Quality control in cochlear implant therapy: clinical practice guidelines and registries in European countries.

PURPOSE: The treatment with a cochlear implant (CI) is the gold standard in therapy of patients with profound hearing loss or deafness. Successful hearing rehabilitation with a CI is a complex, multi-stage process. In medicine, "Clinical Practice Guidelines" (CPG) are widely accepted for the standardization of such processes. These are supplemented by medical registries in which data regarding the treatment can be collected and evaluated. The aim of this paper is to identify currently existing CI-related CPGs and registries in Europe. METHODS: Between 01/2021 and 06/2021, 42 countries on the European continent, including the United Kingdom, Russia and Turkey, were screened using an internet search (search engine: Google) and a key word search in the Pubmed database. Search terms were the respective country name combined with the following terms: "Cochlear Implant", "CI", "Cochlear implant clinical practice guideline", "CI Guideline", "Cochlear Implant Registry", "CI Registry", "Ear nose throat society". The internet search was conducted in English as well as in the corresponding national language. The objective was to identify a CI-related CPG or registry. RESULTS: A CPG was found in 16 of 42 (38%) countries. In terms of population, this accounts for 645 million out of 838 million people (77%). A registry existed in 4 of the 42 (10%) countries assessed. This corresponds to 102 million out of 838 million (12%) people. In total, 4 out of 42 countries (10%) had both a CPG and a registry. CONCLUSION: Our work shows numerous efforts in Europe to standardize CI care at the national level. While most people in Europe already live in countries with a CPG, this is not the case for CI registries. European-wide consensus on CPGs or registries does not yet exist. The present study thus provides a first assessment of the distribution of CI-related CPGs and registries.

[Development of the publication activity at the German university hospitals for Otorhinolaryngology, Head and Neck Surgery during the SARS-CoV-2-pandemic in 2020]. / Entwicklung der Publikationsleistung der Universitätskliniken für Hals-Nasen-Ohrenheilkunde, Kopf- und Hals-Chirurgie während der SARS-CoV-2-Pandemie im Jahr 2020 in Deutschland.

INTRODUCTION: The SARS-CoV-2 pandemic has led to profound limitations in patient care and student teaching at the University Hospitals of Otorhinolaryngology (ORL). In contrast, the impact on research has been variable. To classify the pandemic-related effect on research, the development of the number of scientific publications of the German ORL university hospitals before and during the pandemic was analyzed. MATERIAL AND METHODS: The publication performance between 2015 and 2020 of the 39 current chairmen was surveyed using a literature search (Pubmed). All entries relating to the chairmen of the university hospital as first, last or co-author were included. The absolute and relative development of each author's publication performance was determined and evaluated using nonparametric statistical methods. RESULTS: A total of 2420 publications could be documented. From 2015 to 2019, an average of 368 publications were published per year. In 2020, this number increased by 57.9 % to 581 publications. While the number of monthly publications remained constant between 2015 and 2019, a significant increase was seen from May 2020 up to a maximum of 74 publications in September 2020. In 2020, 34 articles (5.9 %) had a thematic relation to the SARS-CoV-2 pandemic, with 7 of these papers (20.6 %) resulting from cross-site publications. CONCLUSION: In 2020, the number of scientific publications was raised to more than 1.5 times the usual annual publications. This increase was clearly related in time to the reduction of elective patient care during the SARS-CoV-2 pandemic starting in mid-March 2020. Probably, free time capacities enabled this increased publication output. Our results confirm the great scientific potential of the ORL university hospitals, which has been successfully implemented despite the pandemic.

[Effects of the SARS-CoV­2 pandemic on the otolaryngology university hospitals in the field of research, student teaching and specialist training]. / Auswirkungen der SARS-CoV­2-Pandemie auf die universitäre Hals-Nasen-Ohren-Heilkunde im Bereich der Forschung, Lehre und Weiterbildung.

BACKGROUND: From spring 2020, SARS-CoV­2 began to spread worldwide, with what is now known as the first wave of the pandemic, starting in March 2020. This resulted in restructuring and shift of resources at many hospitals. The aim of our work was to detect the effects of the pandemic on the german Oto-Rhino-Laryngology (ORL) university hospitals in terms of research, student teaching and further specialist training. MATERIAL AND METHODS: The chairmen of the 39 ORL university hospitals in Germany were asked about the effects of the pandemic on research, student teaching and ORL specialist training (residency) in the period from March to April 2020 using a structured online survey. RESULTS: All 39 chairmen took part in the survey. Of these, 74.4% (29/39) stated that their research activities had deteriorated as a result of the pandemic. In 61.5% (24/39) pandemic-related research issues were addressed. All hospitals reported a restriction for in-house teaching and 97.5% (38/39) introduced new digital teaching methods. During the observation period, 74.4% of the chairmen did not see ORL specialist training (residency)at risk. CONCLUSION: Our results provide an insight into the heterogeneous effects of the pandemic. The fast processing of pandemic-related research topics and the introduction of innovative digital concepts for student teaching impressively demonstrates the great innovative potential and the ability of the ORL university hospitals to react quickly in order to maintain their tasks in research, student teaching and ORL specialist training in the best possible way even during the pandemic.

[Effects of the SARS-CoV-2 pandemic on the otorhinolaryngology university hospitals in the field of medical care]. / Auswirkungen der SARS-CoV-2-Pandemie auf die universitäre Hals-Nasen-Ohrenheilkunde im Bereich der Krankenversorgung.

INTRODUCTION: Since December 2019, the SARS-CoV-2 virus has been rapidly spreading worldwide. In Germany, an exponential increase in the number of infections was registered at the beginning of March 2020 and led to a call of the Ministry of Health to create more capacity for intensive medical treatment in hospitals. The aim of the present study was to determine the effects of the SARS-CoV-2 pandemic on Oto-Rhino-Laryngology (ORL) university hospitals regarding patient care. MATERIALS AND METHODS: An online survey was sent out to all chairmen of the 39 ORL university hospitals in Germany. The answers to the questions referred to the defined period from March 15th to April 15th 2020 and were carried out using the online survey tool "SurveyMonkey". 87 questions focused on general information, health care, and structural effects in the respective institution. RESULTS: All chairmen of the 39 university hospitals in Germany participated in the survey. The collected data prove the considerable impact on organizational, structural and medical aspects of patient care. For example, the surveyed clinics reported a decrease in outpatient cases by 73.8 % to 26.2 ±â€Š14.2 % and in surgical treatments by 65.9 % to 34.1 ±â€Š13.9 %. In contrast, emergency treatment remained unchanged or even increased in 80 % of the facilities and surgical treatment of emergency patients remained unchanged or even increased in more than 90 %. Emergency outpatient and surgical treatment of patients was provided throughout the pandemic in all facilities. In total, about 35 000 outpatients and about 12 000 surgical cases were postponed. As a result of the acute structural changes, the potential danger of falling below current treatment standards was seen in individual areas of patient care. DISCUSSION: The assessment of the impact of the SARS-CoV-2 pandemic is heterogeneous. The majority of the chairmen are critically aware of the risk of falling below current medical treatment standards or guidelines. In the phase of an exponential increase in the number of infections, significant changes in treatment processes had to be accepted for understandable reasons. However, with the currently significantly reduced number of infections, falling below treatment standards and guidelines should not be allowed to remain constant and tolerated. SUMMARY: This study shows a differentiated picture with regard to the effects of the SARS-CoV-2 pandemic on outpatient, inpatient and operative patient care at the ORL university hospitals in Germany and illustrates the importance of these institutions for ensuring patient care during this critical phase.

Vibrant Soundbridge® in preschool children with unilateral aural atresia: acceptance and benefit.

The aim of this pilot study was to determine the acceptance and benefit from the middle ear implant system Vibrant Soundbridge® (VSB, MED-EL Corporation, Austria) by means of a questionnaire, compared to a previously used conventional bone conducting hearing device, in preschool children with unilateral congenital aural atresia. Prospective cohort study. All nine children with unilateral congenital aural atresia used the VSB and had previous experience with a bone conducting hearing device. The benefit from the VSB was evaluated by questionnaires concerning acceptance of hearing aids, handling, listening effort, behavior, quality of life, and the duration of daily use and compared to the experience with the bone conducting hearing device. In addition, to quantify the benefit from the VSB use, audiological assessment (pure-tone audiometry via free field testing, speech audiometry, and localization test) was performed with and without VSB. The questionnaires and audiological test results were compared pairwise. According to all questionnaire areas, children benefited significantly more from the VSB compared to bone conducting hearing device (ps <.05). The most important finding was a significant increase in daily use from 2 h for the bone conducting hearing device to 10 h for the VSB. Children performed significantly better with the VSB than without it in the audiological assessment. Children with unilateral aural atresia benefited significantly more from the VSB compared to a conventional bone conducting hearing device according to the parents' questionnaires and yielded better results in the audiometry and localization test with the VSB than without it.

[Vibrant Soundbridge®: An Alternative Hearing System for Preschool Children with Aural Atresia]. / Die Vibrant Soundbridge®: Ein alternatives Hörsystem bei Vorschulkindern mit Gehörgangsatresie.

BACKGROUND: The audiological treatment of children with aural atresia makes high demands on physicians and acousticians. Conventional hearing systems are often not tolerated by children and therefore do not meet the needs of the early and efficient therapy of hearing disorders. Aim of the present study was the evaluation of the audiological functional gain in children with uni- and bilateral aural atresia provided with the middle ear implant Vibrant Soundbridge(®) (VSB(®)) below the age of 6 years as well as the analysis of parents' satisfaction assessed with questionnaires. MATERIAL AND METHODS: The VSB(®) was implanted in 16 children, 13 with unilateral and 3 with bilateral aural atresia, with the mean age of 2;11±1;6 years. 3 months after the first fitting of the audio processor, pure-tone audiometry via free field testing with and without the hearing system was performed. Furthermore, parents completed a standardized questionnaire to evaluate their satisfaction with the VSB(®) treatment quality. The questionnaire included items on the acceptance by children, handling, listening effort, behavior, satisfaction, quality of life, aesthetics, and the length of daily use. RESULTS: The use of the VSB(®) resulted in a significantly improved hearing level: 20 dB on average (Z=- 3.06; p=0.002; n=12). The analysis of parents' questionnaire demonstrated high or very high satisfaction with VSB(®) in all subjects. Primarily, the length of daily use of the VSB(®) was significantly higher than that of the hearing system used before with 10.0±2.1 vs. 2.7±2.2 h per day (Z=- 3.06; p=0.002; n=14). CONCLUSION: The VSB(®) presented a good alternative for audiological treatment of uni- and bilateral aural atresia at toddler and pre-school age.

[Secretion scale by Murray et al. for FEES®: comparison of reliability and validity of the German long and short version]. / Sekretbeurteilungsskala nach Murray et al. für FEES(®) : Reliabilitäts- und Validitätsvergleich der deutschen Lang- und Kurzversion.

BACKGROUND: Accumulation of secretions in the hypopharynx, aditus laryngis and trachea constitute a cardinal trait of oropharyngeal dysphagia. For the evaluation of the degree of severity a 4-point secretion scale by Murray et al. is used internationally in a long and a short version. However, a validated German translation of the long version of this scale does not yet exist. Also, it has not yet been scientifically proven that both versions of the scale are equally valid. OBJECTIVES: This study aimed at the validation of the German translation of the long version of the secretion scale by Murray et al. and at a comparison of reliability and validity of the short and long versions. MATERIAL AND METHODS: A total of 40 videos of fiberoptic endoscopic evaluation of swallowing (FEES(®)), 10 for each severity level, were rated by 4 otorhinolaryngologists (ENT specialists) independently and with different randomizations for examination of the reliability and validity. Two rating sessions for each of the scale versions were conducted. Intrarater and interrater reliability as well as the agreement of the ratings with a reference standard were analyzed. RESULTS: Both the intrarater reliability (Spearman correlations: ρs > 0.840***) and the interrater reliability (Krippendorff's alpha: α > 0.850) yielded very good results and the concurrent validity was highly significant (ρs > 0.981***). DISCUSSION: The German translation of the secretion scale by Murray et al. can be considered reliable and valid, with comparable test accuracy of the short and long versions. Hence, the scale can be recommend for the graduation of pharyngolaryngotracheal secretions and should be integrated into the standardized evaluation of FEES(®) diagnostics for clinical and scientific purposes.

Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.

BACKGROUND: We have recently shown that intranasal administration of mouse [D-Leu-4]-OB3 reconstituted in Intravail(®) to male Swiss Webster mice resulted in significantly higher uptake and bioavailability when compared with commonly used injection methods of delivery. AIM AND METHODS: In this study, we examined the effects of intranasal delivery of mouse [D-Leu-4]-OB3 in Intravail(®) on energy balance, glucose regulation, insulin secretion and serum levels of osteocalcin, a specific and sensitive marker of bone formation. Genetically obese C57BLK/6-m db/db mice were allowed food and water ad libitum and given either Intravail(®) alone or mouse [D-Leu-4]-OB3 in Intravail(®) for 14 days by intranasal instillation. RESULTS: Mouse [D-Leu-4]-OB3 reduced body weight gain, daily food intake, daily water intake and serum glucose by 11.5, 2.2, 4.0 and 61.9%, respectively. Serum insulin levels in db/db mice given mouse [D-Leu-4]-OB3 were approximately threefold lower than those in mice receiving Intravail(®) alone. Mouse [D-Leu-4]-OB3 elevated serum osteocalcin in db/db mice by 28.7% over Intravail(®) treated control mice. CONCLUSIONS: The results of our study indicate that intranasal delivery of biologically active mouse [D-Leu-4]-OB3 in Intravail(®) is feasible and has significant effects on regulating body weight gain, food and water intake, serum glucose, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.

Oral delivery of mouse [d-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J wild-type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels.

BACKGROUND: We have recently shown that intranasal administration of mouse [d-Leu-4]-OB3 reconstituted in Intravail to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injections methods of delivery. The absorption profile associated with intranasal delivery of mouse [d-Leu-4]-OB3 showed an early peak representing absorption across the nasal mucosa, and a later peak suggesting a gastrointestinal site of uptake. AIM AND METHODS: In the present study, we examined the effects of orally administered (by gavage) mouse [d-Leu-4]-OB3 on energy balance, glycaemic control and serum osteocalcin levels in male C57BL/6J wild-type and ob/ob mice allowed food and water ad libitum or calorie restricted by 40% of normal intake. RESULTS: In wild-type mice fed ad libitum, oral delivery of mouse [d-Leu-4]-OB3 reduced body weight gain, food intake and serum glucose, by 4.4, 6.8 and 28.2% respectively. Serum osteocalcin levels and water intake were essentially the same in control and treated wild-type mice. In ob/ob mice fed ad libitum, mouse [d-Leu-4]-OB3 reduced body weight gain, food intake, water intake and serum glucose by 11.6, 16.5, 22.4 and 24.4% respectively. Serum osteocalcin in ob/ob mice treated with mouse [d-Leu-4]-OB3 was elevated by 62% over controls. Calorie restriction alone caused significant weight loss in both wild-type (9.0%) and ob/ob (4.8%) mice, and mouse [d-Leu-4]-OB3 did not further enhance this weight loss. As expected, serum glucose levels in wild-type and ob/ob mice were significantly reduced by calorie restriction alone. Mouse [d-Leu-4]-OB3 further reduced serum glucose in wild-type mice and normalized levels in ob/ob mice. Calorie restriction alone reduced serum osteocalcin levels by 44.2% in wild-type mice and by 19.1% in ob/ob mice. Mouse [d-Leu-4]-OB3 prevented this decrease in groups of mice. CONCLUSIONS: The results of this study suggest that oral delivery of mouse [d-Leu-4]-OB3 in Intravail is possible and may have potential not only as an alternative therapy in the treatment of human obesity and some of its associated metabolic dysfunctions, but also may help to prevent and/or reverse at least some of the bone loss which accompanies osteoporosis, anorexia nervosa and other wasting diseases.

Temporal bone imaging: comparison of flat panel volume CT and multisection CT.

BACKGROUND AND PURPOSE: A recent development in radiology is the use of flat panel detectors in CT to obtain higher-resolution images. This technique is known as flat panel volume CT (fpVCT). We sought to compare the image quality and diagnostic value of 2 different flat panel detector-equipped scanners: one is a prototype fpVCT scanner, and the other is a so-called flat panel digital volume tomography (fpDVT) scanner, which is routinely used in clinical setup with current state-of-the-art multisection CT (MSCT) scanners. MATERIALS AND METHODS: Five explanted temporal bones and 2 whole-head cadaveric specimens were scanned with fpVCT, fpDVT, and MSCT scanners. The image series were blindly evaluated by 3 trained observers who rated 38 anatomic structures with regard to their delineation/appearance. RESULTS: Although the image quality obtained with fpVCT and fpDVT was rated significantly better compared with MSCT on isolated temporal bones, the differences were not significant when whole cadaveric heads were scanned. CONCLUSIONS: Theoretic and practical advantages exist for flat panel detector-equipped scanners, including improved image quality. However, when imaging whole cadaveric heads, no significant difference could be demonstrated between them and standard-of-care MSCT.

Clinical feasibility test on a minimally invasive laser therapy system in microsurgery of nerves.

The clinical feasibility test described here evaluates the basis for a laser therapy system that enables tumour tissue to be separated from nerves in a minimally invasive manner. It was first investigated whether, using an Er:YAG laser, laser-induced nerve (specifically, facial nerve) responses in the rabbit in vivo can be reliably detected with the hitherto standard monitoring techniques. Peripherally recordable neuromuscular signals (i.e. compound action potentials, CAPs) were used to monitor nerve function and to establish a feedback loop. The first occurrence of laser-evoked CAPs was taken as the criterion for deciding when to switch off the laser. When drawing up criteria governing the control and termination of the laser application, the priority was the maintenance of nerve function. Five needle-electrode arrays specially developed for this purpose, each with a miniature preamplifier, were then placed into the facial musculature instead of single-needle electrodes. The system was tested in vivo under realistic surgical conditions (i.e. facial-nerve surgery in the rabbit). This modified multi-channel electromyography (EMG) system enabled laser-evoked CAPs to be detected that have amplitudes 10 times smaller than those picked up by commercially available systems. This optimization, and the connection of the neuromuscular unit with the Er:YAG laser via the electrode array to create a feedback loop, were designed to make it possible to maintain online control of the laser ablation process in the vicinity of neuronal tissue, thus ensuring that tissue excision is both reliable and does not affect function. Our results open up new possibilities in minimally invasive surgery near neural structures.

[Image-guided minimal-invasive cochlear implantation--experiments on cadavers]. / Navigationsgeführte minimal-invasive Cochlea-Implantation--Untersuchungen am humanen Felsenbein.

BACKGROUND: The accuracy of navigation systems can be improved significantly by using high-resolution flat panel-based Volume Computed Tomography (fpVCT) so that new surgical therapeutic concepts become feasible. A navigation-guided minimally-invasive cochleostomy places highest requirements on the accuracy of intraoperative navigation. METHODS: A flat-panel Volume Computed Tomograph (fpVCT) was used to scan four human temporal bones. The isometric voxel size was 200 microm. The preoperative planning was used to define an optimized drilling channel from the mastoid surface to the round window niche and the scala tympani providing a safety margin to critical anatomical structures such as facial nerve, chorda tympani, sigmoid sinus and posterior wall of auditory canal. The canal was drilled hand-operated with a navigated drill following the previously planned trajectory. Afterwards the drilled canal was imaged by fpVCT. Conventional dissection including mastoidectomy and posterior tympanotomy assured correct localization of the cochleostomy. RESULTS: Path planning took an average of 54 minutes (range 35-85 minutes). Installation took an average of 16 minutes (range 14-19 minutes). The drilling procedure itself took an average of 7.75 min (range 5-12 minutes.) The RMSE-values varied between 0.1 and 0.2 mm (Table 1). All four specimens showed a cochleostomy located at the scala tympani anterior inferior to the round window. The chorda tympani was damaged in one specimen--this was preoperatively planned as a narrow facial recess was encountered. The time needed for planning and system-installation could be reduced continuously. CONCLUSIONS: This feasibility study demonstrates that using current image-guided surgery technology in combination with fpVCT allows drilling of a minimally invasive channel to the cochlea with loco typico cochleostomy. The necessary accuracy of intraoperative navigation can be achieved by use of fpVCT (technical accuracy between 0.1 and 0.2 mm). Our results demonstrate the feasibility of a navigation-guided minimally-invasive cochleostomy loco typico. While we are enthused by this preliminary work, we recognize the barriers which exist in translation to clinical application. These include surgical issues (e.g. control of unexpected bleeding) and electrode issues (e.g. development of insertion tools).

Homograft patch repair in carotid artery rupture.

The case of a 24-year-old man with a rupture of the left common carotid artery and history of intravenous drug abuse is presented. Due to absence of a suitable autologous vein segment the carotid bulb was repaired with a human allograftpatch.

[Navigation-supported surgery in the head and neck region]. / Navigationsgestützte Chirurgie im Kopf- und Hals-Bereich.

Few of the pioneering manufacturers who attempted to develop navigation systems have been able to establish themselves within the market long-term. The same applies to the technological basis of these systems which aid intraoperative anatomical orientation. The first few systems registered the mechanical displacement of the navigational instrument's axes. Optoelectronic and electromagnetic methods are now prevalent. In contrast to electromagnetic systems, the "line of sight" between the camera system, the reference markers placed on the patient's head and the navigation instruments must remain unobstructed during the navigation process when using electrooptical navigation systems. Whereas, in the past, only preoperative CT scans were used for navigation, the integration of MRI and sonography--whose images can now be fused with each other and with those provided by other intraoperative imaging techniques such as fluoroscopy and endosonography--has become increasingly popular. Navigation systems require input of information about spatial conditions. This is carried out via procedures of registration and referencing, by means of which the relative position of reference markers at the head of the patient is correlated with the image data. The equipment is calibrated in the same way. Headsets, headbands and bone-anchored adapters are available for the fixation of the markers in the patient's head. Whereas the use of a headband or headset requires considerably less time, bone-anchored referencing increases the precision of the navigation system. The surgeon must be able to manage the different methods. In order to reduce the time required for preoperative preparation and to enhance the handling of the navigation processor for the surgeon, it is essential to have a clear menu. The surgeon is able to plan the steps involved in the surgery using the processor, define the access to the surgical site and control the surgery intraoperatively. Preoperative segmentation of functionally and clinically relevant structures enables minimally invasive surgery to be carried out, such as procedures with the aim of acquiring biopsy tissue and the search for foreign bodies. Following the technical development of the systems, the manufacturers are endeavouring to simplify their handling in close coordination with the users. The next step has to be the clinical evaluation of the navigation systems in accordance with the EBM standard, in order to establish this assistive method as routine clinical practice while applying meaningful medical criteria.

[D-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice.

We have recently shown that the activity of a synthetic peptide corresponding to amino acid residues 116-130 of secreted mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116-122 (Ser-Cys-Ser-Leu-Pro-Gln-Thr, OB3). Substitution of the Leu residue at position 4 of OB3 with its D-isomer ([D-Leu-4]-OB3) enhanced the ability of OB3 (1 mg/day, ip, 7 days) to reduce body weight gain, food and water intake, and serum glucose in female C57BL/6J ob/ob mice. In the present study, we have utilized a pair-feeding approach to demonstrate that the antihyperglycemic action of [D-Leu-4]-OB3 is not solely due to its effects on caloric intake. One group of female C57BL/6J ob/ob mice (n=6) was fed ad libitum, and two additional groups (n=6 per group) were allowed 3.0 g food/mouse daily, an amount previously determined to satisfy [D-Leu-4]-OB3-treated mice. At the end of the 7-day test period, vehicle-injected mice fed ad libitum were approximately 10% heavier than their initial body weights, while pair-fed mice injected with vehicle and [D-Leu-4]-OB3-treated mice lost 5% of their initial body weights. After 1 day of treatment, blood glucose was reduced by 20% in pair-fed vehicle-injected mice, and by 40% in mice given [D-Leu-4]-OB3. Food restriction reduced blood glucose throughout the 7-day study, but not to levels seen in wild-type nonobese C57BL/6J mice of the same sex and age. After 2 days of treatment with [D-Leu-4]-OB3, however, blood glucose was reduced to levels comparable to those seen in wild-type nonobese mice. [D-Leu-4]-OB3 also lowered serum insulin levels by 53% when compared to mice fed ad libitum. Neither pair-feeding nor [D-Leu-4]-OB3 treatment had any apparent effect on thermogenesis. These results suggest that [D-Leu-4]-OB3 exerts its effects on serum glucose not only by suppressing caloric intake, but also through a separate effect on glucose metabolism which may involve increased tissue sensitivity to insulin.

Design of a synthetic leptin agonist: effects on energy balance, glucose homeostasis, and thermoregulation.

We have previously reported that a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin, LEP-(116-130), reduces body weight gain, food intake, and blood glucose levels in ob/ob and db/db mice. In the present study we show that the activity of LEP-(116-130) resides in a restricted sequence between amino acid residues 116-122. A synthetic peptide corresponding to this sequence (Ser-Cys-Ser-Leu-Pro-Gln-Thr) has been named OB3. Single point D-amino acid substitution was used to study the structure-function relationship of each residue in OB3. D-Amino acid analogs of OB3 were synthesized by the solid phase method, purified to 98+%, and administered (1 mg/day, ip) for 7 days to female C57BL/6J ob/ob mice. The effects of the peptides on body weight gain, food and water intake, glucose homeostasis, and thermoregulation were assessed. In most cases, the efficacy of OB3 on all parameters tested was reduced by substitution of an L-amino acid with its corresponding D-isoform. A statistically significant increase (2.6-fold) in the weight-reducing effect of OB3, however, was observed by inversion of the configuration of the leucine residue at position 4 (Leu-4) of OB3 by substitution with its D-amino acid isoform [D-Leu-4]. Compared with OB3, mice treated with [D-Leu-4]-OB3 consumed 7.9% less food and 16.5% less water. Blood glucose was normalized to levels comparable to those in wild-type control mice within 2 days after initiation of [D-Leu-4]-OB3 treatment. Unlike native leptin, however, neither OB3 nor any of its D-amino acid-substituted analogs had any apparent effect on thermogenesis. Our results indicate that synthetic peptide strategies may be useful in the development of potent and stabile pharmacophores with potential therapeutic significance in the treatment of human obesity and its related metabolic dysfunctions.