Surface modification of poly(methyl-methacrylate) with farnesol to prevent Candida biofilm formation.

Candida albicans promotes biofilm formation on dentures, which compromises the use of poly(methyl-methacrylate) (PMMA) as a dental material. Farnesol (FAR), a natural compound that prevents C. albicans filamentation and biofilm formation, was incorporated into the PMMA matrix, to obtain antifungal PMMA_FAR materials. The tested concentrations (0·0125% and 0·4%) of FAR, 24 h after incubation on YPD agar, inhibited filamentation of C. albicans. PMMA was modified with different FAR concentrations (3-12%), and physicochemical properties, antifungal activity and cytotoxicity of these modified materials (PMMA_FAR) were tested. The presence of FAR in PMMA_FAR composites was verified by Fourier-transform infrared spectroscopy (FT-IR). Incorporation of FAR into the polymeric matrix significantly decreased hydrophilicity at all tested concentrations and significantly reduced biofilm and planktonic cells metabolic activity in the early stage of biofilm formation at ≥6% FAR in PMMA. PMMA_FAR composites with <9% FAR were non-toxic. Modification of PMMA with FAR is a good strategy for reducing C. albicans biofilm formation on dentures.

Neglected nano-effects of nanoparticles in the interpretation of their toxicity.

Nanoparticles with smaller diameters have larger surface areas. Unfortunately, this fact is often neglected in their biomedical characterization, e.g. in the evaluation of their toxicity with cell viability tests. We here point out the different scientific conclusions drawn in such tests when considering the traditional mass or concentration of nanoparticles, or their surface areas.

Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus.

Herpes simplex virus 1 fuses with the plasma membrane of a host cell, and the incoming capsids are efficiently and rapidly transported across the cytosol to the nuclear pore complexes, where the viral DNA genomes are released into the nucleoplasm. Using biochemical assays, immunofluorescence, and immunoelectron microscopy in the presence and absence of microtubule depolymerizing agents, it was shown that the cytosolic capsid transport in Vero cells was mediated by microtubules. Antibody labeling revealed the attachment of dynein, a minus end-directed, microtubule-dependent motor, to the viral capsids. We propose that the incoming capsids bind to microtubules and use dynein to propel them from the cell periphery to the nucleus.

Transport of peptide-MHC class II complexes in developing dendritic cells.

Major histocompatibility complex class II (MHC II) molecules capture peptides within the endocytic pathway to generate T cell receptor (TCR) ligands. Immature dendritic cells (DCs) sequester intact antigens in lysosomes, processing and converting antigens into peptide-MHC II complexes upon induction of DC maturation. The complexes then accumulate in distinctive, nonlysosomal MHC II+ vesicles that appear to migrate to the cell surface. Although the vesicles exclude soluble lysosomal contents and antigen-processing machinery, many contain MHC I and B7 costimulatory molecules. After arrival at the cell surface, the MHC and costimulatory molecules remain clustered. Thus, transport of peptide-MHC II complexes by DCs not only accomplishes transfer from late endocytic compartments to the plasma membrane, but does so in a manner that selectively concentrates TCR ligands and costimulatory molecules for T cell contact.

Herpes simplex virus type 1 entry into host cells: reconstitution of capsid binding and uncoating at the nuclear pore complex in vitro.

During entry, herpes simplex virus type 1 (HSV-1) releases its capsid and the tegument proteins into the cytosol of a host cell by fusing with the plasma membrane. The capsid is then transported to the nucleus, where it docks at the nuclear pore complexes (NPCs), and the viral genome is rapidly released into the nucleoplasm. In this study, capsid association with NPCs and uncoating of the viral DNA were reconstituted in vitro. Isolated capsids prepared from virus were incubated with cytosol and purified nuclei. They were found to bind to the nuclear pores. Binding could be inhibited by pretreating the nuclei with wheat germ agglutinin, anti-NPC antibodies, or antibodies against importin beta. Furthermore, in the absence of cytosol, purified importin beta was both sufficient and necessary to support efficient capsid binding to nuclei. Up to 60 to 70% of capsids interacting with rat liver nuclei in vitro released their DNA if cytosol and metabolic energy were supplied. Interaction of the capsid with the nuclear pore thus seemed to trigger the release of the viral genome, implying that components of the NPC play an active role in the nuclear events during HSV-1 entry into host cells.

ATP and NADPH coated iron oxide nanoparticles for targeting of highly metabolic tumor cells.

The metabolic activity of tumor cells is known to be higher as compared to that of normal cells, which has been previously exploited to deliver nanomedicines to highly metabolic tumor cells. Unfortunately, current strategies, which are mostly based on complex energy sources, such as sugars, showed insufficient accumulation at the target sites. We here report the coating of IONPs with two essential units of cellular metabolism: adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH). ATP and NADPH were directly bound to the IONPs' surface using a simple aqueous method. Both molecules were used as coatings, i.e. as stabilizing agents, but also simultaneously as targeting molecules to deliver IONPs to highly metabolic tumor cells. Indeed, we found that the uptake of ATP-IONPs and NADPH-IONPs is correlated with the metabolic activity of tumor cells, especially regarding their cellular ATP levels and NADPH consumption. We also measured one of the highest MRI r2 relaxivities for both ATP-IONPs and NADPH-IONPs. With the direct coating of IONPs with ATP and NADPH, we therefore provide an optimal platform to stabilize IONPs and at the same time promising properties for the targeting and detection of highly metabolic tumor cells.

Pituitary adenoma: a DNA flow cytometric study of 192 clinicopathologically characterized tumors.

A clinically, immunohistochemically and ultrastructurally characterized series of 192 pituitary adenomas was analyzed for DNA content by flow cytometry. Results were assessed not only relative to tumor immunotype, size, and invasiveness, but also with frequency of recurrence. Case selection was non-random; males predominated (1.8:1) and the ratio of macro-to-microadenomas was 4.2:1. Female patients were slightly younger and, in all adenoma categories, less often had invasive tumors: PRL (15%/30%), ACTH (17%/44%), LH/FSH (8%/27%) and null cell adenomas (0%/27%). With the exception of prolactin cell adenomas, similar proportions of macroadenomas and invasive tumors in all tumor subtypes were diploid and non-diploid. Prolactin adenomas differed in that tumors of males showed a high rate of non-diploidy (65%); such tumors were predominantly macroadenomas, but only 28% were invasive. Among GH-containing tumors 78% were macroadenomas, 40% were nondiploid, and the frequency of invasive macroadenomas was higher (49%) than in PRL tumors (21%). ACTH adenomas were mainly microadenomas (81%), their rate invasion (29%) and of non-diploidy being low (14%). Among "non-functioning" (LH/FSH, null cell adenomas), LH/FSH-producing tumors were all macroadenomas, but with low rates of invasion (23%) and non-diploidy (9%). Null cell adenomas, nearly all macroadenomas, had similar low invasion rate (21%), but were more often non-diploid (39%). In all adenoma subgroups S-phase fractions were higher in non-diploid adenomas by an overall ratio of 2.1:1. Prolactin adenomas showed the highest (15.2%) and LH/FSH adenomas the lowest (5.6%) mean S-phase fraction. When compared to long-term follow-up, neither this parameter nor ploidy correlated with tumor size or invasiveness. Lastly, long-term follow-up showed ploidy to be an unreliable predictor of tumor persistence or recurrence.

Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients.

Paragangliomas are rare tumors that arise from extraadrenal chromaffin cells. We examined the clinical characteristics, location, treatment, and outcome of 236 patients (141 females, 60%) with 297 benign paragangliomas evaluated at the Mayo Clinic during 1978-1998. The mean age (+/-SD) at diagnosis was 47 +/- 16 yr. Of the 297 paragangliomas, 205 were in the head and neck region, and 92 were below the neck. Paragangliomas were discovered and diagnosed incidentally on imaging studies in 9% of patients. Biochemical screening was performed in 128 patients; 40 patients (17% of the total and 31% of those screened) had hyperfunctional tumors. Of the 40 patients with tumoral catecholamine excess, 38 had documented hypertension. In patients identified with catecholamine-secreting paragangliomas, the sensitivities achieved by measurements in the 24-h urine collection were 74% for total metanephrines, 84% for norepinephrine, 18% for dopamine, and 14% for epinephrine. Multiple imaging modalities were used for tumor localization. The false negative rates were 0% for magnetic resonance imaging, 5.8% for computed tomography, 3.4% for angiography, 10.7% for ultrasonography, and 39% for radioactive iodine-labeled metaiodobenzylguanidine scintigraphy. Of 192 patients (81.4%) with follow-up data (mean, 43.9 months; range, 0.5-240), operative cure was achieved in 133 (69%). Of the 59 patients without cure, 23 had persistent disease, 5 had recurrent disease, 16 had multiple persistent synchronous tumors, and 15 subsequently developed metachronous tumors. In conclusion, most paragangliomas are nonhypersecretory and located in the head and neck region. Magnetic resonance imaging was associated with the lowest false negative rate, and metaiodobenzylguanidine was the least sensitive imaging study. A significant proportion of patients (31%) has persistent or recurrent disease, and long-term follow-up is important.

Tension pneumocranium, a rare complication of transsphenoidal pituitary surgery: Mayo Clinic experience 1976-1998.

We describe four cases of symptomatic pneumocranium, a rare, potentially life-threatening complication of transsphenoidal pituitary surgery. Symptomatic pneumocranium manifested as impaired mental status, headaches, and grand mal seizures, early in the postoperative course after transsphenoidal pituitary surgery. Furthermore, a Cushing response, including systemic hypertension and bradycardia (secondary to intracranial hypertension) was seen, which has not been previously described in association with symptomatic pneumocranium. We describe a previously unreported risk factor for tension pneumocranium, untreated obstructive sleep apnea. Other factors predisposing to tension pneumocranium in our patients included: cerebrospinal fluid leaks, postoperative positive-pressure mask ventilation, large pituitary tumors, and intraoperative lumbar drainage catheters. Surgical drainage of the pneumocranium and repair of any coexistent cerebrospinal fluid leak markedly improved neurologic status. Symptomatic pneumocranium occurring early in the postoperative course after transsphenoidal pituitary surgery is rare, but prompt recognition and treatment of this condition can be life-saving.

Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation.

The cause of gigantism in most patients is a GH-secreting pituitary tumor. In this report, a case of congenital gigantism due to probable central hypersection of GH-releasing hormone (GHRH) is described. Normal at birth (4.4 kg; 53 cm), our 7-yr-old male patient grew progressively thereafter to attain a height of 182 cm and a weight of 99.4 kg at the time of our evaluation. The markedly increased baseline plasma levels of GH (730 micrograms/L) did not suppress during a standard 3-h oral glucose tolerance test, but did increase 54% after iv infusion of GHRH. Baseline plasma levels of insulin-like growth factor-I, PRL, and immunoreactive GHRH were also markedly increased. Computed imaging of the head showed a large, partially cystic sellar and suprasellar mass. Extensive imaging studies did not localize a potential source of GHRH. Preoperative treatment with octreotide and bromocriptine for 4 months resulted in a 25% reduction of suprasellar tissue mass. The pituitary tissue removed at transsphenoidal and transfrontal operations showed massive somatotroph, lactotroph, and mammosomatotroph hyperplasia. Areas of GH- and PRL-secreting cell adenomatous transformation were also evident. No histological or immunohistochemical evidence of a pituitary source of GHRH was found. The peripheral plasma immunoreactive GHRH concentration remained unaffected by pharmacological and surgical interventions. We suspect that a congenital hypothalamic regulatory defect may be responsible for the GHRH excess in this case.

Effect of BAEP monitoring on hearing preservation during acoustic neuroma resection.

We measured the effect of brainstem auditory evoked potential (BAEP) monitoring on hearing preservation in acoustic neuroma resection in 90 consecutive patients with monitoring compared with 90 historical controls matched for tumor size and preoperative hearing status. In small tumors (less than 2 cm), BAEP monitoring was associated with a higher rate of hearing preservation and a greater chance that the hearing preserved was clinically useful. Changes in the BAEP intraoperatively showed a good correlation with postoperative hearing status.

Esthesioneuroblastoma: the role of adjuvant radiation therapy.

PURPOSE: We describe our experience with adjuvant radiation therapy in patients who underwent operation for esthesioneuroblastoma. METHODS AND MATERIALS: Between January 1951 and December 1990, 49 patients with esthesioneuroblastoma received their initial treatment at the Mayo Clinic. There were 27 male and 22 female patients; their ages ranged from 3 to 79 years (median, 54 years). The tumors were Kadish Stage A in 4 patients, Stage B in 13, Stage C in 29, and modified Kadish Stage D in three (cervical nodal or distant metastasis). The tumors were graded according to Hyams' classification. Treatment included gross total resection alone in 22 patients and gross total resection and postoperative adjuvant radiation therapy in 16. The patients treated with adjuvant radiation had a greater proportion of advanced-stage and high-grade tumors. RESULTS: The 5-year actuarial overall survival, disease-free survival, and local control rates were 69.1% + 7.0%, 54.8% + 7.6%, and 65.3% + 7.4%, respectively. The only significant predictor for overall survival, disease-free survival, and local control was Hyams' grade. Local control was improved in patients who received postoperative adjuvant radiation even though this group of patients had more advanced and higher-grade tumors (5-year rate of local control was 85.9% + 9.3%, compared with 72.7% + 9.5% for those who had operation alone, p = 0.26). CONCLUSION: Adjuvant radiation therapy for esthesioneuroblastoma improves local tumor control, particularly for high-grade and high-stage tumors. We recommend additional treatment with radiation (55.5 Gy) after complete resection of esthesioneuroblastoma.

Summated auditory evoked potentials in the cerebellum and inferior colliculus in the young rat.

The summated auditory evoked responses recorded at the superior surface and depth of the cerebellum of the young rat had a similar latency and configuration as did summated auditory evoked potentials in the inferior colliculus. Electric stimulation of the inferior colliculus did not evoke a response (other than the shock-artifact response) at the cerebellum. Stimulation of the cerebellum did not modify the evoked responses to click in the inferior colliculus (unless current levels were large enough to cause current spread to the brain stem). There is insufficient evidence to conclude that the cerebellum has an auditory receiving area in the young rat.

Measurements of autonomic function before, during, and after transcutaneous stimulation in patients with chronic pain and in control subjects.

Transcutaneous stimulation (TCS) has been reported to modify peripheral blood flow, skin temperature, blood pressure, and heart rate, all of which are under the influence of the autonomic nervous system (ANS). In 20 patients with intractable pain and in 10 control subjects, TCS was not found to alter significantly any of the observed properties of ANS function of control subjects or patients, except to decrease skin impedance in the patient group after the stimulation. Patients reporting pain relief during TCS were found to have significantly higher systolic blood pressure under all test conditions than patients reporting no pain relief (p less than 0.05). No other significant differences were found between these two groups. Finally, in the patients, no significant localized autonomic changes were demonstrated in the painful area by comparison with the homologous body part.

Cervical fractures and spinal cord injury: outcome of surgical and nonsurgical management.

Data were collected retrospectively for 102 consecutive patients with a cervical spinal cord injury admitted to a spinal cord injury center between 1976 and 1986. Frankel's classification and level of spinal cord injury stayed the same or improved in all patients. The complications that occurred compared favorably with outcomes reported in the literature. Approximately 60% of patients achieved a catheter-free voiding status before dismissal from primary rehabilitation. Patients treated with early surgical stabilization of the cervical column were hospitalized a mean of 21 fewer days than their nonsurgical counterparts. In addition, patients treated with early surgical stabilization achieved their first therapeutic leave of absence from primary rehabilitation approximately 40 days sooner than patients stabilized nonsurgically. At final follow-up, however, no appreciable differences in achievement in activities of daily living and mobility were noted between patients treated with surgical stabilization of the cervical spinal column and those treated nonsurgically.

Sarcoid masquerading as optic nerve sheath meningioma.

Sarcoid manifesting as an optic nerve tumor without evidence of systemic disease is uncommon. Throughout a 2-year period, a 22-year-old white woman had progressive monocular loss of vision to the level of no light perception. Optic atrophy but no uveitis was noted in the affected eye. Magnetic resonance imaging revealed thickening and enhancement of the apical optic nerve, with "tram-tracking." The presumptive diagnosis was optic nerve sheath meningioma; however, a biopsy specimen from the optic nerve revealed sarcoid. Extensive postoperative investigations revealed no systemic sarcoidosis. To our knowledge, 17 cases similar to ours, with the diagnosis proved by optic nerve biopsy, have been previously reported in the English-language literature. Most of these were mistaken preoperatively for optic nerve sheath meningioma. None of the patients had evidence of systemic sarcoidosis on initial postoperative testing. Neuroimaging, serum level of angiotensin-converting enzyme, and clinical characteristics such as age, race, sex, and optochoroidal collaterals do not distinguish optic nerve sheath meningioma from sarcoid of the optic nerve. In the absence of uveitis or systemic involvement, optic nerve sarcoid manifesting as an orbital tumor is virtually impossible to diagnose without results of biopsy.

Improved preservation of facial nerve function with use of electrical monitoring during removal of acoustic neuromas.

Continuous spontaneous electromyographic activity and responses to electrical stimulation of the facial nerve in the surgical field were monitored in 48 patients undergoing primary removal of an acoustic neuroma. The operative and postoperative results in these patients were compared with the results in 48 patients who were matched for age and size of tumor and who underwent the same surgical procedure without intraoperative monitoring. Eighty-three percent of the patients had preoperative evidence of facial neuropathy, which was more severe with larger tumors. Postoperative facial nerve function was most accurately predicted on the basis of the extent of facial neuropathy on preoperative electrophysiologic testing. Anatomic preservation of the facial nerve in patients with large tumors was substantially improved in the monitored patients (67%) in comparison with those without monitoring (33%). No difference was noted in facial nerve function in the two groups of patients immediately postoperatively. By 3 months, the degree of improvement in the monitored group exceeded that in those who were not monitored, particularly in patients with medium-sized and large tumors.

Transfrontal orbital decompression after failure of transantral decompression in optic neuropathy of Graves' disease.

Transantral and transfrontal orbital decompression procedures are effective for treating optic neuropathy of Graves' disease. We studied 10 patients with Graves' disease to clarify whether transfrontal decompression is effective after prior failure of transantral orbital decompression. All patients had persistent or recurrent optic neuropathy after transantral decompression and had failed to respond to systemic corticosteroid therapy. After transfrontal decompression, visual acuity improved in 70% of the eyes, and visual field scotomas decreased in 80%. No major intraoperative or postoperative complications occurred. We conclude that in optic neuropathy of Graves' disease, transfrontal orbital decompression after failure of transantral decompression is an acceptable and beneficial salvage procedure.

Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas. Results in 100 patients.

One hundred patients, 84 females and 16 males, with presumed prolactin-producing pituitary adenomas were treated with transsphenoidal microsurgery. Criteria for success of the operation were return of serum prolactin values to normal and reversal of the endocrine effects of hyperprolactinemia, eradication of the adenoma, and preservation of anterior pituitary function. Of the 84 females, 54 had a microadenoma (a noninvasive adenoma 10 mm or less in diameter), and of the 32 with preoperative values of serum prolactin of less than 100 ng/ml, 28 (88%) had a successful operative result, whereas 11 of 22 (50%) with preoperative values of 100 ng/ml or more had a successful result. Five of 10 patients (50%) with a diffuse adenoma (a noninvasive adenoma more than 10 mm in diameter) and 5 of 20 (25%) with an invasive adenoma had a successful result. Of the 16 males, 3 of 7 (43%) with diffuse adenoma and 3 of 16 (19%) with invasive adenoma had a successful result. There were no males with microadenoma. The largest success rate (88%) was among female patients with microadenoma and preoperative serum prolactin values of less than 100 ng/ml.

Pituitary adenomas associated with hyperprolactinemia: a clinical and immunohistochemical study of 97 patients operated on transsphenoidally.

Immunohistochemical studies were performed on the tumors of 97 of 100 patients who had undergone an operation for a presumed prolactin-secreting pituitary adenoma; no tissue was available for study in the other 3 patients. Appropriate immunohistochemical studies were done to identify the presence of growth hormone, prolactin, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone within the adenoma cells. The presence of a prolactin-producing pituitary adenoma was confirmed in 91 patients, 3 of whom had an adenoma that consisted of cells that contained prolactin and growth hormone. One other patient, not counted among the 91 with prolactinoma, had lactotrope and thyrotrope hyperplasia. Among the five patients whose adenoma did not contain prolactin cells, four had a null cell adenoma and one had a tumor consisting of follicle-stimulating hormone and luteinizing hormone immunoreactive cells. On the basis of preoperative serum prolactin values in these patients, we concluded that moderately increased values (30 to 200 ng/ml) of serum prolactin are not a reliable guide for determining whether a prolactin-producing pituitary adenoma is present, whereas levels exceeding 200 ng/ml are usually associated with a prolactin-secreting tumor.