Somatostatin

Anti-diarrhoea1 drugs reduce the symptoms of diarrhoea (loose stool consistency, frequency of defecation and excessive stool weight) by effects on intestinal transit, mucosal transport or luminal contents. Opiates and opioids are the most useful anti-diarrhoea1 agents. Opiates have major effects on intestinal transit : pro-absorptive and anti-secretory effects are less well documented, but may be important for some of these drugs. Alpha-adrenergic agonists, somatostatin analogues and several other agents have had limited clinical use: these drugs may modify mucosal transport in addition to slowing transit. Adsorbents, bismuth and stool texture modifiers are used frequently by the public, but their efficacy is largely unproven. Oral rehydration solutions have had the greatest impact in saving lives and continue to be improved. Many new approaches to the treatment of diarrhoea are yet to be exploited.

Patients and Methods Cirrhotic patients with acute esophageal variceal bleeding that was initially controlled with emergency sclerotherapy and in whom a hemodynamic evaluation could be performed within the first 24 hours of admission, were considered for inclusion in this study. All patients were admitted to our hospital with hematemesis and/or melena. Diagnostic endoscopy was performed between 1 and 5 hours later, as soon as safely possible after initial resuscitation. Variceal hemorrhage was defined when endoscopy showed active hemorrhage

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/ cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the reninangiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower renal retention may be developed. Furthermore, knowledge on kidney protection from radiolabelled somatostatin analogues may be expanded to other peptides.

Chelated somatostatin agonists have been shown to be sensitive to N-terminal radiometal modifications, with Ga-DOTA agonists having significantly higher binding affinity than their Lu-, In-, and Y-DOTA correlates. Recently, somatostatin antagonists have been successfully developed as alternative tracers to agonists. The aim of this study was to evaluate whether chelated somatostatin antagonists are also sensitive to radiometal modifications and how. We have synthesized 3 different somatostatin antagonists, DOTA-p-NO 2-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH 2 , DOTA-Cpa-c[D-Cys-Aph (Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH 2 (DOTA-JR11), and DOTA-p-Cl-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH 2 , and added various radiometals including In(III), Y(III), Lu (III), Cu(II), and Ga(III). We also replaced DOTA with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and added Ga(III). The binding affinity of somatostatin receptors 1 through 5 was evaluated in all cases. In all 3 resulting antagonists, the Ga-DOTA analogs were the lowest-affinity radioligands, with a somatostatin receptor 2 binding affinity up to 60 times lower than the respective Y-DOTA, Lu-DOTA, or In-DOTA compounds. Interestingly, however, substitution of DOTA by the NODAGA chelator was able to increase massively its binding affinity in contrast to the Ga-DOTA analog. The 3 NODAGA analogs are antagonists in functional tests. In vivo biodistribution studies comparing 68 Ga-DOTATATE agonist with 68 Ga-DOTA-JR11 and 68 Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that 68 Ga-NODAGA-JR11 was the tracer of choice and preferable to 68 Ga-DOTA-JR11 in transplantable HEK293-hsst 2 tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a 68 Ga-NODAGA chelator-radiometal complex.

In the literature, neuropeptide Y (NPY) has been described in the brain and peripheral nerves. More recently, it has also been detected in endocrine cells of hamster, embryonic mouse, and rat pancreas. However, the presence of NPY in avian embryos and the possible colocalization of this peptide with the other pancreatic hormones have not been reported previously. In this study, NPY presence was studied by immunocytochemical methods in the endocrine pancreas of domestic duck during pre-and postnatal development. NPY immunoreactivity (IR) was detected in embryos and adult animals. Around hatching the intensity of IR in endocrine cells decreased. Double immunohistochemical staining revealed that: 1) NPY-IR is extensively colocalized in small and mixed islets with insulin-IR both in embryos and in adults; and 2) in early embryos NPY-IR occasionally colocalized with glucagon and somatostatin. In early embryos, the colocalization of NPY-IR with several pancreatic hormones could be related to the presence of multihormonal progenitor cells. The close relation between insulin and NPY, both in embryos and adults, led us to hypothesize a key role for NPY on insulin cells of duck pancreas. Anat Rec 259: 35-40, 2000.

The use of somatostatin analogues for the treatment of acromegaly is now well established. Recently long-acting preparations of octreotide and lanreotide have been introduced. In this study we have assessed the efficacy and tolerability of the long acting somatostatin analogue octreotide LAR in patients with acromegaly, and compared it with lanreotide SR. Five patients with active acromegaly were recruited; they were treated with lanreotide SR for 6 months and then, following a wash-out period, received octreotide LAR for 6 months. They were assessed at baseline, 3- and 6-months, by clinical score, GH and IGF1. Adverse effects were carefully monitored. Both treatments effectively reduced GH and IGF1 levels. Four of five patients achieved a mean GH level of <2.5 ng/ ml with both drugs; with octreotide LAR only, these patients also had GH <1 ng/ml after oral glucose loading. The clinical symptoms score improved significantly with octreotide LAR, as did the ring size; the clinical score correlated significantly with GH. Blood glucose was not adversely affected. All patients experienced minor GI symptoms with lanreotide SR, but less frequently with octreotide LAR. Both drugs caused biliary stasis and had a tendency to form biliary sludge. Octreotide LAR proved effective for the treatment of acromegaly and was well tolerated. Octreotide LAR had some advantages over lanreotide SR, although the differences were not great.

Lanreotide, a synthetic, therapeutic octapeptide analog of somatostatin, self-assembles in water into perfectly hollow and monodisperse (24-nm wide) nanotubes. Lanreotide is a cyclic octapeptide that contains three aromatic residues. The molecular packing of the peptide in the walls of a nanotube has recently been characterized, indicating four hierarchical levels of organization. This is a fascinating example of spontaneous self-organization, very similar to the formation of the gas vesicle walls of Halobacterium halobium. However, this unique peptide self-assembly raises important questions about its molecular origin. We adopted a directed mutation approach to determine the molecular parameters driving the formation of such a remarkable peptide architecture. We have modified the conformation by opening the cycle and by changing the conformation of a Lys residue, and we have also mutated the aromatic side chains of the peptide. We show that three parameters are essential for the formation of lanreotide nanotubes: i), the specificity of two of the three aromatic side chains, ii), the spatial arrangement of the hydrophilic and hydrophobic residues, and iii), the aromatic side chain in the b-turn of the molecule. When these molecular characteristics are modified, either the peptides lose their self-assembling capability or they form less-ordered architectures, such as amyloid fibers and curved lamellae. Thus we have determined key elements of the molecular origins of lanreotide nanotube formation.

Nanofabrication by molecular self-assembly involves the design of molecules and self-assembly strategies so that shape and chemical complementarities drive the units to organize spontaneously into the desired structures. The power of self-assembly makes it the ubiquitous strategy of living organized matter and provides a powerful tool to chemists. However, a challenging issue in the self-assembly of complex supramolecular structures is to understand how kinetically efficient pathways emerge from the multitude of possible transition states and routes. Unfortunately, very few systems provide an intelligible structure and formation mechanism on which new models can be developed. Here, we elucidate the molecular and supramolecular self-assembly mechanism of synthetic octapeptide into nanotubes in equilibrium conditions. Their complex hierarchical self-assembly has recently been described at the mesoscopic level, and we show now that this system uniquely exhibits three assembly stages and three intermediates: (i) a peptide dimer is evidenced by both analytical centrifugation and NMR translational diffusion experiments; (ii) an open ribbon and (iii) an unstable helical ribbon are both visualized by transmission electron microscopy and characterized by small angle X-ray scattering. Interestingly, the structural features of two stable intermediates are related to the final nanotube organization as they set, respectively, the nanotube wall thickness and the final wall curvature radius. We propose that a specific self-assembly pathway is selected by the existence of such preorganized and stable intermediates so that a unique final molecular organization is kinetically favored. Our findings suggests that the rational design of oligopeptides can encode both molecular-and macro-scale morphological characteristics of their higherorder assemblies, thus opening the way to ultrahigh resolution peptide scaffold engineering.

Previous investigations of centrally administered somatostatin (SRIF) have tended to employ pharmacological (nmol and greater) doses of the peptide. Under this protocol contradictory findings of feeding effects have been reported. There is evidence that the use of physiological doses can induce a completely distinct response from that obtained with pharmacological doses. In order to discern whether physiological doses of centrally administered somatostatin have any effect on feeding, SRIF in doses ranging from 0.4 pmol to 3 nmol were administered into the lateral ventricles of rats. Low pmol doses (0.4-40) administered during the light photoperiod increased 1 h feeding whereas 3 nmol decreased 1 h feeding. None of the doses tested during the dark photoperiod significantly altered 1 h food intake. Similarly, no significant change in 24-h food intake was observed following injections of any of the doses tested, whether in the light or dark. A dose of SRIF that increased feeding (1 pmol) did not significantly alter 1 h water intake when applied centrally in the light nor did it alter spontaneous locomotor activity. Furthermore, when applied peripherally it did not change 1 h food intake. These studies suggest that SRIF may work centrally to regulate food intake. A similarity exists between SRIF's feeding effects and the feeding effects we have previously described following central injections of growth hormone-releasing factor (GRF), both in terms of dose-response and photosensitivity. This suggests that these 2 peptides may act via a common mechanism to regulate food consumption; possibly in coordination with their regulation of growth hormone release. The possibility that such feeding regulation occurs as part of a short intrahypothalamic feedback loop is discussed.

Background: The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated 68 Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. Methods: We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age = 54.3 years, median = 59 years, range = 19-78 years). In all patients, [ 18 F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and 68 Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with 111 In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq 90 Y-DOTATOC/administration. Serial 68 Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by 68 Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. Results: 68 Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by 68 Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT ( p = 0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. Conclusions: In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. 68 Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role.

In-pentetreotide. Forty-five patients were evaluated for carcinoid, 15 for islet cell tumour, seven for metastatic NE tumour, four for medullary thyroid carcinoma, and one patient had ophthalmopathy. SPECT/CT induced improvement in the interpretation of SPECT and conventional CT and resultant clinical management changes were recorded.

Thyroid eye disease (TED) is the most frequent extrathyroidal manifestation of Graves&amp;amp;amp;amp;amp;amp;amp;#39; disease. In most instances it is mild and non-progressive, but in 3%-5% of cases it is severe. Non-severe TED requires only supportive measures, such as eye ointments, sunglasses and prisms. By contrast, severe TED requires aggressive treatment, either medical (high-dose glucocorticoids, orbital radiotherapy) or surgical (orbital decompression). The choice of treatment relies on the assessment of both TED severity and activity. Removal of controllable risk factors, especially cigarette smoking, is important to improve the course and the therapeutic outcome. A coordinated approach to the treatment of hyperthyroidism and TED is also required. Novel promising treatments, to be verified in large series of patients, include somatostatin analogues and cytokine antagonists.

Introduction Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy.

Cerebrospinal fluid-contacting (CSF-c) neurons line the central canal of the spinal cord and a subtype of CSF-c neurons expressing somatostatin, forms a homeostatic pH regulating system. Despite their importance, their intricate spatial organization is poorly understood. The function of another subtype of CSF-c neurons expressing dopamine is also investigated. Imaging methods with a high spatial resolution (5–10 nm) are used to resolve the synaptic and ciliary compartments of each individual cell in the spinal cord of the lamprey to elucidate their signalling pathways and to dissect the cellular organization. Here, light-sheet and expansion microscopy resolved the persistent ventral and lateral organization of dopamine- and somatostatin-expressing CSF-c neuronal subtypes. The density of somatostatin-containing dense-core vesicles, resolved by stimulated emission depletion microscopy, was shown to be markedly reduced upon each exposure to either alkaline or acidic pH and being part o...

The formation and recall of sensory, motor, and cognitive representations require coordinated fast communication among multiple cortical areas. Interareal projections are mainly mediated by glutamatergic pyramidal cell projections; only few long-range GABAergic connections have been reported. Using in vivo recording and labeling of single cells and retrograde axonal tracing, we demonstrate novel long-range GABAergic projection neurons in the rat hippocampus: (1) somatostatin- and predominantly mGluR1alpha-positive neurons in stratum oriens project to the subiculum, other cortical areas, and the medial septum; (2) neurons in stratum oriens, including somatostatin-negative ones; and (3) trilaminar cells project to the subiculum and/or other cortical areas but not the septum. These three populations strongly increase their firing during sharp wave-associated ripple oscillations, communicating this network state to the septotemporal system. Finally, a large population of somatostatin-ne...

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with 111 In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and g-emitter 111 In-diethylenetriaminepenta-acetic acid (DTPA) 0 ,octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with 90 Y, a pure b-emitter, 90 Y-1,4,7,10-tetraazacyclododecane-N,N 0 ,N 00 ,N 000 -tetraacetic acid (DOTA) 0 ,Tyr 3 ,octreotide ( 90 Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. 111 In-and 90 Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with 177 Lu-DOTA 0 ,Tyr 3 octreotate ( 177 Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both 90 Y-DOTATOC and 177 Lu-DOTA 0 ,Tyr 3 octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on 111 In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours.

Recent research has shown that in the chicken important interactions take place between the adrenal and the thyroidal axis both at the central and the peripheral level. In vivo as well as in vitro experiments showed that ovine corticotropin-releasing hormone (oCRH) clearly increases thyrotropin (TSH) secretion in late embryonic and early posthatch chicks. In vivo experiments in older chickens, however, suggested that this response might disappear at a later stage. Therefore we started to study in detail the ontogeny of the TSH releasing activity of oCRH using the in vitro perifusion technique. Several embryonic stages (E14, E16, and E18) as well as posthatch stages (C1, C8, C22, and adult chickens) were included in the study. We also investigated the possible regulatory role of somatostatin (SRIH) in this specific endocrine function of CRH. The perifusion studies show that CRH stimulated the TSH release at all stages tested. The 10 and 100 nM oCRH doses were almost equally effective at the early embryonic stages while in most posthatch stages the higher oCRH dose was significantly more effective than the lower one. The stimulation factor, representative for the relative increase in TSH secretion following oCRH challenge, was high at early embryonic stages and clearly lower in adult animals. This seemed to be related to an age-dependent increase in basal TSH secretion levels. In both embryonic (E19) and posthatch (C8) chicks a pretreatment of the pituitaries with SRIH lowered the sensitivity of the thyrotropes to an oCRH challenge. This effect was more pronounced in the posthatch chicks compared to the embryos. The results show that CRH is capable of stimulating the TSH secretion during the entire life cycle of the chicken and that SRIH may play an important role in the fine-tuning of this response by lowering the sensitivity of the thyrotropes to CRH.

The number of G cells and D cells per area unit and the G cell/D cell ratio was studied in control subjects and patients with duodenal or gastric ulcer. A great inter-individual variation in the population density of both types of cells was observed in the three groups studied. G cell density was significantly decreased in both duodenal and gastric ulcer patients, when compared with controls; whereas no difference in G cell density was seen between duodenal ulcer patients and gastric ulcer patients. However, D cell density was significantly decreased in duodenal ulcer patients when compared with control subjects and gastric ulcer patients. In this latter group, D cell density was also lower than in control subjects. A significant positive linear correlation between G cell number and D cell number was found in the three groups studied. The G cell/D cell ratio was significantly increased in duodenal and gastric ulcer patients when compared with controls. This was mainly due to a decrease in D cell numbers. It is concluded that a local deficit in antral D cells in patients with peptic ulcer may favor the pathogenesis of ulcer disease.

Although urotensin II (UII) and somatostatin 1 (SS1) exhibit some structural similarities, their precursors do not show any appreciable sequence identity and, thus, it is widely accepted that the UII and SS1 genes do not derive from a common ancestral gene. The recent characterization of novel isoforms of these two peptides, namely urotensin II-related peptide (URP) and somatostatin 2 (SS2)͞ cortistatin (CST), provides new opportunity to revisit the phylogenetic relationships of UII and SS1 using a comparative genomics approach. In the present study, by radiation hybrid mapping and in silico sequence analysis, we have determined the chromosomal localization of the genes encoding UII-and somatostatin-related peptides in several vertebrate species, including human, chicken, and zebrafish. In most of the species investigated, the UII and URP genes are closely linked to the SS2͞CST and SS1 genes, respectively. We also found that the UII-SS2͞CST locus and the URP͞SS1 locus are paralogous. Taken together, these data indicate that the UII and URP genes, on the one hand, and the SS1 and SS2͞CST genes, on the other hand, arose through a segmental duplication of two ancestral genes that were already physically linked to each other. Our results also suggest that these two genes arose themselves through a tandem duplication of a single ancestral gene. It thus appears that the genes encoding UII-and somatostatinrelated peptides belong to the same superfamily.

Enteric neurons are highly adaptive in their response to various pathological processes including in£ammation, so the aim of this study was to describe the chemical coding of neurons in the ileal intramural ganglia in porcine proliferative enteropathy (PPE). Accordingly, juvenile LargeWhite Polish pigs with clinically diagnosed Lawsonia intracellularis infection (PPE; n ¼ 3) and a group of uninfected controls (C; n ¼ 3) were studied. Ileal tissue from each animal was processed for dual-labelling immuno£uorescence using antiserum speci¢c for protein gene product 9.5 (PGP 9.5) in combination with antiserum to one of: vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SOM), neuropeptideY (NPY) or galanin (GAL). In infected pigs, enteric neurons were found in ganglia located within three intramural plexuses: inner submucosal (ISP), outer submucosal (OSP) and myenteric (MP). Immuno£uorescence labelling revealed increases in the number of neurons containing GAL, SOM,VIP and CGRP in pigs with PPE. Neuropeptides may therefore have an important role in the function of porcine enteric local nerve circuits under pathological conditions, when the nervous system is stressed, challenged or a¥icted by disease such as PPE. However, further studies are required to determine the exact physiological relevance of the observed adaptive changes. r

The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural alpha- and beta-amino acids. The N- fluorenylmethoxycarbonyl protected cyclic beta-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cbetaAA), for the replacement of the Phe(6)-Pro(1) moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] with the structure of l-363,301, a nearly perfect match of the betaII&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-turn region with d-Trp in the i + 1 position was observed. The cyclic beta-amino acid cbetaAA is likely needed for the bioactive conformation of the peptide.

The various types of striatal projection neurons and interneurons show a differential pattern of loss in Huntington's disease (HD). Since striatal injury has been suggested to involve similar mechanisms in transient global brain ischemia and HD, we examined the possibility that the patterns of survival for striatal neurons after transient global ischemic damage to the striatum in rats resemble that in HD. The perikarya of specific types of striatal interneurons were identified by histochemical or immunohistochemical labeling while projection neuron abundance was assessed by cresyl violet staining. Projection neuron survival was assessed by neurotransmitter immunolabeling of their efferent fibers in striatal target areas. The relative survival of neuron types was determined quantitatively within the region of ischemic damage, and the degree of fiber loss in striatal target areas was quantified by computer-assisted image analysis. We found that NAD-PHd ؉ and cholinergic interneurons were largely unaffected, even in the striatal area of maximal damage. Parvalbumin interneurons, however, were as vulnerable as projection neurons. Among immunolabeled striatal projection systems, striatoentopeduncular fibers survived global ischemia better than did striatopallidal or striatonigral fibers. The order of vulnerability observed in this study among the striatal projection systems, and the resistance to damage shown by NADPHd ؉ and cholinergic interneurons, is similar to that reported in HD. The high vulnerability of projection neurons and parvalbumin interneurons to global ischemia also resembles that seen in HD. Our results thus indicate that global ischemic damage to striatum in rat closely mimics HD in its neuronal selectivity, which supports the notion that the mechanisms of injury may be similar in both.

Excitatory amino acids have been implicated in ischemic neuronal injury. T o test this hypothesis in neonatal hypoxiaischemia, lesions of the cortex and striatum were induced in 7-day-old rats by unilaterally ligating their carotid arteries and subjecting them to hypoxic conditions for 2 hours. Brains examined 1 week later demonstrated, within the regions of ischemic damage, a striking preservation of neurons that stained histochemically for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity. Concentrations of the neuropeptides somatostatin and neuropeptide Y, which colocalize in neurons containing NADPH-d, were unaffected in the areas of ischemic damage. The same pattern of injury with sparing of NADPH-d-reactive neurons was reproduced by focal microinfusion of the excitotoxin quinolinic acid, an endogenous N-rnethyl-d-aspartate (NMDA) agonist, into the striatum. These results support the hypothesis that neonatal hypoxic-ischemic injury is mediated through excitatory transmitters acting at the NMDA receptor and that the NADPH-d-reactive neurons in the neonate are resistant to excitotoxic damage. This pattern of cell vulnerability is unique to the developing striatum and may relate to the distinct pathological appearance of the basal ganglia that follows neonatal asphyxia.

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography

Abstract: This study was primarily conducted to investigate influencing factors for insurance companies specifically for private insurance operating in Ethiopia. To attain the objective both industry-specific and macro-economic factors include the ratio of liquidity, leverage, the volume of capital, age of the insurance, underwriting risk, premium growth, market share,  inflation, and economic growth. The study included ten insurance companies with operations from 2011 to 2020. Secondary data was collected from the Ethiopian central bank (National Bank of Ethiopia). An explanatory research design with a mixed approach was used for this study. Furthermore, this study employed OLS to estimate a multiple regression model constructed through E-views 10 software after all the necessary diagnostic tests were undertaken. The finding indicates liquidity, firm premium growth, the age of the company, and market share have significant positive effects on insurance profitability. Whereas,  underwriting risk, leverage, the volume of capital, and inflation reveal significant but adverse effects on insurance profitability.  The study suggests insurances companies adopt different techniques such as improving loss handling mechanisms, assessing
and gathering adequate information about the insured before selection, and marketing managers should pay a great deal of  attention to maximizing market share through the use of user-friendly information technology for both the insurance and it is
customers.
Keywords: Profitability, Private Insurance Company, Panel, Ethiopia

The aim of this review is to summarize the developments and briefly characterize the somatostatin analogs which are currently used for somatostatin receptor imaging in clinical routine or in early phase clinical trials. Somatostatin (sst) receptor targeting with radiolabeled peptides has become an integral part in nuclear oncology during the last 20 years. This integration process has been initiated in Europe with the introduction to the market of 111In-DTPA-DPhe1-octreotide [111In-pentetreotide]. Introducing 99mTc in somatostatin receptor targeting radiopeptides resulted in much better image quality, higher sensitivity of tumor detection and lower mean effective dose for the examined patient. The next generation are 68Ga labeled somatostatin analogs. Due to the spatial resolution of PET technique and increasing number of PET scanners, the PET or PET/CT technique became very important in somatostatin receptor imaging. Until up to a couple of years ago the analogs of somatostatin wer...

A szerzők súlyos hypercortisolismussal, hypokalaemiával, diabetes mellitusszal és osteoporosissal járó ectopiás ACTHszindrómás esetüket ismertetik. Az ACTH-elválasztó tumorszövet a tüdőben helyezkedett el, amelynek szegmentális eltávolítását követő szövettani vizsgálat ACTH-termelő neuroendokrin daganatot igazolt. Az első műtétet követően a plazmakortizol-és -ACTH-szintek nem csökkentek szignifi kánsan, ennek hátterében a tumor szubtotális eltávolítása állt. Tartós hatású szomatosztatinanalóg-terápia bevezetését követően mind a kortizol-, mind az ACTH-szintek számottevően csökkentek, és a beteg általános állapota szignifi kánsan javult. Reoperációt követően a beteg véglegesen meggyógyult és jelenleg is panasz-és tünetmentes. Orv. Hetil., 2011, 152, 403-406. Kulcsszavak: ectopiás ACTH-szindróma, hypokalaemia, szomatosztatin, tüdő neuroendokrin daganat

It is common to describe the endocrine and the exocrine pancreas as if they were two distinct and independent entities. However the pancreas is an integrated organ involved in the digestion and absorption of nutrients on the one hand, and in the regulation of blood glucose homeostasis, on the other. Most probably, the unique anatomical architecture of this organ, characterized by the dispersion of the endocrine component throughout the acinar parenchyma as hun-dreds of thousands variable-sized clusters of endocrine cells (islets of Langerhans), has evolved to facilitate interactions between the two glandular components . In order to determine reciprocal influences, many aspects of the relations occurring between exocrine and endocrine pancreas have been investigated in the past three decades . Because of the observation that, in contrast to ªtele-insularº acini, ªperiinsularº acini are formed by larger cells, containing more zymogen granules [2, 4±6], numerous studies have addressed the role(s) played by the islet hormones in tuning acinar cell secretion and the anatomical pathways, the so called ªislet-acinar axisª, through which this influence is exerted . A large body of evidence indicates that a continuous insulo-acinar venous portal system conveys hormone enriched blood from the islets to the acinar parenchyma . The amount of acinar tissue that is ac-Diabetologia (2001) 44: 575±584 Abstract Aims/hypothesis. Studies on the functional and morphological relations between exocrine and endocrine pancreas have been conducted mainly to disclose the influence of islets of Langerhans on acinar parenchyma. Less attention has been paid to the relations occurring between islets and pancreatic ducts. Methods. A series of consecutive sections of normal adult rat pancreas were double stained with islet (hormones) and duct (cytokeratin 20) markers. Electron microscopy was conducted to investigate the ultrastructural features of duct-islet relations and anti-insulin immunogold labelling was carried out to reveal the presence of insulin in the pancreatic duct system. Results. Consecutive double-stained sections demonstrated that 73.60 2.97 % of the islets were attached to the ducts. For each series, 93.48 5.43 % of the islets contacting the duct tree were associated with small-sized ducts or centroacinar cells. Electron microscopy revealed that some insulin and somatostatin cells do face the duct lumen. Insulin was detected within the duct lumen and in the endosomal compartment of the duct cells. Conclusions/interpretation. The finding that most islets are connected with the duct system in the adult pancreas is discussed in terms of hormone secretion into the ducts, islet histogenesis and the relation among the three tissue components of the pancreas, the endocrine, the exocrine and the duct system. [Diabetologia (2001) 44: 575±584]

Gonadal sex steroids modulate GH synthesis and secretion with effects on both the hypothalamus and anterior pituitary. In the post-pubertal animal, androgens and oestrogens modulate hypothalamic somatostatin (SS) and GHRH synthesis respectively. These effects may be direct as SS neurons express the androgen receptor and many GHRH neurons are oestrogen receptor positive. The neonatal steroid environment modulates the number of GHRH neurons in the adult hypothalamus, as well as their responsivity to post-pubertal steroids. Furthermore, both neonatal and post-pubertal steroids modulate hypothalamic synaptic organisation affecting the number of synaptic inputs and the morphology of glial cells. This in turn has important effects on the ability of the hypothalamus to drive the secretory pulsatility of anterior pituitary hormone release. At the level of the somatotroph, androgens and oestrogens have been reported to stimulate, inhibit or have no effect on GH synthesis. In primary cultures, we found no effect of either androgens or oestrogens on GH mRNA levels. However, the sex steroid environment significantly modified the response of somatotrophs to SS. Furthermore, males have more somatotrophs compared with female rats and this partially depends on the neonatal sex steroid environment. In conclusion, sex steroids have both organisational and activational effects on the GH axis. These effects range from modulating the number of hypothalamic neurons controlling GH secretion, their responsiveness to later steroids, and the synaptic connectivity and neuropeptide production, to modulation of somatotroph numbers in the anterior pituitary and their responsiveness to inputs controlling GH synthesis and secretion.