High molecular weight PEGylation of human pancreatic polypeptide at position 22 improves stability and reduces food intake in mice.

BACKGROUND AND PURPOSE: Human pancreatic polypeptide (hPP) is known to suppress appetite and food intake, thereby representing a potential therapeutic approach against obesity and associated metabolic disorders. The aim of this study was to improve hPP stability by covalent PEGylation with diverse molecular weight polyethylene glycols (PEGs) at two positions using promising lead structures while maintaining target activity. EXPERIMENTAL APPROACH: Modified peptides were synthesized by combined solid-phase and solution-phase peptide synthesis. Their potency was investigated in constitutively expressing human epithelial cells and isolated human colonic mucosa as well as receptor-transfected artificial cell lines. Human blood plasma and porcine liver homogenates were used to examine the in vitro stability of the analogues. The most promising variants were injected s.c. in C57BL/6JRj mice to monitor fasting-induced food intake and bioavailability. KEY RESULTS: In human epithelia and colonic mucosal preparations, activity of the modified hPP peptides depended on the core sequence and latency of the peptides was related to PEG size. Peptides modified with a 22 kDa PEG (PEG22) remained intact in blood plasma and on incubation with liver homogenates for more than 96 h. Finally, hPP2-36 , [K22 (PEG22)]hPP2-36 and [K22 (PEG22),Q34 ]hPP significantly reduced cumulative food intake in mice over 16 h after s.c. administration. CONCLUSIONS AND IMPLICATIONS: Modification with PEG22 at position 22 stabilizes hPP significantly while extending its biological activities and could be used in drug development prospectively.

Pancreatic polypeptide and its central Y4 receptors are essential for cued fear extinction and permanent suppression of fear.

BACKGROUND AND PURPOSE: Avoiding danger and finding food are closely related behaviours that are essential for surviving in a natural environment. Growing evidence supports an important role of gut-brain peptides in modulating energy homeostasis and emotional-affective behaviour. For instance, postprandial release of pancreatic polypeptide (PP) reduced food intake and altered stress-induced motor activity and anxiety by activating central Y4 receptors. EXPERIMENTAL APPROACH: We characterized [K(30) (PEG2)]hPP2-36 as long-acting Y4 receptor agonist and injected it peripherally into wildtype and Y4 receptor knockout (Y4KO) C57Bl/6NCrl mice to investigate the role of Y4 receptors in fear conditioning. Extinction and relapse after extinction was measured by spontaneous recovery and renewal. KEY RESULTS: The Y4KO mice showed impaired cued and context fear extinction without affecting acquisition, consolidation or recall of fear. Correspondingly, peripheral injection of [K(30) (PEG2)]hPP2-36 facilitated extinction learning upon fasting, an effect that was long-lasting and generalized. Furthermore, peripherally applied [K(30) (PEG2)]hPP2-36 before extinction inhibited the activation of orexin-expressing neurons in the lateral hypothalamus in WT, but not in Y4KO mice. CONCLUSIONS AND IMPLICATIONS: Our findings suggests suppression of excessive arousal as a possible mechanism for the extinction-promoting effect of central Y4 receptors and provide strong evidence that fear extinction requires integration of vegetative stimuli with cortical and subcortical information, a process crucially depending on Y4 receptors. Importantly, in the lateral hypothalamus two peptide systems, PP and orexin, interact to generate an emotional response adapted to the current homeostatic state. Detailed investigations of feeding-relevant genes may thus deliver multiple intervention points for treating anxiety-related disorders.

[Orofacial pain - Trigeminal neuralgia and posttraumatic trigeminal neuropathy: Common features and differences]. / Orofazialer Schmerz - Trigeminusneuralgie und posttraumatische Trigeminusneuropathie : Gemeinsamkeiten und Unterschiede.

Neuropathic pain is the result of a lesion or disease of the somatosensory system in the peripheral or central nervous system. Classical trigeminal neuralgia and posttraumatic trigeminal neuropathy are pain disorders which oral and maxillofacial surgeons and dentists are confronted with in the differential diagnostics in routine daily practice. The etiopathogenesis of classical trigeminal neuralgia is attributable to pathological blood vessel-nerve contact in the trigeminal nerve root entry zone to the brain stem. The typical pain symptoms are characterized by sudden stabbing pain attacks. The pharmaceutical prophylaxis is based on the individually titrated administration of anticonvulsant drugs. The indications for interventional treatment are dependent on the course, response to drug treatment, resilience and wishes of the patient. The neuropathic mechanism of posttraumatic trigeminal neuropathy originates from nerve damage, which leads to peripheral and central sensitization with lowering of the pain threshold and multiple somatosensory disorders. The prophylaxis consists of avoidance of excessive acute and long-lasting pain stimuli. Against the background of the biopsychosocial pain model, the treatment of posttraumatic trigeminal neuropathy necessitates a multimodal, interdisciplinary concept.

Snoring in cleft patients with velopharyngoplasty.

Some patients with cleft lip/palate or isolated cleft palate seem to develop snoring as one possible symptom of an obstructive sleep apnoea syndrome after velopharyngoplasty (VPP). The aim of this paper was to determine whether there was a difference in the posterior airway space (PAS) between patients with a VPP who snored and those who did not. Four standard parameters were measured in lateral cephalograms of 20 patients with cleft lip/palate and isolated cleft palate, without diagnosis of further syndromes (e.g. Pierre Robin sequence), having undergone VPP, to examine the dimensions of the PAS. Data were set in correlation to the symptom of snoring, and compared with those of 40 patients without cleft undergoing orthodontic treatment and with 20 patients with cleft lip/palate or isolated cleft palate but not VPP. Metric parameters were significantly different after VPP in patients with clefting and snoring compared to the group of cleft patients without snoring. All patients with clefts exhibited at least in one dimension a constriction when compared to patients without clefting. In conclusion, cleft lip/palate and isolated cleft palate patients tend to have constrictions of the PAS. VPP may induce snoring and further narrowing. Recall and analysis for obstructive sleep apnoea syndrome should be mandatory.

[Pierre Robin sequence: postoperative complications following cleft palate surgery. A retrospective study covering 25 years]. / Pierre-Robin-Sequenz -- postoperative Komplikationen nach Gaumenspaltverschluss. Eine retrospektive Studie über 25 Jahre.

BACKGROUND: In a 25-year retrospective review of 1976-2000, the postoperative course after cleft palate surgery and pharyngeal flap surgery in 87 children with Pierre Robin sequence was studied. PATIENTS AND METHODS: The study comprised 114 interventions with 87 primary palatoplasties; 17 patients required palatal fistulae repair and 10 children were treated with secondary pharyngoplasty procedures. All children were divided into three postnatal risk groups according to the severity of their symptoms at birth and in the course of the early months of life. RESULTS: A direct correlation was seen between the incidence of early postnatal difficulties and the postoperative obstructive complications after cleft palate surgery and pharyngeal flap surgery. Thus, children experiencing obstructive problems at birth (high postnatal risk group) displayed more severe complications at the time after cleft palate repair. In children undergoing pharyngeal flap surgery not only early postoperative obstruction but also late obstructive sleep apnea can occur.

[Experiences with surgical management of facial basal cell carcinoma and procedures for plastic reconstruction]. / Erfahrungen in der chirurgischen Versorgung von Gesichtshautbasaliomen und plastischen Rekonstruktionsverfahren.

BACKGROUND: No recurrences and optimal aesthetic outcomes after R0 resection and plastic reconstruction of the face are the goals in the surgical treatment of basal cell carcinoma. The aim of this study was to evaluate recurrence rates and to evaluate different reconstructive techniques. PATIENTS AND METHODS: This study included 205 follow-up patients undergoing R0 resection of primary basal cell carcinoma and facial skin reconstruction between 1998 and 2002; data were analyzed retrospectively. RESULTS: The most frequent locations of basal cell carcinoma were the nasal (40.5%) and orbital (22.9%) regions. The rate of recurrence after 2.5 years (6 months-5 years) was 7.3%. Local flaps, full-thickness skin grafts, and sliding flaps were usually performed; indications for split-thickness skin grafts were rare. Disturbances of sensation were found in only 3.6% of the sliding flaps and in 11.7% of the local flaps, but 22.7% in full-thickness and 38.7% in split-thickness skin grafts. The aesthetic outcome, evaluated by clinical inspection and a patient satisfaction score, was classified as "unobtrusive" and "good or excellent" for 88.4% of local flaps, 92.6% of sliding flaps, but only for 66.4% of full-thickness and 54% of split-thickness skin grafts. CONCLUSION: Local flaps and sliding flaps result in better aesthetic and neurological outcomes after reconstruction of facial skin regions. Skin grafts have their indications as an alternative procedure in cases of critical indications for flaps.

[Iatrogenic injuries of the trachea]. / Iatrogene Verletzungen der Trachea.

As a basis for quality assurance measures, we analysed over a period of three years all iatrogenic tracheobronchial injuries that had to be repaired operatively at a university hospital. Twelve patients were affected. In most of these cases, the injuries were the result of an intubation during resuscitation attempts prior to or after admission to hospital (6 patients; 4 of them died later). The ruptures of 5 patients were due to complications of a dilational tracheostomy (1 died). In one case the laceration occurred in the course of a reoperation after oesophagectomy (conservative treatment after dehiscence of the tracheal suture). The tracheobronchial ruptures (length: 2 to 8 cm) were located in the pars membranacea and had surgical repair through a thoracotomy on the right side. During the period of this investigation, 43,773 elective intubations were performed. No such serious tracheal injuries were observed. The cause of death in the patients with tracheal injuries was mainly the underlying disease (resuscitation after myocardial infarction; tracheostomy because of pulmonary failure in septic disorders); however, it is likely that the injuries or the surgical intervention played an additional role in the negative outcome of the patients. The conclusion is that this complication rate must be reduced by in-service training and alteration of the procedures.

[Melanotic neuroectodermal tumor of infancy]. / Der melanotische neuroektodermale Tumor des Säuglingsalters.

BACKGROUND: The melanotic neuroectodermal tumor of infancy is a rare and so far as being classified neoplasm with a high rate of recurrence for one year after diagnosis. Since Krompecher described 1918 the tumor at first, only about 200 cases are reported until today, mostly with manifestation in the maxillary region. CASE-REPORTS: The authors present two infants at the age of six and eight weeks with first clinical manifestation of the tumor in the maxillary region. Although there were no other common signs, the tumor destroyed wide areas of the mid-face. In spite of a treatment with radical surgery, recurrences occur rapidly in the first living year. CONCLUSIONS: Our clinical and histological findings show characteristics of local malignant growth. For these facts the radical resections of the primary tumor and its recurrences are individually the therapeutical consequences. A follow up of seven years of one infant shows a hypoplasm of the mid-face as a result of the inhibition of further growth by the loss of germs after maxillary hemisection.

[Associated anomalies in lip-maxillopalatal clefts]. / Assoziierte Anomalien bei Lippen-Kiefer-Gaumen-Spalten.

BACKGROUND: Retrospective studies of cleft lip and palate patients suggest a multifactorial aetiology for this condition. Many patients exhibit multiple defects, often removed from the orofacial region. The frequency and location of such coexistent abnormalities vary between studies. PATIENTS: A retrospective case-note study of 1,737 individuals with orofacial cleft, treated between 1974 and 1998 at our centre, was undertaken to assess the frequency of associated malformations and syndromes. RESULTS: Associated malformations were found to be present in 33% of all cases investigated. In nearly one half of these individuals (48%), defects could be attributed to recognisable syndromes. Patients with isolated palatal clefts (45.6%) and those with bilateral clefts of the lip and palate (35.3%) were particularly well-represented. The following problems were observed relatively frequently: Cerebral anomalies (16%), facial anomalies (14%), heart malformations (15%), anomalies of the extremities (9%) and urogenital tract abnormalities (8%). In contrast, endocrine aberrations were identified sporadically (0.5%). A partial situs inversus was found only in one case. CONCLUSION: As clefts of the lip and palate are frequently associated with additional malformations, the importance of thorough interdisciplinary neonatal screening cannot be over emphasised.

[The effects of perioperative continuous administration of mivazerol on early postoperative hemodynamics and plasma catecholamines after major surgery]. / Die Auswirkungen der perioperativen Gabe des alpha 2-Adrenorezeptor-Agonisten Mivazerol auf frühpostoperative Hämodynamik und Plasmakatecholaminspiegel nach grossen chirurgischen Eingriffen.

OBJECTIVE: During and after surgical procedures a strong activation of the sympatho-adrenergic system is common with correlation to adverse cardiac outcome. Several drugs (alpha 2-adrenoceptor-agonists, beta blockers) are discussed to prevent this reaction. The new alpha 2-adrenoceptor-agonist mivazerol with marked specificity for alpha 2-adrenergic receptors may be suitable for this indication. The aim of the present study was to investigate the effects of perioperative continuous administration of mivazerol on plasma catecholamines, body temperature and calculated haemodynamic parameters in the early postoperative period in cardiac risk patients undergoing non-cardiac surgery. METHODS: 36 patients with known coronary heart disease or risk factors for coronary heart disease scheduled for elective abdominal or vascular surgery were included in the study. Patients received either mivazerol (n = 18) or placebo (n = 18) [initial dose 4 micrograms kg-1 for 10 minutes before induction of anaesthesia, followed by a continuous infusion of 1.5 micrograms kg-1 h-1 intraoperatively and for as long as 72 h after surgery] in a double-blinded, randomized manner. Blood pressure, heart rate and body temperature were measured every 10 minutes until 240 minutes after arrival at the ICU. During 240 minutes after arrival at the ICU measured parameters (CVP, PAP, PCWP, SaO2, SvO2, CO), calculated parameters (CI, SVR, PVR, VO2) and plasma catecholamines were measured at defined time intervalls. RESULTS: The plasma concentrations of epinephrine and norepinephrine and the heart rate were significantly lower in the mivazerol group in the study period. Regarding blood pressure and body temperature there were no differences between the groups. At some measuring points preload was higher in the mivazerol group, but there were no differences between the groups for measured (SaO2, SvO2, CO) and calculated (CI, SVR, PVR, VO2) cardiorespiratory parameters. The incidence of shivering, nausea and vomiting were similar in both groups. CONCLUSION: Continuous, perioperative administration of mivazerol decreased the heart rate and the plasma catecholamines in the early postoperative period, but did not affect blood pressure, body temperature and the incidence of shivering. There were also no effects of mivazerol on calculated haemodynamic parameters (CO, SVR, PVR, VO2). These findings show a selective decrease in heart rate by Mivazerol without markedly cardiorespiratory side effects.

[Premedication in maxillofacial surgery under total intravenous anesthesia . Effects of clonidine compared to midazolam on the perioperative course]. / Prämedikation im Rahmen einer TIVA bei kieferchirurgischen Operationen--Vergleich der perioperativen Verläufe nach Clonidin versus Midazolam.

OBJECTIVE: The effects of the currently favoured preanaesthetic drugs (benzodiazepines, alpha 2-adrenoceptor agonists) on the perioperative course are inadequately investigated for new ways of performing anaesthesia with recently introduced drugs (e.g. remifentanil). Therefore clonidine and midazolam were used for premedication in maxillo-facial surgery under total intravenous anesthesia, and the perioperative courses were analyzed. METHODS: Thirty patients (ASA 1-2) were included in the present doubleblinded, prospective study. 60-90 minutes preoperatively these patients got an oral premedication with 5 micrograms kg-1 clonidine or 100 micrograms kg-1 midazolam. For anaesthesia a standardized procedure with propofol, remifentanil and rocuronium was performed. After induction of anaesthesia the infusion of remifentanil was regulated by using spectral edge frequency (target-SEF90, 10-13 Hz). The efficiency of the premedication as well as the emergence and recovery were assessed by using established standardized tests. The perioperative stress response was assessed by recording the effects on haemodynamic parameters (NIBP. heart rate. Holter-ECG). RESULTS: Referring to the effects of premedication (sedation, anxiety) there were no differences between the groups. The clonidine group required a lower remifentanil rate in keeping a steady-target-SEF90 (-24%). The time until emergence and recovery was not significantly different. Even the occurrence of PONV, VAS or the postoperative analgetic requirement did not differ between the two groups. However, the incidence of postoperative shivering was significantly higher in the midazolam group. Intraoperatively the values of MAP were quite equal between the groups. However, heart rate was significantly lower in the clonidine group. Postoperatively both MAP as well as heart rate were lower in the clonidine group. Furthermore, in the midazolam group there was a significantly higher cumulative duration of tachycardia (heart rate > 100 min-1; following descripted as medium with 25% and 75%-percentage; clonidine: 29/0/563 sec.: midazolam: 1058/232/3171 sec.). CONCLUSION: After remifentanil supplemented anesthesia there is, especially in the postoperative period, a benefit in using clonidine compared to the premedication with midazolam.

[Clinical manifestations of CHARGE association in the area of the mouth, jaw and face]. / Klinische Manifestationen der CHARGE-Assoziation im Mund-, Kiefer- und Gesichtsbereich.

Clinical experience of 11 patients with CHARGE association is reviewed. The study comprised six girls and five boys. All presented with congenital heart disease. Eight had bilateral choanal atresia. Coloboma affecting either one or both eyes was detected in nine children. Nine patients suffered abnormal pinnae or deafness. In addition to major abnormalities, further anomalies of the orofacial region and the upper airways occurred in all patients. All children exhibited velopharyngeal incoordination and swallowing problems often resulting in recurrent aspiration pneumonia. Three patients had cleft lip and palate. Both micrognathia and high-arched palate were present in two patients. Facial palsy was observed in six patients. Optimal management requires a multidisciplinary approach with active coordination and cooperation between the appropriate specialties. The anatomical repair of bilateral choanal atresia should be performed as early as possible. In our experience, the transpalatal approach is far more satisfactory than the transnasal. It gives the surgeon the opportunity of direct access and anatomical repair. After the child has grown stronger, a long-term management is desirable including developmental and feeding training.

[Clonidine within the scope of balanced inhalation anesthesia with sevoflurane--effects on pEEG parameters]. / Clonidin im Rahmen einer balancierten Inhalationsanästhesie mit Sevofluran--Effekte auf Parameter des pEEG.

The anaesthetic-saving property of clonidine has often been reported. In our own prospective, randomized study, in which the depth of anaesthesia was controlled by using spectral edge frequency (target-SEF90 = 10 Hz) and clinical parameters, we confirmed the anaesthetic-saving property only for fentanyl (-20%). On the other hand, there was no difference in MAC-sevoflurane values between the groups in keeping a steady target-SEF. For this reason, we analysed the stored pEEG data with regard to clonidine-specific effects. Twenty-eight patients were included in our study. The patients were randomly treated preoperatively with an infusion of 4 micrograms/kg KG Clonidine (clonidine group) or a placebo (placebo group). For anaesthesia, a standardized procedure with fentanyl, propofol, rocuronium, N2O/O2/sevoflurane was performed. The depth of anaesthesia was controlled by using SEF90 and clinical parameters. SEF90, SEF50 and the EEG power-spectrum were analysed over a five-minute period in the steady state of anaesthesia without surgical manipulation. Both placebo and the clonidine showed comparable values for SEF90 (9.9 +/- 1 vs. 10.7 +/- 0.9 Hz). On the other hand, there were differences in the SEF50 values between the groups (3.3 +/- 0.7 vs. 6.4 +/- 2.2 Hz). In the clonidine group, relative alpha-power was higher than in the placebo group (36.3 +/- 15.8 vs. 16.8 +/- 8.8%). Parallel to this effect, there was a reduction in relative delta-power in the clonidine group (47.6 +/- 15.2 vs. 65.4 +/- 9.1%). The described EEG effects on the power-spectrum inevitably influence SEF50 and SEF90. In our opinion, SEF50 is not a powerful predictor of depth of anaesthesia, when anaesthesia is performed in the way described. By performing this variation of balanced anaesthesia and co-medication with clonidine, higher values of SEF90 (11-14 Hz) seem to be adequate for surgical manipulation.

[Preoperative clonidine comedication within the scope of balanced inhalation anesthesia with sevoflurane in oral surgery procedures]. / Präoperative Clonidin-Komedikation im Rahmen einer balancierten Inhalationsanästhesie mit Sevofluran bei kieferchirurgischen Operationen.

Both clonidine and sevoflurane are interesting drugs for anaesthesia in maxillo-facial surgery. The present study was performed to discover how far it is possible to combine the benefits of sevoflurane (fast modulation of depth of anaesthesia, rapid emergence and recovery) and clonidine (reduction of perioperative stress response, prophylaxis of postoperative shivering, analgetic, antiemetic and anaesthetic-saving effect) without compromising the pharmacokinetic of sevoflurane. Twenty-eight patients were included in the present double-blinded prospective study. These patients were randomly treated with an infusion of 4 micrograms kg-1 clonidine (group 1) or a placebo (group 2) preoperatively. For anaesthesia a standardized procedure with fentanyl, propofol, rocuronium, N2O/O2/sevoflurane and an antiemetic prophylaxis with DHB was performed. The depth of anaesthesia was controlled by using spectral edge frequency (target--SEF90 = 10 Hz). Perioperative stress response was assessed by noting the effects on haemodynamic parameters (MAP, heart rate), and emergence and recovery were assessed by using established standardized tests. We confirmed the anaesthetic-saving property of clonidine only for fentanyl (-20%). On the other hand, there was no difference in MAC-sevoflurane values between the groups in keeping a steady target--SEF90 (1.62 +/- 0.26 versus 1.65 +/- 0.24 vol.%). The time until emergence and recovery was not significantly different. Even the occurrence of PONV, the VAS level or the postoperative analgesic requirement did not differ in the two groups. However, the incidence of postoperative shivering was significantly higher in the placebo group. The stress response to intubation or extubation was lower in the clonidine group. The haemodynamic parameters in the clonidine group were intraoperatively always below the baseline, in some cases by more than 20%, making therapy for hypotension or bradycardia frequently necessary. Postoperatively, the majority of the patients showed similar changes in these parameters, but did not reach the 20% mark. Preoperative clonidine comedication seems to complicate the management of anaesthesia. On the other hand, it is beneficial during the early postoperative period (e.g. stability in haemodynamics, prophylaxis of shivering) without compromising emergence and recovery. Our results show that therapy with clonidine should be better placed at the end of anaesthesia.

[Remifentanil and alfentanil: Sympathetic-adrenergic effect in the first postoperative phase in patients at cardiovascular risk]. / Remifentanil und Alfentanil: Sympathiko-adrenerge Effekte in der frühen postoperativen Phase beim kardiovaskulären Risikopatienten.

UNLABELLED: Extubation and the immediate postoperative period are critical periods with strong sympatho-adrenergic stimulation. The aim of the present study was to investigate this period after balanced anaesthesia with remifentanil and alfentanil in cardiac risk patients. METHODS: 52 patients with coronary artery disease or with risk factors for coronary heart disease scheduled for elective extraperitoneal and extrathoracic operation were included in this study. Anaesthesia was induced by intravenous administration of etomidate, vecuronium and remifentanil (n = 27, 1 microgram/kg) or alfentanil (n = 25, 25 micrograms/kg). Anaesthesia was maintained with an Isoflurane/N2O/O2 mixture and by continuous intravenous infusion of remifentanil (0.25 microgram/kg/min) or alfentanil (45 micrograms/kg/h). During the first 60 minutes after extubation haemodynamic parameters were monitored and catecholamines were determined at defined time intervals. Parameters of recovery, the requirement of analgesics and cardiac medications were compared in both groups. Myocardial ischaemia was assessed by two-channel Holter electrocardiography. RESULTS: The beginning of spontaneous respiration and time of extubation were similar in both groups. The time interval until opening eyes and the time between the beginning of spontaneous respiration and extubation was shorter in the patients treated with remifentanil. In this group patients suffered earlier from pain and had a higher pain score. Although the plasma catecholamines were comparable in both groups, in the patients treated with remifentanil changes in haemodynamic parameters were more pronounced. The incidence of shivering and the requirements of analgesics and cardiac medications were higher in these patients. The incidence of ST-segment changes indicating myocardial ischaemia was similar. CONCLUSIONS: After balanced anaesthesia with remifentanil a more pronounced sympatho-adrenergic stimulation occurs because of the more rapid clearance of the analgesic effect in the recovery period compared to alfentanil requiring more analgesics and medications for the control of the haemodynamic parameters. Because of these specific pharmacological effects the use of remifentanil in cardiac risk patients has to be critically discussed.