An online intervention for carers to manage behavioral symptoms in motor neuron disease (MiNDToolkit): a randomized parallel multi-center feasibility trial.

BACKGROUND: Evidence on management of behavioral symptoms in motor neuron disease (MND) is lacking. The MiNDToolkit, an online psychoeducational platform, supports carers dealing with behavioral symptoms (BehSymp). The study objectives were to ascertain recruitment and retention rates, carer and healthcare professional (HCP) use of the platform, and completion of online assessments, to inform a full-scale trial. Design: Randomized, parallel, multi-center, feasibility trial. SETTING: England and Wales, across diverse MND services; recruitment from July/21 to November/22; last participant follow-up in March/23. PARTICIPANTS: Carers of people with motor neuron disease (PwMND) with BehSymp, recruited through MND services. After confirming eligibility, participants completed screening and baseline assessments online via the MiNDToolkit platform and were randomized centrally in a 1:1 ratio to MiNDToolkit or control. INTERVENTION: MiNDToolkit offered tailored modules to carers for the 3-month study period. Carers in the intervention group could receive additional support from MiNDToolkit trained HCPs. The control group was offered access to the intervention at the end of the study. Data were collected on platform usage and psychosocial variables. MAIN OUTCOMES: One hundred and fifty-one carers from 11 sites were invited to join the study (letter, face-to-face); 30 were screened; 29 were randomized. Fifteen people were allocated to the control arm; 14 to intervention. Carers were mostly female; median age for was 62.5 (IQR: 58, 68; intervention) and 57 (IQR: 56, 70; controls). Study retention was high (24/29 = 82.76%); carers engaged with the platform on average 14 times (median (IQR):14.0 (10.0, 18.5)) during the study period. CONCLUSION: The MiNDToolkit study was feasible and well accepted by carers and trained HCPs. A definitive trial is warranted.

Differentiation-dependent inhibition of proteolysis by norepinephrine in brown adipocytes.

The objective was to evaluate whether norepinephrine (NE) and other hormonal factors have direct effects on protein degradation in brown fat cells. NE inhibited proteolysis by 35-45% in mouse brown adipocytes differentiated in culture. Insulin also inhibited protein degradation but significantly less than NE, whereas glucagon and leptin had no effect. The inhibitory effect of NE was partially antagonized by propranolol but not by prazosin, and dose-response curves with BRL-37344 (a beta(3)-agonist), isoproterenol (a beta(1)/beta(2)-agonist) and dobutamide (a beta(1)-agonist) were consistent with the involvement of a beta(3)-adrenergic receptor. Furthermore, forskolin mimicked the effects of NE, whereas additions of A-23187 or phorbol esters had no effect, alone or in combination with NE or forskolin. Thus inhibition of proteolysis by NE likely involves a beta(3)-adrenergic receptor-mediated increase in cAMP. In contrast, NE, BRL-37344, and dobutamide had no effect on proteolysis in preadipocytes. Inhibition of proteolysis by NE was due at least in part to inhibition of autophagy. Thus inhibition of proteolysis by NE and insulin in mature brown adipocytes is likely an important process contributing to brown fat growth and atrophy under many physiological or pathological conditions.

Unipolar sensing in contemporary pacemakers: using myopotential testing to define optimal sensitivity settings.

Bipolar lead use has increased due to oversensing concerns with older unipolar systems. Data on contemporary unipolar devices with improved hardware design and greater programming flexibility is lacking. Using a randomized crossover design, unipolar and bipolar sensing characteristics of 22 atrial and 16 ventricular leads were compared in 34 patients who had pulse generators of programmable polarity. Unipolar and bipolar intracardiac electrogram amplitudes, pacing and sensing thresholds at rest were similar. Provocative maneuvers were used to assess for myopotential inhibition. At atrial sensitivities of 0.625-1.50 mV, myopotential inhibition occurred in 11 (50%) atrial leads in the unipolar mode compared to 1 (5%) in the bipolar mode (p < 0.001). At sensitivities of > 1.50 mV myopotential inhibition occurred in only 1 ventricular (unipolar) lead. An optimal sensitivity setting for each polarity was derived using clinic test results and assessed by ambulatory ECG (AECG). At these optimal settings, oversensing occurred in 1 (6%) atrial and 1 (8%) ventricular unipolar lead during AECG monitoring, whereas oversensing was not seen in any leads programmed to the bipolar mode. Undersensing occurred in 5 (29%) atrial unipolar versus 1 (6%) bipolar lead (p = 0.08). Undersensing was not observed in any of the ventricular leads. Myopotential inhibition may be frequently provoked by provocative maneuvers at higher sensitivity settings in atrial unipolar leads. The frequency of oversensing can be significantly reduced by defining an optimal sensitivity setting using simple isometric maneuvers. Given present day concerns over bipolar lead longevity, increased utilization of unipolar ventricular leads should be considered.

A 4-year follow-up study of the effects of calcium supplementation on bone density in elderly postmenopausal women.

To determine the long-term effect of calcium supplementation on bone density, 84 elderly women (54-74 years) more than 10 years past the menopause were studied for 4 years as part of a follow-up study of a randomized, double-masked, placebo-controlled trial. The placebo group who did not take calcium supplements at all during the 4-year study (control group, n = 21) served as a comparison with the treated group who took calcium supplements for 4 years (calcium supplement group, n = 14). We also studied subjects who were treated for 2 years with calcium supplements and then ceased taking them (non-compliant group, n = 49). The changes in bone density at the lumbar spine, hip and ankle sites, current calcium intake and activity were monitored. Over the 4 years the calcium supplement group (mean calcium intake 1988 +/- 90 mg/day) did not lose bone at the hip and ankle site. The control group (mean calcium intake 952 +/- 109 mg/day) lost significantly more bone than the calcium supplement group at all sites of the hip and ankle. No overall bone loss was seen at the spine, in either group, over the 4 years of this study. Between years 2 and 4 the non-compliant group (mean calcium intake 981 +/- 75 mg/day) lost significantly more bone at all sites of the ankle than the calcium supplement group. Therefore, calcium supplementation produces a sustained reduction in the rate of loss of bone density at the ankle and hip sites in elderly postmenopausal women. Increasing dietary calcium intake in women should be the aim of a public health campaign.

The effect of estrogen deficiency on bone mineral density, renal calcium and phosphorus handling and calcitropic hormones in the rat.

The oophorectomized (OOX) rat has been proposed as a good model of postmenopausal osteoporosis in women. The aim of this study was to compare the effect of OOX in 6-month-old rats to the effects of menopause in women with respect to bone mass, the renal handling of calcium and phosphorus, and calcitropic hormones. To more closely replicate the human situation the rats were pair fed a 0.1% calcium diet. Thirty four, 6-month-old rats were randomized to sham operation or OOX. Whole body and regional bone density was performed at baseline and 6 weeks postoperation. Blood and 24-hour urine samples were obtained at baseline, 1, 3, and 6 weeks and assayed for various biochemical variables, parathyroid hormone (PTH), and calcitriol. The OOX rats lost significantly more bone than the sham-operated rats (change in global bone mineral density, sham -1.7 +/- 2.0%, OOX -3.9 +/- 2.6%, P < 0.001). In the OOX animals, an increase in the 24-hour urine calcium was observed at 1 and 3 weeks, which had returned to sham-operated levels by 6 weeks. In the whole group, the increase in urine calcium at 1 week was negatively correlated with the change in bone mass at 6 weeks (r = -0.39, P = 0. 029). OOX resulted in an increased filtered load of calcium and phosphorus. There was an increase in the maximal renal tubular reabsorption of phosphorus (TmP-GFR) but no clear change in renal calcium handling. Neither calcitriol nor parathyroid hormone showed a significant change as a result of OOX. As in postmenopausal women, following oophorectomy in the rat, there was significant generalized bone loss and a negative calcium balance. This was associated with an initial rise in urine calcium due to a rise in the filtered calcium load; plasma phosphorus and TmP-GFR also rose. The rat model may differ from postmenopausal bone loss in that the initial rise in urine calcium was not present at later time points as occurs in natural menopause in women. Calcitropic hormone levels did not change. This study has shown that the 6-month-old OOX rat fed a 0.1% calcium diet has many similarities of calcium and phosphorus homeostasis to that seen at menopause in women.

Soybean lectin stimulates pancreatic exocrine secretion via CCK-A receptors in rats.

Rats fed raw soy flour (RSF) show pancreatic growth due to excessive cholecystokinin (CCK) release. Soybean trypsin inhibitors are implicated, but rats fed soybean lectin also showed pancreatic growth. Therefore, we studied the effect of soybean lectin on pancreatic protein secretion in anesthetized rats. Intraduodenal administration of 30 mg of RSF stimulated a 1-h integrated rise in pancreatic protein output of 2.2 +/- 1.1 mg/h (mean +/- SE) in rats with bile pancreatic (BP) juice returned to the duodenum. Selective removal of the lectin by affinity to N-acetyl-D-galactosamineagarose abolished the response (-0.1 +/- 0.2 mg/h). Adding back the 84 micrograms of lectin restored the output of 2.2 +/- 0.9 mg/h. With BP juice returned to the duodenum, 84 micrograms of lectin required the added presence of protein and protease inhibitors to have this effect. However, when BP juice was not returned, 84 micrograms of lectin given alone produced a pancreatic response of 3.2 +/- 1.3 mg/h. Plasma CCK concentrations rose significantly from 6.6 +/- 1.9 to 14.3 +/- 2.9 pmol/l, and the pancreatic response was abolished by CCK-A receptor blockade (0.0 +/- 0.1 mg/h). We conclude that soybean lectin plays a major role in the acute stimulation of pancreatic protein secretion by RSF. The lectin releases CCK and the effect is mediated by CCK-A receptors.