Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats

Melanotan-II (MT-II), a cyclic heptapeptide, is a potent, non-selective melanocortinergic agonist. When administered centrally or systemically, MT-II elicited a profound inhibitory effect on food intake in rodents, presumably via activation of melanocortin-4-receptor (MC4R). In this study, we sought to investigate whether penetration of MT-II and iodo-MT-II into brain parenchyma is required for the anorectic effect following intravenous (IV) administration. Firstly, both MT-II and iodo-MT-II were effective at suppressing appetite in rats following their IV administration. We next surveyed by in vitro autoradiographic studies the distribution of selective (125)I-MT-II binding sites in multiple brain regions including areas important for feeding regulation such as the hypothalamus and caudal brainstem. Upon IV administration of (125)I-MT-II, significant radioactivity could not be detected in various brain regions by autoradiography except for a group of circumventricular organs (CVOs), which are anatomically situated outside the blood-brain barrier (BBB). The most intensely labeled CVOs include the subfornical organ, median eminence, area postrema and choroid plexus, and accumulation of radioactivity at these sites can be blocked by co-injection of excess unlabeled MT-II. Direct measurement of MT-II in the brain and plasma by LC-MS-MS following IV injection confirmed that the degree of MT-II penetration into the brain is negligible. Furthermore, when given peripherally under conditions that suppressed food intake, MT-II did not result in a detectable induction of c-Fos-like immunoreactivity in brain regions where a significantly elevated c-Fos expression was observed following intracerebroventricular injection of this peptide. Our results indicate that MT-II has a very limited brain penetration capability, and its effect on feeding behavior following systemic administration may be mediated by either the brain regions in close proximity to the CVOs or sites outside of the BBB, including CVOs or other peripheral systems.     

Conformational diversity of T-kinin in DMSO, water and HFA

T-kinin (Ile-Ser-BK) is related to BK in its biological profile, but unlike BK, is more resistant to the action of ACE. A detailed NMR and molecular modeling study of T-kinin has been carried out in three diverse media: water (pH 4.0), DMSO-d(6) and HFA solution. In DMSO-d(6), T-kinin adopts a structure with two tandem beta-turns: the first at the mid segment tetrad Pro(4)-Pro(5)-Gly(6)-Phe(7) (type I) and the C-terminal end Ser(8)-Pro(9)-Phe(10)-Arg(11) harbors the second turn (also type I). While the first beta-turn is lost in presence of water, the second persists. In HFA, NMR reveals a alpha-helix like structure spanning residues Arg(3) to Arg(11). Structures with cis peptide bonds (XX-Pro) have been observed for T-kinin in DMSO-d(6) but not in water and HFA. Differences in the structures of BK and T-kinin in water may explain their susceptibility/resistance to the action of ACE.     

What factors predetermine the risk of having a high-order multiple pregnancy with gamete intra-Fallopian transfer?

Limiting the number of oocytes transferred at gamete intra-Fallopiantransfer (GIFT) has limited the incidence of high-order pregnancybut at the same time compromised the fertility potential ofsome patients. A review of 300 patients who have undergone GIFTusing a flexible approach as to the number of oocytes transferredidentifies the patients at risk of high-order pregnancy as thoseaged under 30 years hi whom more than six oocytes are returnedand whose partner's spermatozoa have high progressive motUity.     

Sedative drug requirements during bronchoscopy are higher in cystic fibrosis after lung transplantation

BACKGROUND: We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronchoscopy. We undertook this study to assess the sedative drug doses administered during bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation. METHODS: In all, 773 transbronchial biopsy procedures performed via flexible bronchoscopy were analyzed in 140 consecutive lung transplant recipients. Conscious sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam doses of 0.20 to 0.25 mg/kg and fentanyl 2 to 2.5 micrograms/kg. RESULTS: Mean doses of midazolam and fentanyl administered were 0.15+/-0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8+/-0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. Midazolam and fentanyl doses administered to patients with cystic fibrosis were the highest compared to those with other disease types (P<0.0001). Examining the sedative doses administered over time following transplantation, there was a significant linear (P<0.001) and quadratic (P=0.0023) effect of time for midazolam and a significant linear (P=0.003) and a trend (P=0.08) for a quadratic effect for fentanyl. Propofol was effectively used in seven lung transplant recipients in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl. CONCLUSIONS: There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with cystic fibrosis.     

Non malignant tracheo-esophageal fistula: Our experience

Background Non malignant tracheo-esophageal fistula is a rare entity, which is usually post traumatic, post inflammatory or could be a delayed presentation of congenital tracheo-esophageal fistula. Patients and Methods In this retrospective study of seven cases, we aim to document and evaluate the causes, presentation and treatment modalities. Results All the cases underwent surgical intervention, with single stage definitive repair in four cases and two stage repair in three cases. There was no mortality, and minimal morbidity. Conclusions Being a benign disease with fatal complications, early diagnosis and early surgical intervention is the key to successful management of non-malignant tracheo-esophageal fistula.     

Cryptococcal fungemia in a neutropenic patient with AIDS while receiving caspofungin

Empiric choice of anti-fungal therapy in febrile neutropenia should be based upon a host's susceptibility to specific fungal pathogens. We present a case of a patient with multiple risk factors for fungemia including HIV infection, Hodgkin's disease, corticosteroid use and chemotherapy-induced neutropenia who developed disseminated cryptococcal infection while receiving caspofungin.     

Novel Mannich ketones of oxazolidinones as antibacterial agents

A few Mannich ketones of piperazinyl oxazolidinone derivatives have been synthesized and their antibacterial activity in various Gram-positive organisms such as Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis were evaluated by MIC determination. Compound 12 showed comparable activity (MIC) to linezolid and superior to eperezolid.     

Identification and quantification of antigens associated with HLA class I molecules on a bladder tumour cell line. Implications for vaccine design

The aim of this study was to isolate and identify antigenic peptides associated with HLA class I molecules on a bladder tumour cell line. HLA-A1 molecules were purified using an immunobead-purification technique and following elution of nonapeptides associated with the complex, their HPLC profile was determined by Tandem mass spectrometry (MS/MS). Three peptides were identified namely: (1) P991 (VTDPGNLLY); (2) P1041.5 (LTDLGFLVY), and (3) P1057.7 (LTDPHLLSY); these sequences matched elements of hepatitis B, MAGE1-A1 and herpes simplex viruses. These antigens had half-lives of approximately 120 min which is within the theoretical range of such short peptides. These results indicate that identification of MHC-associated peptides is possible without using an assay for cytotoxic T cells. Although this approach was applied on a relatively small scale, broader applications can be foreseen.