Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice.

OBJECTIVE: Mice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic phenotype of mice with either Nestin Cre-mediated neuronal loss of TRPM8, or with deletion of TRPM8 in Advillin Cre positive sensory neurons of the peripheral nervous system (PNS). METHODS: Nestin Cre- and Advillin Cre-Trpm8 knock-out (KO) mice were metabolically phenotyped under chronic exposure to either chow or high-fat diet (HFD), followed by assessment of energy and glucose metabolism. RESULTS: At room temperature, chow-fed neuronal Trpm8 KO are obese and show decreased energy expenditure when acutely treated with the TRPM8 selective agonist icilin. But body weight of neuronal Trpm8 KO mice is indistinguishable from wildtype controls at thermoneutrality, or when mice are chronically exposed to HFD-feeding. In contrast to previous studies, we show that the TRPM8 agonist icilin has no direct effect on brown adipocytes, but that icilin stimulates energy expenditure, at least in part, via neuronal TRPM8 signaling. We further show that lack of TRPM8 in sensory neurons of the PNS does not lead to a metabolically relevant phenotype. CONCLUSIONS: Our data indicate that obesity in TRPM8-deficient mice is centrally mediated and likely originates from alterations in energy expenditure and/or thermal conductance, but does not depend on TRPM8 signaling in brown adipocytes or sensory neurons of the PVN.

Are peptide conjugates the golden therapy against obesity?

Obesity is a worldwide pandemic, which can be fatal for the most extremely affected individuals. Lifestyle interventions such as diet and exercise are largely ineffective and current anti-obesity medications offer little in the way of significant or sustained weight loss. Bariatric surgery is effective, but largely restricted to only a small subset of extremely obese patients. While the hormonal factors mediating sustained weight loss and remission of diabetes by bariatric surgery remain elusive, a new class of polypharmacological drugs shows potential to shrink the gap in efficacy between a surgery and pharmacology. In essence, this new class of drugs combines the beneficial effects of several independent hormones into a single entity, thereby combining their metabolic efficacy to improve systems metabolism. Such unimolecular drugs include single molecules with agonism at the receptors for glucagon, glucagon-like peptide 1 and the glucose-dependent insulinotropic polypeptide. In preclinical studies, these specially tailored multiagonists outperform both their mono-agonist components and current best in class anti-obesity medications. While clinical trials and vigorous safety analyses are ongoing, these drugs are poised to have a transformative effect in anti-obesity therapy and might hopefully lead the way to a new era in weight-loss pharmacology.

On-chip free beam optics on a polymer-based photonic integration platform.

This paper presents on-chip free beam optics on polymer-based photonic components. Due to the circumstance that waveguide-based optics allows no direct beam access we use Gradient index (GRIN) lenses assembled into the chip to collimate the beam from the waveguides. This enables low loss power transmission over a length of 1432 µm. Even though the beam propagates through air it is possible to create a resonator with a wavelength shift of 0.002 nm/°C, hence the allowed deviations from the ITU-T grid (100 GHz) are met for ± 20 °C. In order to guarantee reliable laser stability, it is necessary to implement optical isolators at the output of the laser. This requires the insertion of bulk material into the chip and is realized by a 1050 µm thick coated glass. Due to the large gap of the free-space section, it is possible to combine different resonators together. This demonstrates the feasibility of an integrated wavelength-meter.

Nonlinear pulse propagation in a quantum dot laser.

We investigate the nonlinear propagation of an ultra-short, 150 fs, optical pulse along the waveguide of a quantum dot (QD) laser operating above threshold. We demonstrate that among the various nonlinear processes experienced by the propagating pulse, four-wave mixing (FWM) between the pulse and the two oscillating counter-propagating cw fields of the laser is the dominant one. FWM has two important consequences. One is the creation of a spectral hole located in the vicinity of the cw oscillating frequency. The width of the spectral hole is determined by an effective carrier and gain relaxation time. The second is a modification of the shape of the trailing edge of the pulse. The wave mixing involves first and second order processes which result in a complicated interaction among several fields inside the cavity, some of which are cw while the others are time varying, all propagating in both directions. The nonlinear pulse propagation is analyzed using two complementary theoretical approaches. One is a semi-analytical model which considers only the wave mixing interaction between six field components, three of which propagate in each direction (two cw fields and four time-varying signals). This model predicts the deformation of the tail of the output signal by a secondary idler wave, produced in a cascaded FWM process, which co-propagates with the original injected pulse. The second approach is a finite-difference time-domain simulation, which considers also additional nonlinear effects, such as gain saturation and self-phase modulation. The theoretical results are confirmed by a series of experiments in which the time dependent amplitude and phase of the pulse after propagation are measured using the cross-frequency-resolved optical gating technique.

Unrecognised ventricular dysfunction in COPD.

While both chronic congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) impose a substantial disease burden and share aetiological and epidemiological associations, they have largely been studied separately. The aim of our study was to assess the prevalence and the prognostic implications of the coexistence of left ventricular dysfunction in COPD patients and airway obstruction in CHF patients. We used a prospective cohort study including stable ≥ 60-yr-old patients with echocardiographically confirmed CHF (n=201) and stable ≥ 60-yr-old patients with clinically and spirometry-confirmed COPD (n=218). All CHF patients underwent routine spirometry, and all COPD patients underwent routine echocardiographic assessment and B-type natriuretic peptide (BNP) measurement. Patients were followed for 2 yrs. The prevalence of airway obstruction among CHF patients was 37.3% and the prevalence of ventricular dysfunction among COPD patients was 17%. The presence of ventricular dysfunction in patients with COPD tended to increase the risk of mortality during follow-up (hazard ratio 2.34, 95% CI 0.99-5.54; p=0.053). The presence of airway obstruction in patients with CHF did not influence survival. CHF and COPD frequently coexist, and ventricular dysfunction worsens survival in patients with COPD. Considering the high prevalence and the prognostic implications of ventricular dysfunction, routine assessment with either BNP or echocardiogram should be considered in COPD patients.

Spectral properties of atrial and ventricular endocardial signals.

The spectral energy distributions of signals picked up by endocardial, atrial and ventricular electrodes have been investigated. The results show similar spectral distributions for P-waves and QRS-complexes with maximum spectral densities at frequencies between 10 and 30 Hz.

Clinical experience with a new transvenous atrial lead.

Although systems using atrial pacemakers offer potential clinical advantages for many patients now receiving ventricular devices, atrial systems have been used in less than 1% of the implantations of permanent pacemakers. The unavailability of clinically successful, easily positioned atrial leads is regarded as the most significant factor in the underutilization of atrial pacing systems. A permanent transvenous atrial lead has been developed and has performed well in 16 months of evaluation in 28 patients. Acute thresholds for voltage at a pulse width of 1 msec ranged from 0.40 v to 2.0 v (average, 1.1 v). Acute peak-to-peak amplitudes of the atrial electrogram were notably high, ranging from 2.5 mv to 7.5 mv (average, 5.1 mv) as measured oscilloscopically. Intermittent failure of sensing occurred in three patients during the period immediately after implantations. Spontaneous dislodgment of the lead from the right atrial appendage occurred in two patients. Atrial sensing and pacing functions remained intact in the first case, and no revision was performed. The lead was repositioned in the second patient and has remained in good position. No complications relating to the lead have been noted in the remaining patients.

[First clinical experiences with a new transvenous endocardial screw-in lead (author's transl)]. / Erste klinische Erfahrungen mit einer neuen transvenös endokardialen Schraubelektrode in Vorhof- und Kammerposition.

From November 1976 to January 1977 a total of 10 patients were served with a new transvenous endocardial screw-in lead. In every 5 cases the lead was anchored in the right atrium respectively in the right ventricle. The lead presented itself by good biomechanical (flexibility, tension resistance) and bioelectrical properties. Because of its constructural features it was to insert easily and without any complication. Moreover, it could be placed anatomically stable by choice either in the right atrium or ventricle.

[Comparative studies of thresholds after implantation of pacemaker leads of different size (author's transl)]. / Vergleichende Untersuchungen des Reizschwellenverhaltens nach Implantation verschieden grosser Herzschrittmacherelektroden

Within the first 14 days after implantation, thresholds were measured at three transvenous pacemaker electrodes with different surface areas. It should be verified, 1. to what extent a correlation existed between maximal threshold increase and electrode surface, 2. how electrode impedance and 3. how the amplitudes of the R-wave voltages developed. The results were: At initial implantation, thresholds were all the lower the smaller the electrode-surface area was. On overage, 9-10 days after implantation the highest thresholds were reached. Thereby, in small surface area electrodes the threshold-increase factor was greater than in larger ones. In all cases the current threshold increase exceeded that one for voltage thresholds. 14 days later, thresholds had dropped again compared to the maximum. And this decrease was depending on the electrode-surface area also. The electrode impedance decreased after implantation to rise later on once more to 80-88% of the original value. The magnitude of the detected R-wave was independent on electrode-surface area. Indeed, using small surface electrodes, signal reductions up to 50% could be found. But 14 days later they reached again 80-95% of the initial amplitude. The key finding there is that when applying small surface-area electrodes and presuming suitable initial thresholds it seems to be possible to connect low-output pacemakers (output 5,4 V and impluse duration 0.25 ms or 4 V at 0.5 ms) to those electrodes. By this reduction of the safety margin, a considerable increase in pacemaker lifetime could be achieved.

[One year experiences with a new atrial lead (j-version) in 53 patients (author's transl)]. / Einjährige Erfahrungen mit einer neuen Vorhofelektrode (J-Version) an 53 Patienten

The new atrial leads (J-version) of type Medtronic 6991, of which we implanted endocardially a total of 53 between April 1975 and May 1976, are characterized by properties, as, up to now, were exclusively to be seen in the so-called flange electrodes of ventricular position. 1. The tined J-leads were easily to introduce and required only an average of 5 minutes to position into the right appendage. 2. Moreover, these atrial leads guaranteed an anatomic stable anchorage with a dislodgement ratio of less than 6% (3 of 53). 3. Additionally, the action voltages sensed the J-shaped electrodes showed themselves averaging 5.2 mV of very high amplitude. Up to this time comparable results could not be achieved neither by other atrial leads nor techniques of their emplacement. The intraatrial voltage thresholds exceeded, as described before, the intraventricular ones by two to three times. In spite of this, no exit block was seen in 34 cases with atrial pacing systems, not even during an observation time of maximal 13 months. Therefore, the tined J-leads fulfill all requirements of a suitable atrial electrode.

[Possibilities of pacing the heart by transmediastinal retrocardially inserted leads (author's transl)]. / Möglichkeiten der Elektrostimulation des Herzens mittels transmediastinal retrokardial verlegter Elektroden

Based upon experiences with 14 patients the clinical feasibility of transmediastinal retrocardial stimulation of the heart, of the left atrium as well as in one case of the left ventricle, is reported. Principally both can be stimulated by thus introduced pacemaker electodes. Thus on the one hand thresholds and consequently pulse effectivity appear to be a function of the electrode distance from the myocardium, whilst on the other hand the transmediastinal retrocardial thresholds are initially rather high in analogy to the majority taken from the atrial endocardial surface. Nevertheless, the transmediastinal retrocardial technique is possibly applicable for permanent cardiac pacing. However, additional tests about this are still necessary.

[Experiences with 87 permanent atrial electrodes of various types and emplacement technics]. / Erfahrungen mit 87 permanenten Vorhofelektroden verschiedener Ausführungen und Verlegungstechniken

Between March 1972 and December 1975 87 atrial leads were implanted into 85 patients. In 37 cases the transmediastinal retrocardial approach was preferred. In all the other cases the electrodes were introduced transvenous endocardially. The results showed: 1. There exist techniques of atrial lead emplacement which, when applying suitable lead designs, guarantee an anatomic stable positioning either on the left or in the right atrium. Especially the new transvenous J-shaped electrodes of type Medtronic TJL can be positioned easily. The dislodgement ratio of these leads amounts of only 6%. 2. Retro- as well as intracardially very high action voltages were found. The ones sensed by the J-tip-electrodes from the endocardial surface of the right appendage even run up to 5,4 mV. 3. In spite of relatively high initial thresholds, no exit block was seen in any of the 34 cases, in whom atrial leads were inserted transvenous endocardially for permanent atrial pacing.

Special pacemaker catheter techniques. The transmediastinal placement of sensing electrodes.

The clinical utilization of atrial programmed pacemakers is limited by the lead systems available for sensing of atrial activity. The endocardial method of lead placement is burdened by a dislodgement rate of up to 30 per cent. Alternatively, the patient must submit to the risks of a thoracotomy. Thirty-one patients have been treated with a transmediastinally, retrocardially positioned atrial detector electrode. In 20 patients (65 per cent) the detector performed as desired with no postimplant revision. In 11 patients (35 per cent) corrective measures were required primarily to correct lead placement; seven of these were corrected under local anesthesia merely by pulling the catheter. Spontaneous lead dislocation occurred in four patients. Four patients (13 per cent) underwent remediastinoscopy due to cranial displacement of the detector electrode with a resulting decrease in atrial potential to less than 0.5 mV. For technical reasons, the lead placements were performed without the benefit of x-ray illumination, with only an ECG check of the posterior atrial wall, and this may account for the relatively high incidence of revision. Transmediastinal placement of sensing electrodes presents a practicable alternative to methods presently used.