Standard of Care Versus Octreotide in Angiodysplasia-Related Bleeding (the OCEAN Study): A Multicenter Randomized Controlled Trial.

BACKGROUND & AIMS: Gastrointestinal angiodysplasias are vascular anomalies that may result in transfusion-dependent anemia despite endoscopic therapy. An individual patient data meta-analysis of cohort studies suggests that octreotide decreases rebleeding rates, but component studies possessed a high risk of bias. We investigated the efficacy of octreotide in reducing the transfusion requirements of patients with angiodysplasia-related anemia in a clinical trial setting. METHODS: The study was designed as a multicenter, open-label, randomized controlled trial. Patients with angiodysplasia bleeding were required to have had at least 4 red blood cell (RBC) units or parental iron infusions, or both, in the year preceding randomization. Patients were allocated (1:1) to 40-mg octreotide long-acting release intramuscular every 28 days or standard of care, including endoscopic therapy. The treatment duration was 1 year. The primary outcome was the mean difference in the number of transfusion units (RBC + parental iron) between the octreotide and standard of care groups. Patients who received at least 1 octreotide injection or followed standard of care for at least 1 month were included in the intention-to-treat analyses. Analyses of covariance were used to adjust for baseline transfusion requirements and incomplete follow-up. RESULTS: We enrolled 62 patients (mean age, 72 years; 32 men) from 17 Dutch hospitals in the octreotide (n = 31) and standard of care (n = 31) groups. Patients required a mean number of 20.3 (standard deviation, 15.6) transfusion units and 2.4 (standard deviation, 2.0) endoscopic procedures in the year before enrollment. The total number of transfusions was lower with octreotide (11.0; 95% confidence interval [CI], 5.5-16.5) compared with standard of care (21.2; 95% CI, 15.7-26.7). Octreotide reduced the mean number of transfusion units by 10.2 (95% CI, 2.4-18.1; P = .012). Octreotide reduced the annual volume of endoscopic procedures by 0.9 (95% CI, 0.3-1.5). CONCLUSIONS: Octreotide effectively reduces transfusion requirements and the need for endoscopic therapy in patients with angiodysplasia-related anemia. CLINICALTRIALS: gov, NCT02384122.

Predicting Mortality in COPD with Validated and Sensitive Biomarkers; Fibrinogen and Mid-Range-Proadrenomedullin (MR-proADM).

Although fibrinogen is a FDA qualified prognostic biomarker in COPD, it still lacks sufficient resolution to be clinically useful. Next to replication of findings in different cohorts also the combination with other validated biomarkers should be investigated. Therefore, the aim of this study was to confirm in a large well-defined population of COPD patients whether fibrinogen can predict mortality and whether a combination with the biomarker MR-proADM can increase prognostic accuracy. From the COMIC cohort study we included COPD patients with a blood sample obtained in stable state (n = 640) and/or at hospitalization for an acute exacerbation of COPD (n = 262). Risk of death during 3 years of follow up for the separate and combined biomarker models was analyzed with Cox regression. Furthermore, logistic regression models for death after one year were constructed. When both fibrinogen and MR-proADM were included in the survival model, a doubling in fibrinogen and MR-proADM levels gave a 2.2 (95% CI 1.3-3.7) and 2.1 (95% CI 1.5-3.0) fold increased risk of dying, respectively. The prediction model for death after 1 year improved significantly when MR-proADM was added to the model with fibrinogen (AUC increased from 0.78 to 0.83; p = 0.02). However, the combined model was not significantly more adequate than the model with solely MR-proADM (AUC 0.83 vs 0.82; p = 0.34). The study suggests that MR-proADM is more promising than fibrinogen in prediciting mortality. Adding fibrinogen to a model containing MR-proADM does not significantly increase the predictive capacity of the model.

Voluntary activation of ankle muscles is accompanied by subcortical facilitation of their antagonists.

Flexion and extension movements are organized reciprocally, so that extensor motoneurones in the spinal cord are inhibited when flexor muscles are active and vice versa. During and just prior to dorsiflexion of the ankle, soleus motoneurones are thus inhibited as evidenced by a depression of the soleus H-reflex. It is therefore surprising that soleus motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) have been found not to be reduced and even facilitated during a voluntary dorsiflexion. The objective of this study was to investigate if MEPs, evoked by TMS, show a similar facilitation prior to and at the onset of contraction of muscles that are antagonists to the muscle in which the MEP is evoked and if so, examine the origin of such a facilitatory motor programme. Eleven seated subjects reacted to an auditory cue by contracting either the tibialis anterior (TA) or soleus muscle of the left ankle. TMS was applied to the hotspot of TA and soleus muscles on separate days. Stimuli were delivered prior to and at the beginning of contraction. Soleus MEPs were significantly facilitated when TMS was applied 50 ms prior to onset of plantar flexion. Surprisingly, soleus MEPs were also facilitated (although to a lesser extent) at a similar time in relation to the onset of dorsiflexion. TA MEPs were facilitated 50 ms prior to onset of dorsiflexion and neither depressed nor facilitated prior to plantar flexion. No difference was found between the facilitation of the soleus MEP and motor evoked responses to cervicomedullary stimulation prior to dorsiflexion, suggesting that the increased soleus MEPs were not caused by changes at a cortical level. This was confirmed by the observation that short-latency facilitation of the soleus H-reflex by subthreshold TMS was increased prior to plantar flexion, but not prior to dorsiflexion. These findings suggest that voluntary contraction at the ankle is accompanied by preceding facilitation of antagonists by a subcortical motor programme. This may help to ensure that the direction of movement may be changed quickly and efficiently during functional motor tasks.

Contribution of afferent feedback and descending drive to human hopping.

During hopping an early burst can be observed in the EMG from the soleus muscle starting about 45 ms after touch-down. It may be speculated that this early EMG burst is a stretch reflex response superimposed on activity from a supra-spinal origin. We hypothesised that if a stretch reflex indeed contributes to the early EMG burst, then advancing or delaying the touch-down without the subject's knowledge should similarly advance or delay the burst. This was indeed the case when touch-down was advanced or delayed by shifting the height of a programmable platform up or down between two hops and this resulted in a correspondent shift of the early EMG burst. Our second hypothesis was that the motor cortex contributes to the first EMG burst during hopping. If so, inhibition of the motor cortex would reduce the magnitude of the burst. By applying a low-intensity magnetic stimulus it was possible to inhibit the motor cortex and this resulted in a suppression of the early EMG burst. These results suggest that sensory feedback and descending drive from the motor cortex are integrated to drive the motor neuron pool during the early EMG burst in hopping. Thus, simple reflexes work in concert with higher order structures to produce this repetitive movement.

Short-term pressure induced suppression of the short-latency response: a new methodology for investigating stretch reflexes.

During experiments involving ischemic nerve block, we noticed that the short-latency response (SLR) of evoked stretches in m. soleus decreased immediately following inflation of a pneumatic cuff surrounding the lower leg. The present study aimed to investigate this short-term effect of pressure application in more detail. Fifty-eight healthy subjects were divided into seven protocols. Unilateral stretches were applied to the calf muscles to elicit a SLR, and bilateral stretches to evoke a subsequent medium-latency response (MLR). Furthermore, H-reflexes and sensory nerve action potentials (SNAPs) were recorded. Additionally, stretches were applied with different velocities and amplitudes. Finally, the SLR was investigated during hopping and in two protocols that modified the ability of the muscle-tendon complex distal to the cuff to stretch. All measurements were performed with deflated and inflated cuff. Results of the protocols were as follows: 1) inflation of the cuff reduced the SLR but not the MLR; 2) the H-reflex, the M-wave, and, 3) SNAPs of n. tibialis remained unchanged with deflated and inflated cuff; 4) the SLR was dependent on the stretch velocity with deflated and also inflated cuff; 5 and 6) the reduction of the SLR by the cuff was dependent on the elastic properties of the muscle-tendon complex distal to the cuff; and 7) the cuff reduced the SLR during hopping. The present results suggest that the cuff did not affect the reflex arc per se. It is proposed that inflation restricted stretch of the muscles underlying the cuff so that most of the length change occurred in the muscle-tendon complex distal to the cuff. As a consequence, the muscle spindles lying within the muscle may be less excited, resulting in a reduced SLR. Due to its applicability in functional tasks, the introduced method can be a useful tool to study afferent feedback in motor control.

Tibialis anterior stretch reflex in early stance is suppressed by repetitive transcranial magnetic stimulation.

A rapid plantar flexion perturbation in the early stance phase of walking elicits a large stretch reflex in tibialis anterior (TA). In this study we use repetitive transcranial magnetic stimulation (rTMS) to test if this response is mediated through a transcortical pathway. TA stretch reflexes were elicited in the early stance phase of the step cycle during treadmill walking. Twenty minutes of 1 Hz rTMS at 115% resting motor threshold (MT(r)) significantly decreased (P < 0.05) the magnitude of the later component of the reflex at a latency of approximately 100 ms up to 25 min after the rTMS. Control experiments in which stretch reflexes were elicited during sitting showed no effect on the spinally mediated short and medium latency stretch reflexes (SLR and MLR) while the long latency stretch reflex (LLR) and the motor-evoked potential (MEP) showed a significant decrease 10 min after 115% MT(r) rTMS. This study demonstrates that 1 Hz rTMS applied to the leg area of the motor cortex can suppress the long latency TA stretch reflex during sitting and in the stance phase of walking. These results are in line with the hypothesis that the later component of the TA stretch reflex in the stance phase of walking is mediated by a transcortical pathway. An alternative explanation for the observed results is that the reflex is mediated by subcortical structures that are affected by the rTMS. This study also shows that rTMS may be used to study the neural control of walking.