 months (primary outcome), and 6 months follow‐up. A significant improvement in all functional secondary outcome measurements and in some SF‐36 subscales was also observed. This pilot study suggests that balance exercise is safe and well tolerated and might be effective in ameliorating disability and HRQoL in patients with chronic peripheral sensory ataxia.     

Difference in safety and humoral response to mRNA SARS-CoV-2 vaccines in patients with autoimmune neurological disorders: the ANCOVAX study

Journal of Neurology - Assessing the safety of SARS-CoV-2 mRNA vaccines and the effect of immunotherapies on the seroconversion rate in patients with autoimmune neurological conditions (ANC) is...     

IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence

Interleukin (IL)-1β plays a crucial role in the mechanisms of limbic seizures in rodent models of temporal lobe epilepsy. We addressed whether activation of the IL-1β signaling occurs in rats with genetic absence epilepsy (GAERS) during the development of spike-and-wave discharges (SWDs). Moreover, we studied whether inhibition of IL-1β biosynthesis in GAERS could affect SWD activity.IL-1β expression and glia activation were studied by immunocytochemistry in the forebrain of GAERS at postnatal days (PN)14, PN20, and PN90 and in age-matched non-epileptic control Wistar rats. In PN14 GAERS, when no SWDs have developed yet, IL-1β immunostaining was undetectable, and astrocytes and microglia showed a resting phenotype similar to control Wistar rats. In 3 out of 9 PN20 GAERS, IL-1β was observed in activated astrocytes of the somatosensory cortex; the cytokine expression was associated with the occurrence of immature-type of SWDs. In all adult PN90 GAERS, when mature SWDs are established, IL-1β was observed in reactive astrocytes of the somatosensory cortex but not in adjacent cortical areas or in extra-cortical regions.An age-dependent c-fos activation was found in the somatosensory cortex of GAERS with maximal levels reached in PN90 rats; c-fos was also induced in some thalamic nuclei in PN20 and PN90 GAERS.Inhibition of IL-1β biosynthesis in PN90 GAERS by 4-day systemic administration of a specific ICE/Caspase-1 blocker, significantly reduced both SWD number and duration.These results show that IL-1β is induced in reactive astrocytes of the somatosensory cortex of GAERS at the onset of SWDs. IL-1β has pro-ictogenic properties in this model, and thus it may play a contributing role in the mechanisms underlying the occurrence of absence seizures.