Development of controlled drug delivery systems using uniform nanoporous materials as matrices

Ph.DDOCTOR OF PHILOSOPH

Value of endoscopy of the internal auditory canal for microsurgery of intracanalicular vestibular schwannoma

Objective: The objective of this study was to evaluate the feasibility and efficiency of the endoscope-assisted technique in the surgical treatment of intracanalicular vestibular schwannoma (IVS). Methods: From May 2011 to October 2013, endoscope-assisted microneurosurgery (EAM) was applied on 24 patients undergoing IVS surgery via the retrosigmoid suboccipital approach. Bayonet rigid endoscopes with 0-, 30-and 70- degree lenses were used to inspect and guide the tumor dissection in the cerebellopontine angle (CPA) and internal auditory canal (IAC) under microscopic control. Results: No one case of endoscopically thermal or mechanical injury, postoperative cerebrospinal fluid (CSF) leak, or other severe complications was encountered. Endoscopes confirmed the completeness of the tumor resection in 23 cases, as verified in 15 out of 16 patients with at least 6 months MRI follow-up. Anatomic preservation of the facial nerve and cochlear nerve was achieved in 24 (100%) cases. Postoperative facial weakness was never seen in 16 patients with at least 6 months follow-up. Hearing function was preserved postoperatively in 9 (75%) patients out of all 12 patients who showed preoperative serviceable hearing. Conclusion: Adjunctive use of endoscopy during the retrosigmoid approach can provide more information to evaluate neurovascular relationship, the residual tumor and opened air cells than was possible with microscopy alone, ensuring completed IVS removal and neurological function preservation with less operation complications. It is our belief that the improved endoscopic equipment and special training in the future will optimize the outcome of IVS surgical treatment.Ziel: Das Ziel dieser Studie ist, die Machbarkeit und Effizienz der endoskopisch-unterstützten Technik der chirurgische Behandlung des Intracanaliculären Vestibularisschwannom (IVS), zu bewerten. Methoden: Von Mai 2011 bis Oktober 2013 wurde die endoskopisch-unterstützte Mikroneurochirurgie an 24 Patienten mit IVS, über den retrosigmoidalen subokzipitalen Zugang, angewendet. Das bajonettförmige Endoskop mit 0-, 30- und 70- Grad-Optik wurde zur Inspizierung und Einleitung der Resektion von Tumoren des Kleinhirnbrückenwinkels (CPA) und inneren Gehörgangs (IAC) unter mikroskopischer Kontrolle eingesetzt. Ergebnisse: Keine thermischen oder mechanischen Verletzungen wurden durch das Endoskop verursacht, ebenso entwickelte keiner der Patienten postoperative Komplikationen oder Liquorrhoen. Das Endoskop bestätigte die Vollständigkeit der Tumorresektion in 23 von 24 Fällen. Dies bestätigte sich in 15 von 16 MRT-Follow-ups, die mindestens sechs Monate postoperativ gelaufen sind. Anatomische Erhaltung der Nervi Facialis und Cochlearis wurde in allen Fällen erreicht. Postoperative Fazialisparese wurde bei keinen der 16 Patienten mit Follow-up gesehen. Die Erhaltung der Hörfunktion wurde postoperativ bei 9 von 12 Patienten, die präoperativ über Hörvermögen verfügten, festgestellt. Schlussfolgerungen: Der zusätzliche Einsatz der Endoskopie bei dem retrosigmoidalen Zugang kann mehr Informationen liefern, um über neurovaskuläre Strukturen, sowie Tumorreste und geöffneten Luft-Zellen zu urteilen. Komplett IVS Resektion mit Erhalt der neurologischen Funktionen kann dadurch mit weniger Komplikationen gewährleistet werden. Die verbesserten endoskopischen Geräte sowie die spezielle Ausbildung hierfür werden in der Zukunft das Ergebnis der IVS Chirurgie optimieren

Precursors for mitochondrial DNA replication : metabolic sources and relations to mutagenesis and human diseases

It is well known that the mitochondrial genome has a much higher spontaneous mutation rate than the nuclear genome. mtDNA mutations have been identified in association with many diseases and aging. mtDNA replication continues throughout the cell cycle, even in post-mitotic cells. Therefore, a constant supply of nucleotides is required for replication and maintenance of the mitochondrial genome. However, it is not clear how dNTPs arise within mitochondria nor how mitochondrial dNTP pools are regulated. Recent evidence suggests that abnormal mitochondrial nucleoside and nucleotide metabolism is associated with several human diseases. Clearly, to uncover the pathogenesis of these diseases and the mechanisms of mitochondrial mutagenesis, information is needed regarding dNTP biosynthesis and maintenance within mitochondria, and biochemical consequences of disordered mitochondrial dNTP metabolism. The studies described in this thesis provide important insight into these questions. First, we found that a distinctive form of ribonucleotide reductase is associated with mammalian liver mitochondria, indicating the presence of de novo pathway for dNTP synthesis within mitochondria. Second, we found that long term thymidine treatment could induce mtDNA deletions and the mitochondrial dNTP pool changes resulting from thymidine treatment could account for the spectrum of mtDNA point mutations found in Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients. These results support the proposed pathogenesis of this disease. Third, we found that normal intramitochondrial dNTP pools in rat tissues are highly asymmetric, and in vitro fidelity studies show that these imbalanced pools can stimulate base substitution and frameshift mutations, with a substitution pattern that correlates with mitochondrial substitution mutations in vivo. These findings suggest that normal intramitochondrial dNTP pool asymmetries could contribute to mitochondrial mutagenesis and mitochondrial diseases. Last, Amish lethal microcephaly (MCPHA) has been proposed to be caused by insufficient transport of dNTPs into mitochondria resulting from a loss-of-function mutation in the gene encoding a mitochondrial deoxynucleotide carrier (DNC). We found that there are no significant changes of intramitochondrial dNTP levels in both a MCPHA patient's lymphoblasts with a missense point mutation in Dnc gene and the homozygous mutant cells extracted from Dnc gene knockout mouse embryos. These results do not support the proposed pathogenesis of this disease and indicate that the DNC protein does not play a crucial role in the maintenance of intramitochondrial dNTP pools

Assigning the Absolute Configurations of Chiral Primary Amines Based on Experimental and DFT-Calculated 19F Nuclear Magnetic Resonance

In this work, a novel method for assigning the absolute configuration of a chiral primary amine has been developed based on the experimental and DFT-calculated 19F NMR chemical shift differences of its derived two fluorinated amides by reacting with two enantiomers of a chiral derivatizing agent FPP (α-fluorinated phenylacetic phenylselenoester) separately. Comparing the experimental chemical shift difference Δδα-FR,S of (R)-FPA-amide/(S)-FPA-amide with the calculated Δδα-FR,S of (R)-FPA-(R)-amide/(S)-FPA-(R)-amide, if the experimental Δδα-FR,S has the same symbol (positive or negative) as one of the theoretical Δδα-FR,S, the assigned configuration of the amine is considered to be consistent with the theoretical one. Our method could be applied to a broad substrate scope avoiding wrong conclusion due to empirical judgment

Bunching Transitions on Vicinal Surfaces and Quantum N-mers

We study vicinal crystal surfaces with the terrace-step-kink model on a discrete lattice. Including both a short-ranged attractive interaction and a long-ranged repulsive interaction arising from elastic forces, we discover a series of phases in which steps coalesce into bunches of n steps each. The value of n varies with temperature and the ratio of short to long range interaction strengths. We propose that the bunch phases have been observed in very recent experiments on Si surfaces. Within the context of a mapping of the model to a system of bosons on a 1D lattice, the bunch phases appear as quantum n-mers.Comment: 5 pages, RevTex; to appear in Phys. Rev. Let