Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.

The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.

The microsurgical anatomy of the cisternal segment of the trochlear nerve, as seen through different neurosurgical operative windows.

OBJECTIVE: To describe the anatomy of the cisternal segment of the trochlear nerve as seen through different neurosurgical approaches. METHODS: The cisternal course of ten trochlear nerves was observed in five cadaveric embalmed heads, through the view afforded by the median infratentorial-supracerebellar, the extreme-lateral infratentorial-supracerebellar, and the combined presigmoid-subtemporal transtentorial approaches. The relationships of the trochlear nerve with the surrounding neuro-vascular structures were analyzed. RESULTS: We identified 3 segments of the cisternal trochlear nerve: quadrigeminal, ambient and tentorial. The median infratentorial-supracerebellar approach allowed exposure of the quadrigeminal segment, including the origin of the nerve. The extreme-lateral supracerebellar and the combined presigmoid-subtemporal transtentorial approaches provided visualization of the ambient and tentorial segments of the nerve. The tentorial segment runs in a dural canal contained in the free edge of the tentorium, surrounded by its own arachnoidal sleeve. CONCLUSION: The trochlear nerve is a very delicate structure that can be easily injured during approaches to the tentorial incisura. Accurate knowledge of its anatomy as seen through different operative windows is helpful in maintaining its integrity during surgery.

Detection of TNF inhibitors (soluble receptors) in the sera and tumor cyst fluid of patients with malignant astrocytomas of the brain.

Patients with malignant astrocytomas of the brain exhibit varying degrees of immunosuppression with only a few factors responsible for this immunosuppression having been characterized. The soluble forms of the 55 kDa and 75 kDa membrane receptors for tumor necrosis factor (sTNF-R's) have been shown to bind to and inhibit the activity of TNF. The present studies analyze levels of sTNF-R's in the sera and tumor cyst fluids of patients with malignant astrocytomas. Using sensitive ELISA techniques, serum levels of the 55 and 75 kDa sTNF-R's in 17 patients tested were found to be elevated (55 kDa of 2.29 ( 2.85 ng/ml and 75 kDa of 4.98 ( 4.03 ng/ml( as compared to 20 normal controls (55 kDa of of 1.21 ( 0.91 ng/ml and 75 kDa of 1.85 ( 0.40 ng/ml( although this was only statistically significant for the 75 kDa sTNF-R (P=0.006). Brain tymor cyst fluid samples obtained from eight patients were shown to have very high levels of both sTNF-R's ranging from 4.16 to 17.17 ng/ml for the 55 kDa receptor and 4.83 to 19.96 ng/ml for the 75 kDa receptor. Six of these cyst fluid samples were also tested for their ability to inhibit TNF cytolytic activity using an in vitro assay. All samples tested had TNF inhibitory activity. Immunohistochemical studies on patient tumor samples showed high levels of expression of these receptors both in the cytoplasm and the cell surface of astrocytoma cells. We propose that sTNF-R's may be shed by astrocytoma cells and may have a role in both local and systemic immunosuppression observed in astrocytoma patients. Finally, the potential role of serum level of sTNF-R's as tumor markers to follow the treatment and the progression of disease in these patients are discussed.

Stereotactic Radiotherapy of Central Nervous System and Head and Neck Lesions, Using a Conformal Intensity-Modulated Radiotherapy System (Peacocktrade mark System).

The objective of this article is to evaluate single-fraction or fractionated stereotactic radiotherapy of central nervous system (CNS) and head and neck lesions using intensity-modulated radiotherapy (IMRT) with a commercially available system (Peacocktrade mark, Nomos Corporation, Sewickley, PA). This system allows tomotherapeutic delivery of intensity-modulated radiation, that is, the slice-by-slice treatment of the volume of interest with an intensity-modulated beam, making the delivery of highly conformal radiation to the target possible in both single or multiple fractions mode. During an 18-month period, 43 (21 males and 22 females) patients were treated, using a removable cranial screw-fixation device. Ages ranged from 10 to 77 years (mean, 52.2; median, 53.5). Intra- and extra-axial lesions, including head and neck malignancies and spine metastases, were treated. Clinical target volume ranged from 0.77 to 195 cm(3) (mean, 47.8; median, 29.90). The dose distribution was normalized to the maximum and was prescribed, in most cases, at the 80% or 90% isodose line (range, 65 to 96%; median, 85%; mean, 83.4%) and ranged from 14 to 80 Gy (mean, 48; median, 50). The number of fractions ranged from 1 to 40 (mean, 23; median, 25). In all but one patient, 90% of the prescription isodose line covered 100% of the clinical target volume. The heterogeneity index (the ratio between the maximum radiation dose and the prescribed dose) ranged between 1.0 and 1.50, whereas the conformity index (the ratio between the volume encompassed by the prescription isodose line and the clinical target volume) ranged between 1.0 and 4.5. There were no complications related to the radiation treatment. With a median follow-up of 6 months, more than 70% of our patients showed decreased lesion size. Stereotactic IMRT of CNS and head and neck lesions can be delivered safely and accurately. The Peacock system delivers stereotactic radiation in single or multiple fractions and has no volume limitations. It has been used to treat intracranial, head and neck, and spinal lesions. The option of fractionation, the lack of volume constraint, and the capability of treating intracranial, head and neck, and spinal pathology make stereotactic IMRT a valuable adjunct to established stereotactic radiotherapy systems delivering convergent-beam irradiation using the Linac or Gamma Knife. In a clinical setting that offers Linac, Gamma Knife radiosurgery, and conformal stereotactic radiotherapy, the latter may have advantages for treating large (> 25-cm(3)) and irregular lesions, especially when fractionation is considered useful.

Human liver glycogen phosphorylase inhibitors bind at a new allosteric site.

BACKGROUND: Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate for glycolysis. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. RESULTS: The binding site in human liver glycogen phosphorylase (HLGP) for a class of promising antidiabetic agents was identified crystallographically. The site is novel and functions allosterically by stabilizing the inactive conformation of HLGP. The initial view of the complex revealed key structural information and inspired the design of a new class of inhibitors which bind with nanomolar affinity and whose crystal structure is also described. CONCLUSIONS: We have identified the binding site of a new class of allosteric HLGP inhibitors. The crystal structure revealed the details of inhibitor binding, led to the design of a new class of compounds, and should accelerate efforts to develop therapeutically relevant molecules for the treatment of diabetes.

Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core.

Glycogen phosphorylases catalyze the breakdown of glycogen to glucose-1-phosphate, which enters glycolysis to fulfill the energetic requirements of the organism. Maintaining control of blood glucose levels is critical in minimizing the debilitating effects of diabetes, making liver glycogen phosphorylase a potential therapeutic target. To support inhibitor design, we determined the crystal structures of the active and inactive forms of human liver glycogen phosphorylase a. During activation, forty residues of the catalytic site undergo order/disorder transitions, changes in secondary structure, or packing to reorganize the catalytic site for substrate binding and catalysis. Knowing the inactive and active conformations of the liver enzyme and how each differs from its counterpart in muscle phosphorylase provides the basis for designing inhibitors that bind preferentially to the inactive conformation of the liver isozyme.

Management of skull base chordoma.

Two management modal-ities appear to be important in treating skull base chordomas: surgery and radiation therapy. Radical resection of lesions of the distal sacrum (S3-S5) and coccyx may be curative, as total removal is often achieved. In contrast, complete resection of chordomas of the base of the skull is rarely successful because of the inability to achieve a true complete surgical resection. On the other hand, treatment of skull base chordomas by radiation therapy alone is often difficult owing to the large size of the lesion and the dose limitation imposed by the sensitivity of the adjacent structures. Local relapse is the predominant type of treatment failure of skull base chordoma. Skull base surgery and radiation therapy have significantly improved over the last 20 years. The following papers review the most significant recent analyses of therapeutic options in treating skull base chordomas. It seems that the combination of aggressive surgery followed by combined proton-photon radiation therapy offers the best chance of long-term local control to patients harboring cranial chordomas.

Analytical evaluation of complex anterior approaches to the cranial base: an anatomic study.

OBJECTIVE: The purpose of the present study was to evaluate the anatomic areas of the cranial base exposed by different complex anterior approaches. METHODS: Using 20 embalmed cadaveric heads, we executed five different anterior approaches, i.e., Le Fort 1 approach with splitting or down-fracturing of the hard palate, extended maxillectomy, median mandibulotomy with glossotomy, and mandibular swing transcervical approach. Each approach was performed a minimum of three times. The areas of the intra- and extracranial cranial base exposed by each approach were analytically examined by using a numerical grading system to assess the exposure of major anatomic and neurovascular structures. RESULTS: Good exposure of the midline compartment of the cranial base was provided by the median mandibulotomy with glossotomy and by the Le Fort 1 approach with splitting of the hard palate, whereas the mandibular swing transcervical and extended maxillectomy approaches provided good exposure of the lateral compartment of the cranial base. CONCLUSION: Use of the numerical grading system allowed quantification of the exposure afforded by each approach, with respect to the different compartments (midline and lateral) of the intra- and extracranial cranial base, highlighting the differences among the approaches examined.

Anatomo-radiological evaluation of lateral approaches to the skull base.

Our objective is to correlate the anatomical exposure provided by complex skull base approaches to the lateral skull base with their CT and MRI scans counterparts and to introduce a modular concept emphasizing the derivation of complex skull base approaches from simpler ones.We executed 10 lateral approaches to the skull base in 20 embalmed cadaveric heads (40 sides). Each approach was executed a minimum of three times on each specimen. These approaches were the pterional and its modifications, the subtemporal and its modifications, and the suboccipital and its modifications. We correlated the approaches and the areas of the skull base exposed by scanning the surgical cavity filled with material imageable by CT and MRI and throughly surveying the operative field.Visualization of the area of the skull base exposed was excellent using our CT-MRI imageable cadaveric preparation. The topographic areas of the skull base exposed correlated well with their radiological counterparts.The areas of the skull base exposed by each of the complex surgical approaches to the skull base were clearly delineated by using our anatomo-radiological correlation. Complex approaches to the skull base are formed by simple neurosurgical approaches (building blocks) to which different modules are added.

Inflammatory bowel disease and immune thrombocytopenic purpura: is there a correlation?

Different hematologic abnormalities are often encountered in patients with inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side effect of therapy, particularly with use of immunosuppressive drugs. Immune thrombocytopenic purpura is rarely reported in association with inflammatory bowel disease. We present two cases with combination of these entities along with a literature review and treatment options. Immune thrombocytopenic purpura in these patients presented as an extraintestinal manifestation of inflammatory bowel disease mediated by a disturbance of the immune system.

Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet(M)- and Tet(O)-mediated ribosomal protection.

N,N-dimethylglycylamido (DMG) derivatives of 6-demethyl-6-deoxytetracycline and doxycycline bind 5-fold more effectively than tetracycline to the tetracycline high-affinity binding site on the Escherichia coli 70S ribosome, which correlates with a 10-fold increase in potency for inhibition of E. coli cell-free translation. The potencies of DMG-doxycycline and DMG-6-demethyl-6-deoxytetracycline were unaffected by the ribosomal tetracycline resistance factors Tet(M) and Tet(O) in cell-free translation assays and whole-cell bioassays with a conditional Tet(M)-producing E. coli strain.

The endolymphatic sac: microsurgical topographic anatomy.

The endolymphatic sac is part of the membranous labyrinth; it plays an important role in the hearing mechanism. Injury to the endolymphatic sac may, over time, severely compromise hearing. The endolymphatic sac is located in a duplication of the dura of the posterior aspect of the petrous pyramid and is, therefore, in the surgical field of many neurosurgical operations performed on the posterolateral cranial base. The endolymphatic sac was exposed bilaterally in 10 anatomic specimens; the distance from the center of the sac to the posterior lip of the internal auditory meatus and to the XIth nerve in the jugular foramen was measured with a caliper. Also measured was the distance between the center of the sac and the closest point on the petrous ridge and the distance between that point and the petro-sigmoid intersection. The petro-sigmoid intersection was defined as the point at which the medial aspect of the sigmoid sinus intersects the lateral aspect of the petrous ridge. The dimensions of the sac were also recorded. On the average, the sac was found to be 15.7 mm posterosuperior (superolateral) to the XIth nerve in the jugular foramen (range, 11.0-18.5 mm) and 13.3 mm posterior (lateral) to the internal auditory meatus (range, 10.0-18.0 mm). The center of the sac was 24.1 mm (mean value) (range, 20.0-28.0 mm) in front of the petro-sigmoid intersection at a point 11.5 mm (mean value) (range, 8-17 mm) below the petrous ridge. The mean width and height of the sac were 3.83 (range, 2-6 mm) and 3.80 mm (range, 2.5-8 mm), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Intramedullary tuberculoma of the spinal cord: case report.

A case report of intramedullary tuberculoma is presented. Only one other case of intramedullary tuberculoma has been reported in the North American literature in the last 30 years. It is also unique because it is the only documented case of the paradoxical enlargement of an intramedullary tuberculoma after the initiation of antituberculous chemotherapy. Excellent results were obtained with a combination of medical and surgical management.

Preservation of the temporal branch of the facial nerve in pterional-transzygomatic craniotomy.

The temporal branch of the facial nerve may be saved in a pterional-transzygomatic craniotomy if the dissection is carried beneath the superficial temporal fascia. The anatomical and technical aspects of this exposure are described in this report.

An anatomicosurgical study of the temporal branch of the facial nerve.

The surgical anatomy of the temporal branch of the facial nerve was studied bilaterally in 10 embalmed cadaveric heads. Particular attention was paid to the relationships between the temporal branch, the galeal-fascial layers, and the fat pads of the temporal-zygomatic region. The temporal branch of the facial nerve pierces the parotidomasseteric fascia below the zygomatic arch. This branch travels first in the subcutaneous tissue and then, above the zygomatic arch, in the subgaleal space. The temporal branch divides into an anterior, a middle (frontal), and a posterior ramus soon after it pierces the parotid fascia. The course of the terminal twigs of the temporal branch of the facial nerve in the subgaleal space is extremely variable, with their location being at times posterior to the anterior one-fourth of the temporalis muscle. Occasionally, a twig for the frontalis muscle may run in between the two layers of the superficial temporal fascia. Because of these findings (anteroposterior variability of temporal branch twigs and recurrent intrafascial twig), Yasargil's interfascial dissection may at times fail. A combined frontotemporal scalp/superficial temporal fascia dissection is anatomically suited to preserve the temporal branch of the facial nerve.

Clinical trial of Serratia marcescens extract and radiation therapy in patients with malignant astrocytoma.

PURPOSE: A clinical trial was undertaken to determine the safety and efficacy of combining a biologic response modifier derived from the bacterium Serratia marcescens (ImuVert) and radiation therapy (RT) in patients with newly diagnosed anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM). PATIENTS AND METHODS: Fifteen patients who had undergone either a gross total resection, a partial resection, or a biopsy were treated concurrently with ImuVert and RT. Safety and tolerance were examined by assessment of symptomatic reactions recorded at each ImuVert treatment. Efficacy of treatment was examined in terms of time to progression of tumor and survival. RESULTS: All patients experienced local reactions at the injection sites that consisted of erythema and induration. The majority of patients experienced flu-like symptoms. Hypotension was responsible for the most significant morbidity (which required fluid resuscitation and extended observation) and dose deescalation. No patients were removed from the study because of toxicity. There were no on-study deaths related to ImuVert treatment. Median time to progression was 33.4 weeks, and median survival was 78 weeks. CONCLUSION: These results compare favorably with those of recent studies in patients with malignant astrocytomas who received multimodality therapy.

The mandibular swing-transcervical approach to the skull base: anatomical study. Technical note.

This report describes in a stepwise fashion the surgical anatomy of an approach to the midline and lateral compartments of the skull base (clivus, infralabyrinthine/infratemporal regions). The salient features of this procedure are represented by a mandibulotomy and by detachment of the pharynx from the skull base through a combined oral and cervical approach. There is full neurovascular control of the internal carotid artery and lower cranial nerves with the possibility of complete exposure of the intrapetrous and intracavernous segments of the internal carotid artery on the side of the exposure. This approach, which may be regarded as an expansion of the original work of Krespi, should be considered when dealing aggressively with extensive skull-base lesions invading the midline and lateral compartments of the skull base.

Drilling the posterior wall of the petrous pyramid: a microneurosurgical anatomical study.

Posterior approaches to the petroclival area requiring extensive drilling of the posterior pyramidal wall have been described in the last 10 years. If hearing is to be preserved, damage to the inner-ear structures must be avoided; however, the fine points of this pyramidal drilling technique have never been reported in detail. A microneurosurgical anatomical study was undertaken in 15 cadavers to determine the relationships between bone landmarks and labyrinthine structures that could be used to give some practical drilling guidelines. Drilling of the posterior pyramidal wall is facilitated on identification of the intersection of the petrous ridge with the most anterior portion of the bone ledge covering the sigmoid sinus (petrosigmoid intersection), the bony operculum of the endolymphatic sac, and the petrous ridge. Drilling may proceed rather safely at a minimum depth of 2.5 mm in an area 0.9 cm anterior and 1 cm inferior to the petrosigmoid intersection and petrous ridge, respectively. From there, identification of the vestibular aqueduct, genu, and horizontal portion is necessary to safely open the posterior wall of the internal auditory canal. The vestibular aqueduct represents the lateral and superior limits of drilling. The bone between these areas may then be safely drilled to a depth of at least 2.5 mm. A microneurosurgical dissection of the posterior pyramidal wall conducted in cadaveric material according to these guidelines did not violate any inner-ear structures.