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To assess whether the type of surgical approach to the sella (sublabial transseptal vs transnasal) affects surgical outcome among patients with Cushing disease.Both procedures were performed at our institution from January 1, 1995, through January 31, 2003. From a total of 106 patients with Cushing disease who had had surgery, we identified 42 adults undergoing an initial surgery, with microadenoma (1 cm) determined by magnetic resonance imaging and a minimal follow-up of 3 months.We identified 21 patients (4 male, 17 female) for sublabial transseptal transsphenoidal microsurgery. Mean+/-SD age was 45.0+/-12.9 years (range, 27.0-69.0 years); median duration of symptoms was 2.5 years (range, 1.5-7.5 years). Median follow-up was 1.0 year (range, 0.3-11.0 years). We identified another 21 patients (5 male, 16 female) for endoscopic transsphenoidal microsurgery whose mean+/-SD age was 43.8+/-14.1 years (range, 19.0-70.0 years); median duration of symptoms was 2.4 years (range, 0.2-6.0 years). Median follow-up was 2.5 years (range, 0.3-8.7 years). Complications (cerebrospinal fluid leak and transient diabetes insipidus) and cure (86% initial cure; 76% relapse-included cure) were equivalent between the 2 procedures. However, the endoscopic approach was associated with shorter anesthesia time, less blood loss, and shorter hospital stays.The endoscopic transnasal surgical approach led to shorter total anesthesia time, less blood loss, and shorter hospital stay when compared with the sublabial transseptal approach. However, we found no difference between the 2 surgical procedures with respect to cure or complications, suggesting that outcome is more closely related to the experience of the operating team.

Nichtkovalente Wechselwirkungen werden bisweilen als additiv behandelt. Mit diesem Verfahren lassen sich brauchbare mittlere Bindungsenergien fur typische Wechselwirkungen in wassriger Losung ableiten, der Ansatz scheitert jedoch in vielen Fallen, da sich nichtkovalente Wechselwirkungen oft gegenseitig verstarken (positiv kooperativ sind) oder abschwachen (negativ kooperativ sind). Bindungsenergie wird gewonnen, wenn ein Ligand die innere Beweglichkeit seines Rezeptors einschrankt (positiv kooperative Bindung). Auf ahnliche Weise wird bei enzymatisch katalysierten Reaktionen Energie fur die Bindung des Ubergangszustands gewonnen, wenn das Substrat im Ubergangszustand innere Bewegungen des Enzyms einschrankt. Liganden und Substrate erhohen auf diese Weise ihre Affinitaten fur Proteine. Diese Organisation geht einher mit einem Gewinn an Bindungsenthalpie und einer Einschrankung der Dynamik (einem Entropieaufwand), erfordert aber nicht, dass neue nichtkovalente Wechselwirkungen entstehen, sondern lediglich, dass die bereits existierenden Wechselwirkungen gestarkt werden. Negativ kooperative Effekte wirken sich umgekehrt aus: Die Packungsdichte wird verringert, und Enthalpie wird aufgewendet, wahrend Entropie gewonnen wird.

Die letzte Verteidigungslinie gegen „Superbakterien” bilden die Antibiotica der Vancomycin-Gruppe. Wie aus der umfassenden Aufklarung des Wirkungsmechanismus der Antibiotica und eines Resistenzmechanismus gegen diese Wirkstoffe hevorgeht, kann diese Form der Resistenz uberwunden werden, ohne die Bindungsstelle des Antibioticums fur die Zellwandvorstufen pathogener Bakterien direkt zu modifizieren.

Background: The emergence of bacteria that are resistant to vancomycin, the drug of choice against methicillin-resistant Staphylococcus aureus , has made the study of the binding characteristics of glycopeptides to biologically relevant depsipeptides important. These depsipeptides, terminating in -d-alanyl-d-lactate, mimic the cell-wall precursors of resistant bacteria. Results: The use of 19 F-labelled ligands in the study of the therapeutically important vancomycin series of antibiotics is demonstrated. The substantial simplification of spectra that occurs when such labelled ligands are employed is used in the measurement of binding affinities of depsipeptides to chloroeremomycin (CE). Large enhancements of binding affinities are found at a model bacterial cell-wall surface (constituted from depsipetides that are anchored into vesicles) relative to those measured in free solution. Conclusions: Surface-enhanced binding, previously shown for strongly dimerising glycopeptide antibiotics to normal -d-alanyl-d-alanine-terminating cell-wall precursors, is now demonstrated for CE to the surface of models of VanA- and VanB-resistant bacteria. The effect of depsipeptide chain length is shown to be critically important in producing and maximising this enhancement.

Two patients with spine disease were unable to tolerate supine placement for magnetic resonance imaging (MRI) because of severe back pain. General anesthesia was administered to enable the patients to undergo MRI. Both patients awakened from anesthesia with new-onset paraplegia and underwent emergency decompressive laminectomy. Acute paraplegia after anesthesia occurs infrequently and is most commonly associated with mechanical injury, vascular compromise, or anesthetic technique. The physical limitations of the MRI environment make it difficult to position some patients in a manner that accommodates their pathophysiology and may place certain patients at risk of neurologic compromise. For this subset of patients, the necessity of MRI with general anesthesia should be reassessed and alternative imaging methods considered.

Two kaurene glycostdes have been isolated from the dried leaves of the shrub Cestrum parqui, a common weed in parts of South America and Australia, and their structures determined by modern NMR and mass spectrometry techniques. These compounds, named carboxyparquin and parquin, differ only by one carboxylic acid group at C-4. The former is believed to be responsible for widespread poisoning of grazing animals in these areas;/the latter appears to be a relatively non-toxic co-metabolite. There is a close structural similarity between these compounds and carboxyatraciyloside and atractyloside, which are known toxins with strychnine-like action, isolated from Atractylis gummifera L. The parquins possess a different pyranose ring from the atractyiosides and an additional γ-lactone, both with unprecedented functionality.

In this paper we demonstrate the importance of binding geometry and dimerisation at the surface of model cell membranes in the mode of action of the clinically important glycopeptide antibiotics. This has been achieved through the use of model cell membranes (micelles and vesicles) to which cell wall analogues are anchored via a hydrophobic decanoyl chain. A number of –D-Ala-terminating cell wall analogues, ranging from two to six residues in length, have been used. Dipeptide, pentapeptide and hexapeptide display enhanced binding to the antibiotic at the model cell surface, but tripeptide and tetrapeptide do not. The possible implications of the observed binding geometries for bacterial systems are discussed.

Weak interactions, such as those non-covalent interactions that occur in biological systems, are less well characterised than their strong, covalent counterparts. Here, we discuss associations between two or more molecules and consider the effect of interactions with solvent molecules (particularly water) and changes in the internal structure of the associating molecules on binding. We go on to discuss some of the progress that has been made in the estimation of binding constants.

This review is an account of the discoveries in the Cambridge group of the structures and mode of action of the glycopeptide antibiotics of the vancomycin group. These antibiotics are now of enormous clinical importance, for among their members are two (vancomycin and teicoplanin) of the three antibiotics of last resort against resistant bacterial pathogens (particularly methicillin-resistant Staphylococcus aureus (MRSA, or “superbugs”)) in our hospitals, which would otherwise often be lethal. Their combined sales are of the order of US$1 billion per annum. The structure determination in our laboratory started just over 25 years ago. Within ten years the first glycopeptide structures had been determined. This was quickly followed by the determination of the molecular basis of their action, through the making of five hydrogen bonds to a cell wall peptide precursor that terminated in -Lys-d-Ala-d-Ala. In the early 1990s, we established that all the glycopeptides so far examined (other than teicoplanin) form dimers, and shortly after showed that dimerization promotes antibiotic activity. Concurrently, we were able to demonstrate that teicoplanin possesses a membrane anchor that can act to promote antibiotic activity in lieu of dimerization. The devices of dimerization and membrane anchoring, when acting concurrently, appear to be able to account at least in part for the remarkable activity of a new semi-synthetic glycopeptide—developed at Eli Lilly—against bacteria that are resistant even to vancomycin. A full understanding of these devices is important, since occurrences of the “nightmare scenario” that clinicians have feared over recent years—that resistance to vancomycin will appear in new forms of MRSA—have recently been reported.

The biosynthetic pathway to the L-di-meta-hydroxyphenylglycine (DHPG) constituent of chloroeremomycin (A82846B), has been investigated by a combination of feeding experiments with 13C-labelled substrates, and expression and assay of HpgT from the chloroeremomycin biosynthetic cluster.

It is argued that organisms have evolved the ability to biosynthesise secondary metabolites ('natural products') due to the selectional advantages they obtain as a result of the functions of the compounds. Pleiotropic switching, the simultaneous expression of sporulation and antibiotic biosynthesis genes in Streptomyces, is interpreted in terms of the defense roles of antibiotics. The clustering together of antibiotic biosynthesis, regulation, and resistance genes, and in particular the staggering complexity shown in the case of the gene cluster for erythromycin A biosynthesis, implies that these genes have been selected as a group and that the antibiotics function in antagonistic capacities in nature.

Background: The vancomycin group of glycopeptide antibiotics is active against a wide range of gram-positive bacteria. The increasing resistance to vancomycin is the result of a change of an amide linkage ( d -Ala- d -Ala) to an ester linkage ( d -Ala- d -Lactate) in the bacterial cell-wall precursors. Results: We have used a peptide terminating in the sequence -Lys- d -Ala- d -Lactate linked by its amino terminus to a docosanoyl (C22) acyl chain and anchored in a supported lipid monolayer to mimic the surface of vancomycin-resistant enterococci. Surface plasmon resonance analysis was then used to investigate the binding of glycopeptide group antibiotics to this surface. Vancomycin, which dimerises weakly, bound with low affinity, whereas strongly dimerising antibiotics, such as chloroeremomycin, bound with higher affinities. Antibiotics that have attached hydrophobic groups, such as teicoplanin and biphenylchloroeremomycin (LY307599), bound to the lipid monolayer. This resulted in an enhanced affinity for the lipid-anchored peptide at the surface relative to affinities for an analogous non-anchored peptide in solution. Conclusions: We have shown that the affinities of glycopeptide antibiotics for a model of the surface of a vancomycin-resistant bacterium are enhanced relative to affinities determined in free solution. We have also shown that antibiotics that have membrane anchors bind tightly to the model surface and that this feature is an important determinant of the ability of an antibiotic to kill vancomycin-resistant enterococci.

Ideas derived from the study of the process of crystallization may provide insights into molecular recognition in biological systems. Both processes exploit the cooperativity which arises from the formation of a large array of weak interactions.

Seven solitary fibrous tumors (SFTs) of the meninges are presented and their clinicopathologic features are compared with those of 64 fibrous meningiomas (FM). Patients with SFT included 5 females and 2 males age 47 to 73 years. The dura-based tumors involved the parasagittal region (1), tentorium (2), cerebellopontine angle (2), and spinal region (2). One each showed invasion of brain and of a spinal nerve root. Of four SFTs with at least 1-year follow-up, one subtotally resected example recurred. No tumors metastasized. All consisted of spindle cells disposed in fascicles between prominent, eosinophilic bands of collagen. Whorls and storiform cell arrangements were lacking. Mitoses ranged from 1 to 7/10 400 x fields. MIB-1 labeling indices ranged from 1% to 18% (mean 4%). All were PAS negative and showed strong immunoreactivity for vimentin and CD34. Of cases studied, half were estrogen and all were progesterone receptor immunopositive. The majority (72%) of FMs occurred in females and most (72%) were supratentorial. Recurrence was noted in 15%. Mitotic activity varied from 0 to 3 mitoses per 10 400 x fields (mean < 1). MIB-1 labeling indices ranged from 1% to 5% (mean 1.5%). Unlike SFT, FMs were glycogen-containing and variously exhibited a storiform pattern (13 of 20), psammoma body formation (9 of 20), and calcification of collagen (4 of 20). Immunoreactivities included vimentin (100%), focal to patchy EMA (80%), S-100 protein (80%), collagen IV (25%), and patchy, mild-to-moderate CD34 staining (60%). Of cases studied, nearly half were estrogen and all were progesterone receptor staining positive. Meningeal SFTs represent a distinct morphologic entity, the morphologic and immunohistochemical features of which differ from those of FM and suggest a histogenetic relationship to pleural SFT. Although a minority histologically appear to be low grade malignant, our limited experience suggests that they behave in a benign fashion. The classification of mesenchymal tumors affecting the central nervous system must be expanded to include SFT.

Objective To determine the clinical and pathologic features in a large cohort of randomly selected patients with gonadotroph pituitary adenomas. Design We retrospectively reviewed clinical, surgical, and pathologic findings in 100 patients (79 men and 21 women, 30 to 82 years old) with this tumor. Results Diagnosis of a pituitary tumor was prompted by visual loss (43%), symptoms of hypopituitarism (22%) headache (8 %), or a combination of these findings (10%); 17% of the patients were asymptomatic. Visual field defects were present in 68% of the study group, and complete or partial anterior pituitary failure was present in 77%. Serum prolactin concentrations were increased (maximum, 110 ng/mL) in 33% of patients. Hypersecretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was documented in 11 and 5 patients, respectively. The serum level of α-subunit was increased in 1 of 29 patients in whom it was measured. All patients had pituitary macroadenomas, only 21% of which were grossly invasive. The surgical approach was transsphenoidal in all but two patients, who underwent transfrontal craniotomy; gross total tumor resection was achieved in 90%. By definition, all tumors had at least 10% immunoreactivity for LH, FSH, or both. All tumors were chromophobic. Ultrastructurally, the tumors were characterized as gonadotroph adenomas of "male" (45%) or "female" (9%) type as well as null-cell adenomas of the oncocytic (35%) or nononcocytic (11%) type. After a median follow-up of 4.3 years, 69% of the patients who had had visual field defects noted normalization or improvement. Persistent or clinically recurrent pituitary tumor tissue was present in 42%. A second pituitary surgical procedure was required in eight patients. Conclusion Most patients with clinically evident gonadotroph pituitary tumors have loss of vision and hypopituitarism. Hypersecretion of FSH or LH is unusual, and no distinct hormone-dependent clinical phenotype is present. Transsphenoidal surgical treatment generally yields normalization or improvement of visual field defects.

Background: Recent work has indicated that dimerization is important in the mode of action of the vancomycin group of glycopeptide antibiotics. NMR studies have shown that one member of this group, ristocetin A 1 forms an asymmetric dimer with two physically different binding sites for cell wall peptides. Ligand binding by ristocetin A and dimerization are slightly anti-cooperative. In contrast, for the other glycopeptide antibiotics of the vancomycin group that have been examined so far, binding of cell wall peptides and dimerization are cooperative. Results: Here we show that the two halves of the asymmetric homodimer formed by ristocetin A have different affinities for ligand binding. One of these sites is preferentially filled before the other, and binding to this site is cooperative with dimerization. Ligand binding to the other, less favored half of the dimer, is anti-cooperative with dimerization. Conclusions: In dinner complexes, anti-cooperativity of dimerization upon ligand binding can be a result of asymmetry, in which two binding sites have different affinities for ligands. Such a system, in which one binding site is filled preferentially, may be a mechanism by which the cooperativity between ligand binding and dimerization is fine tuned and may thus have relevance to the control of signal transduction in biological systems.

To compare the pituitary pathology of gigantism to that of acromegaly, 19 surgically resected lesions were studied from 10 males and 9 females, ages 13-49 (mean, 19 yr) with excessive height (>/=95th percentile), onset of disease prior to puberty, elevated growth hormone (GH) levels despite glucose suppression, and a pathologically confirmed GH-producing pituitary mass. One patient had MEN-I. The lesions included 18 adenomas and 1 case of pure hyperplasia. The median, mean, and range of serum GH and prolactin (PRL) levels were 64, 235, 5-1000 ng/mL and 47, 146, 29-770 ng/mL, respectively. Of the 8 adenoma specimens accompanied by nontumoral pituitary (i.e., tissue wherein the presence of hyperplasia was assessable), 3 (37%) demonstrated both. Of the 18 tumors, 78% were macroadenomas and 22% were grossly invasive; their immunophenotypes included GH (5%), GH and PRL (19%), and GHPRL and a glycoprotein hormone, usually TSH and/or a-subunit (76%). Of the 10 adenoma-containing lesions subject to electron microscopy (EM), 2 consisted of GH cells alone; 2 of mammosomatotroph (MS) cells alone; 1 of GH and MS cells; 1 of GH and PRL cells; 2 of GH, PRL, and MS cells; 1 of GH, PRL, and glycoprotein cells; and 1 was a subtype 3 adenoma. Ultrastructurally, GH cells and/or MS cells predominated in these lesions. Immuno-EM of one CH and PRL cell and of one GH-PR-MS tumor showed GH and PRL to be present not only in single cells but within the same granules. Nine of 12 adenoma-associated lesions subject to combined in situ hybridization (ISH) and immunostaining showed double labeling for PRL (or GH) mRNA and for GH (or PRL), respectively, features indicating MS differentiation. In the 4 lesions exhibiting hyperplasia, either alone (1) or in association with adenoma (3), EM showed MS cells in 3, and immuno-EM as well as combined immunohistochemistry and ISH showed double labeling for GH and PRL in both of the 2 cases studied. In summary, although in terms of their tinctorial characteristics and tumor size, the lesions of giants resemble those of acromegalics, those of the former are less often invasive and glycoprotein hormone containing, and more often contain ultrastructurally distinctive MS cells. The high frequency of adenoma with hyperplasia (37%) and the occurrence of hyperplasia alone (6%) is of particular notice since this finding is rare in patients with acromegaly. Hyperplasia is, however, seen in ectopic GH-releasing hormone production and the McCune-Albright syndrome. We conclude that the presence of MS is not rare in the pituitary lesions of patients with gigantism. Their presence may be a reflection of either hypothalamic dysfunction or of an intrinsic abnormality of pituitary cells

purpose: The syndrome of inappropriate thyroid-stimulating hormone (TSH) secretion, characterized by elevated serum free thyroxine and triiodothyronine levels in association with measurable serum TSH concentrations, remains an uncommon cause of hyperthyroidism that is being recognized with increasing frequency. The hyperthyroidism may be due to either neoplastic pituitary TSH secretion or selective pituitary resistance to thyroid hormone. In an effort to better understand this rare cause of hyperthyroidism, we undertook a retrospective analysis of our institution's experience with this condition. patients: We reviewed our cumulative experience (10 patients) with hyperthyroidism due to the syndrome of inappropriate secretion of TSH. results: Six patients were diagnosed with TSH-secreting pituitary adenomas and four were found to have selective pituitary resistance to thyroid hormone. One patient with tumor had a TSH-secreting pituitary adenoma in the setting of multiple endocrine neoplasia syndrome. In all patients with tumor, hyperthyroidism was successfully treated with transsphenoidal adenomectomy with or without pituitary radiotherapy. All four patients with pituitary resistance had thyroid ablation or resection prior to their correct diagnosis. Therefore, therapy for this group of patients involved thyroid hormone replacement and efforts to suppress TSH hypersecretion. All 10 patients have done well clinically, with follow-up ranging from 2 weeks to 13 years. conclusions: Adequate treatment exists for the two primary causes of TSH hypersecretion. TSH-secreting pituitary adenomas are treated with surgery and, if necessary, adjuvant pituitary radiotherapy. The results are generally good if the tumor is diagnosed and treated at an early stage. Primary therapy for hyperthyroidism due to selective pituitary resistance to thyroid hormone is aimed at suppression of pituitary TSH hypersecretion. The evaluation of any patient with hyperthyroidism must be thorough and, in some cases, should include measurement of TSH to determine the presence of inappropriate secretion. Eliminating this diagnosis will help avoid improper and potentially harmful treatment of hyperthyroid patients.

Herein we report the preliminary results in nine patients who have undergone selective peripheral denervation for spasmodic torticollis and have been followed up for at least 13 months. All patients had improvement immediately after surgical intervention, and the results have been maintained in five patients. In one patient who had recurrent torticollis, a second procedure in conjunction with injection of botulinum toxin has produced substantial improvement; however, follow-up was brief (6 months). No surgical complications occurred. We believe that selective peripheral denervation is safe and that it can benefit patients with torticollis who have not responded to other types of therapy. These favorable results confirm other published reports on the efficacy of selective peripheral denervation. Long-term follow-up, however, is necessary for determining the role of this procedure in the management of torticollis.

Many neurologic disorders, such as eclampsia, pseudotumor cerebri, stroke, obstetric nerve palsies, subarachnoid hemorrhage, pituitary tumors, and choriocarcinoma, can develop in the pregnant patient. Maternal mortality from eclampsia, which ranges from 0 to 14%, can be due to intracerebral hemorrhage, pulmonary edema, disseminated intravascular coagulation, abruptio placentae, or failure of the liver or kidneys. Associated fetal mortality ranges from 10 to 28% and is directly related to decreased placental perfusion. Pseudotumor cerebri can be associated with serious visual complications; thus, the therapeutic goal is to prevent loss of vision. The risk of stroke in the pregnant patient is 13 times the risk in the nonpregnant patient of the same age. The major causes of stroke in pregnant patients are arterial occlusion and cerebral venous thrombosis. Lumbar disk prolapse is common in pregnant patients, and lumbosacral plexus injuries can occur during labor or delivery. In addition, peripheral nerve compression or entrapment syndromes are thought to be caused by the retention of fluid during pregnancy. The incidence of subarachnoid hemorrhage during pregnancy is 1 in every 10,000 patients, a rate 5 times higher than in nonpregnant women. Because of a proliferation of prolactin-secreting cells, the pituitary gland can enlarge dramatically during pregnancy, a change that can disclose a previously unknown tumor or cause a known pituitary tumor to become symptomatic. The incidence of choriocarcinoma is 1 in 50,000 full-term pregnancies but 1 in 30 molar pregnancies. This malignant tumor has a high rate of cerebral metastatic lesions. In addition to these disorders that develop during pregnancy, the pregnant state can affect numerous preexisting neurologic conditions, including epilepsy, headaches, multiple sclerosis, myasthenia gravis, spinal cord injury, and brain tumors. We discuss advice for patients with such conditions who wish to become pregnant, recommendations for medical and surgical management, and surgical considerations for neurologic complications during pregnancy.

Several model peptides have been trimethylsilylated and their FIB mass spectra obtained; reaction was detected at hydroxy groups and primary amides only, amines and carboxy groups were observed in underivatised form, and thus, in conjunction with standard procedures for the determination of hydroxy groups, this methodology represents a sensitive and extremely rapid means for the detection of primary amides in such molecules.

This paper describes the isolation and structure elucidation of two toxic tannins, named, α- and β-punicalagin, from Terminalia oblongata, an Australian tree. Techniques used in the structure determination included Fast Atom Bombardment (FAB) mass spectrometry, and one- and two-dimensional NMR, UV, and IR spectroscopy. A number of microscale derivatisations were performed, followed by FAB analysis.

A novel antibiotic structurally related to vancomycin has been isolated from a streptomycete fermentation broth. The structure has been elucidated by a combination of FAB-MS and 1H proton n.m.r. studies, and is found to differ from vancomycin in the type of sugars present, and in the positions of aromatic chlorination.

The preparations of the hexapeptides (3) and (6) derived from the antibiotic vancomycin (1), are described. The conformation of the N-terminal regions of (3) and (6) are discussed and compared to previous observations made on vancomycin. The hexapeptides lack any significant binding capability relative to vancomycin, and the reasons for this are discussed.

C54H93N9016.H2 O, Mr = 1142.40, ortho- rhombic, P212~21, a = 14.230 (1), b = 24.370 (5), c = 18.780 (2) A, V =6512.6(11) A 3, Z=4, Dx= 1.16 gcm -3, A(fu Ka) = 1.5418/~, /z = 6.8 cm-1 F(000) = 2472, T = 158 (2) K, R = 0.073 for 6299 unique reflections. The structure of this cycle peptide is that of fl-hydroxydecanoyl-L-Leu-D-Glu-D-allo- Thr-D-Val-D-Leu-D-Ser-D-Ser-L-Ile. Ring closure is through an ester linkage between the carboxyl of L-lie and the hydroxyl of D-allo-Thr, leaving the y-carboxyl of D-Glu free. The stereochemistry of the fl-hydroxy acid is shown to be R. Introduction. Members of the genus Pseudomonas characteristically produce a wide variety of extracel- lular compounds including siderophores, antibiotics, toxins and enzymes. A range of fluorescent Pseudo- monas species are commonly found in association with the sporophore of the edible mushroom, Agari- cus bisporus (Lange) Imbach (Olivier, Guillames &

The technique of nuclear Overhauser effect difference spectroscopy allows the determination, from1H nuclear magnetic resonance spectra, of those protons in a structure which are near in space to a selected, irradiated proton. The experiment is extremely powerful in the determination of structure in solution, and is sufficiently precise often to give stereochemical detail. The method was used in determination of the structures of the antibiotics of the teicoplanin complex (members of the vancomycin group), and the principles are briefly illustrated. Additionally, nuclear magnetic resonance pulse sequences can be used to edit13C spectra (separate the spectrum into four spectra, containing C, CH, CH2, and CH3 carbons), and this technique also aided the structure elucidation of the teicoplanin complex. Finally, it is emphasised that nuclear Overhauser effect difference spectroscopy can be used to determine the molecular details of drug binding sites, and an example is given.

Organische Ionen zerfallen in den feldfreien Bereichen eines Massenspektrometers nach einer wohldefinierten Lebensdauer (t ≈ 10−5 s), die – verglichen mit der Zeitskala von Molekulschwingungen – sehr gros ist. Die im Ubergangszustand einer Dissoziation vorhandene Uberschusenergie („non fixed energy”) ist mit der von Reaktionen in Losung vergleichbar. Allgemein gilt, das nur die energetisch gunstigsten Zerfallswege miteinander konkurrieren konnen. Die Analyse von Ubergangssignalen der unimolekularen Zerfalle metastabiler Ionen liefert Informationen uber die bei der Reaktion freigesetzte kinetische Energie („kinetic energy release”), T; bei Experimenten in Losung sind diese auserst wertvollen Daten aufgrund von Stosen nicht zuganglich. Die Chemie von Ionen kann bequem studiert werden, wenn man die Ionen in einem Massenspektrometer erzeugt und die Zerfalle metastabiler Ionen analysiert.

A computer-assisted stereotactic biopsy technique has been used in 30 patients (ages 5 months to 16 years) with intracranial lesions (supratentorial in 23 and infratentorial in 7). The computer program integrates stereotactically gathered imaging data and permits preoperative planning of a biopsy trajectory. Diagnostic tissue was obtained in 27 cases. In 2 cases, therapeutic interventions – third ventriculostomy and cyst aspiration – were accomplished at the time of the biopsy. There were no major complications related to the procedure; however, 2 patients had transient neurologic deficits. Computer-assisted stereotactic biopsy is a valuable diagnostic procedure in the pediatric patient with an intracranial lesion.

The embryologic origins of congenital abnormalities of the odontoid process are reviewed. Four cases of odontoid dysgenesis in childhood are presented. All of our cases were associated with a head injury, which subsequently led to the diagnosis. Pain was the most common presenting complaint in our patients. Decreased cervical mobility was the most consistent physical finding. There was no major neurological defect implicating spinal cord compression in any of our patients. This is not true of adults with congenital abnormalities of the odontoid, particularly those with atlantoaxial instability. The diagnosis of odontoid dysgenesis is a radiographic one. Flexion-extension films, tomograms and cineradiograms are often required to make the diagnosis. C1–C2 subluxation, either anterior or posterior is often found. Prompt posterior cervical fusion is recommended as the treatment of choice.

Oligomers of ampicillin and amoxicillin were isolated by preparative chromatography on DEAE-Sephadex and purified by chromatography on Amberlite XAD-2. The purity of the oligomers was checked by thin-layer chromatography and by high-performance liquid chromatography. Proton magnetic resonance and fast atom bombardment mass spectrometry showed that ampicillin yielded mainly the dimer, trimer and tetramer, and amoxicillin the dimer, trimer and some tetramer. The corresponding penicilloates were also present. For amoxicillin an important amount of the piperazinedione was formed simultaneously.

Background: The emergence of resistance to vancomycin, the drug of choice against methicillin-resistant Staphylococcus aureus , in enterococci has increased the need for new antibiotics. As chemical modification of the antibiotic structure is not trivial, we have initiated studies towards enzymatic modification by sequencing the DNA coding for the biosynthesis of chloroeremomycin (also known as A82846B and LY264826). Results: Analysis of 72 kilobases of genomic DNA from Amycolatopsis orientalis , the organism that produces chloroeremomycin, revealed the presence of 39 putative genes, including those coding for the biosynthesis of the antibiotic. Translation and subsequent comparison with known proteins in public databases identified enzymes responsible for the biosynthesis of the heptapeptide backbone and 4- epi -vancosamine, as well as those for chlorination and oxidation reactions involved in the biosynthesis of Chloroeremomycin. Conclusions: The genes responsible for the biosynthesis of chloroeremomycin have been identified, and selective expression of these genes could lead to the synthesis of new potent glycopeptide antibiotics.

Background : Siderophores are compounds produced by bacteria to acquire iron. Exochelin MN, the extracellular siderophore from Mycobacterium neoaurum, is of particular interest because it has been shown to transport iron into M. leprae , which is responsible for the disease leprosy. Exochelins from other species cannot mediate iron transport in M. leprae , suggesting a specific uptake mechanism involving exochelin MN. We set out to determine the structure of exochelin MN and identify the features of the molecule that may account for this specificity. Results : The structure of exochelin MN was elucidated by a combination of techniques including nuclear magnetic resonance, mass spectrometry, derivatization and gas chromatography. Exochelin MN is a peptide, containing the unusual amino acid β- hydroxyhistidine and an unusual N -methyl group. The peptide coordinates iron(III) octahedrally using its two cis-hydroxamate groups plus the hydroxyl and imidazole nitrogen of the β-hydroxyhisti-dine. The three-dimensional structure of the hexadentate exochelin/gallium complex was deduced from NMR data. Conclusions : Exochelin MN has some structural features in common with other siderophores, but has a unique three-dimensional structure, which is presumably important for its specific activity in M. leprae. Exochelin MN may be a target for drug design in the fight against infection with this pathogen.

Background: The stability of the secondary structure of particular peptide regions is often used to investigate the involvement of the region in protein folding. When analysing the relatively small populations of associated states that are formed by weak interactions (i.e. those interactions that are comparable to thermal energies), it is common practice to characterise the associated state by a parameter that is measured when this state is highly occupied. The accuracy of this method, however, has not yet been determined. Results: Using as a model the vancomycin group of antibiotics, either forming dimers or binding to cell wall precursors, we have investigated the dependence of the limiting (i.e. fully associated) chemical shifts of two protons on the equilibrium constants for the formation of the fully associated states. The chemical shift shows a large variation with the equilibrium constant for the formation of the fully associated state. Conclusions: The results demonstrate, in two systems, that a parameter representing a fully associated state (chemical shift) varies greatly with the equilibrium constant for the formation of that associated state. The results have implications for two-state analyses of populations of protein fragments in which a parameter representing the fully associated state is taken to be independent of the equilibrium constant for its formation. Using two-state analysis to determine the population of associated states of protein fragments could result in an underestimation of the population of these associated states.