Mary P. Coffey

A prospective study to identify high-yield criteria associated with acute intracranial computed tomography findings in head-injured patients

We conducted a multicenter, prospective study of head-injured patients to identify high-yield clinical criteria for acute intracranial injuries. Emergency patients with a history of blunt head trauma occurring within 2 weeks and who underwent nonenhanced cranial computed tomography (CT) were entered onto the study during a 12-month period. Of the 264 patients, 32 (12%) had abnormal CT findings. Nine high-yield variables were associated with abnormal CT findings: alcohol use before injury, antegrade amnesia, prolonged loss of consciousness, anisocoria and/or fixed and dilated pupils, abnormal Babinski reflex, focal motor paralysis, cranial nerve deficit, Glasgow coma scale score of less than 15, and clinical signs of basilar skull fracture. Patients 2 years old or younger or older than 60 years of age showed a significantly greater prevalence of abnormal CT findings than patients of other ages.

PULSED LOW DOSE RATE BRACHYTHERAPY IN A RAT MODEL: DEPENDENCE OF LATE RECTAL INJURY ON RADIATION PULSE SIZE

PURPOSE Clinical protocols utilizing pulsed low dose rate brachytherapy (PDR) to replace traditional continuous low dose rate brachytherapy (CLDR) employ irradiation in individual pulses given at intervals of a few hours. A critical factor in determining whether PDR will produce equivalent or greater late-occurring normal tissue toxicity is the dose per pulse. A rat rectal model was used to determine the role of pulse size in modifying dose effectiveness in producing late-occurring toxicity. METHODS AND MATERIALS A rat model in which the rectum is irradiated with 192Ir sources was used in conjunction with an intracavitary applicator. A section of rectum 1.3 cm in length was irradiated with either 0.75 Gy/h CLDR or one of five schemes of PDR. The schemes applied 0.375, 0.75, 1.5, 3.0, or 6.0 Gy pulses at 0.5, 1.0, 2.0, 4.0, or 8.0 h intervals, respectively. Rats were observed for up to 300 days after completion of irradiation for rectal obstruction. Rectal specimens were taken at the time of sacrifice for obstruction or at the end of follow-up and analyzed histologically for injury. RESULTS Effectiveness of irradiation was analyzed by calculating the ED50 for incidence of obstruction and severe histological injury. The ED50 for obstruction after treatment with CLDR and pulse sizes of 0.375, 0.75, and 1.5 Gy were 70.5, 68.0, 68.6, and 68.8 Gy, respectively. These values were not significantly different. Compared to CLDR, the ED50 for obstruction after pulse sizes of 3.0 and 6.0 Gy were significantly different at 60.9 and 46.3 Gy, respectively. The relative changes in ED50 for the different radiation schemes in producing ulceration, fibrosis, and vascular sclerosis injury were similar to that observed for obstruction. The endpoints of colitis cystica profunda and atypical epithelial regeneration varied less with increasing pulse size. CONCLUSIONS We have demonstrated that for late rat rectal injury, dose responses to PDR pulse sizes up to 1.5 Gy at 2-h intervals are not distinguishable from that seen with CLDR at a dose rate of 0.75 Gy/h.

Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations

Alpha‐synuclein is the major protein in Lewy bodies, the hallmark pathological finding in Parkinsons disease (PD) and dementia with Lewy bodies (DLB). Although normally intracellular, it also can be secreted, so extracellular alpha‐synuclein may contribute to neuronal injury. Serum antibodies to alpha‐synuclein could exert protective effects by increasing alpha‐synucleins movement out of the brain and, if they cross the blood–brain barrier, by inhibiting its neurotoxic effects. The objective of this study was to measure antibody concentrations to alpha‐synuclein monomer and soluble oligomers in three intravenous immunoglobulin (IVIG) preparations, Gamunex (Talecris Biotherapeutics), Gammagard (Baxter Healthcare) and Flebogamma (Grifols Biologicals). Antibodies were measured in native IVIG preparations and after antibody–antigen complex dissociation. IVIGs non‐specific binding was subtracted from its total binding to alpha‐synuclein to calculate specific anti‐alpha‐synuclein antibody concentrations. Specific antibodies to alpha‐synuclein monomer and/or soluble oligomers were detected in all IVIG products. In native IVIG preparations, the highest anti‐monomer concentrations were in Gammagard and the highest anti‐oligomer concentrations were in Gamunex; the extent to which lot‐to‐lot variation may have contributed to these differences was not determined. Antibody–antigen complex dissociation had variable effects on these antibody levels. The IVIG preparations did not inhibit alpha‐synuclein oligomer formation, although they changed the distribution and intensity of some oligomer bands on Western blots. The presence of antibodies to soluble alpha‐synuclein conformations in IVIG preparations suggests that their effects should be studied in animal models of synucleinopathies, as a first step to determine their feasibility as a possible treatment for PD and other synucleinopathies.

Effects of intravenous immunoglobulin on alpha synuclein aggregation and neurotoxicity.

α-Synuclein is thought to contribute to the pathogenesis of Parkinsons disease (PD). It is the main protein in Lewy bodies, the pathognomonic inclusion bodies in the PD substantia nigra, and mutations which increase its aggregation and/or expression are associated with familial early-onset parkinsonism. Soluble oligomers are considered to be α-synucleins most neurotoxic conformation. We previously reported that intravenous immunoglobulin (IVIG) products contain specific antibodies to α-synuclein which do not prevent development of four-day α-synuclein oligomers. The objective of this study was to further examine IVIGs effects on α-synucleins aggregation and neurotoxicity. The IVIG product Gammagard (Baxter Healthcare) did not prevent the development of nine-day α-synuclein oligomers, nor did it degrade preformed oligomers, as shown by western blots performed on gels run under reducing/denaturing conditions and native gels. In western blots of native gels, an additional low molecular weight band (~22 kDa) was detected in α-synuclein incubated for four days in Gammagard, but not in Gammagard alone. No significant differences were found for Thioflavin-T reactivity between α-synuclein amorphous aggregates grown in Gammagard vs. those grown in phosphate-buffered saline. Gammagard partially protected SK-N-BE(2)M17 human neuroblastoma cells against α-synuclein oligomer toxicity (p = 0.007 vs. protective effects of normal human IgG). These findings suggest that although IVIG does not prevent α-synuclein aggregation, it still may reduce α-synuclein neurotoxicity through an unknown mechanism.

Predictors of Incisional Hernia after Robotic Assisted Radical Prostatectomy

Introduction. To explore the long term incidence and predictors of incisional hernia in patients that had RARP. Methods. All patients who underwent RARP between 2003 and 2012 were mailed a survey reviewing hernia type, location, and repair. Results. Of 577 patients, 48 (8.3%) had a hernia at an incisional site (35 men had umbilical), diagnosed at (median) 1.2 years after RARP (mean follow-up of 5.05 years). No statistically significant differences were found in preoperative diabetes, smoking, pathological stage, age, intraoperative/postoperative complications, operative time, blood loss, BMI, and drain type between patients with and without incisional hernias. Incisional hernia patients had larger median prostate weight (45 versus 38 grams; P = 0.001) and a higher proportion had prior laparoscopic cholecystectomy (12.5% (6/48) versus 4.6% (22/480); P = 0.033). Overall, 4% (23/577) of patients underwent surgical repair of 24 incisional hernias, 22 umbilical and 2 other port site hernias. Conclusion. Incisional hernia is a known complication of RARP and may be associated with a larger prostate weight and history of prior laparoscopic cholecystectomy. There is concern about the underreporting of incisional hernia after RARP, as it is a complication often requiring surgical revision and is of significance for patient counseling before surgery.

Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson’s Disease-Associated LRRK2 Gene Mutations

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson’s disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27). 8-OHdG and 8-ISO levels were increased in LRRK2 CTL subjects, while TAC was similar between groups. 8-ISO was negatively correlated, and TAC was positively correlated, with Montreal Cognitive Assessment scores in LRRK2 PD, LRRK2 CTL, and CTL subjects. Correlations in both groups of PD patients between the two oxidative stress markers and Unified Parkinson Disease Rating Scale Total scores were weak, while TAC was negatively correlated with these scores. These findings suggest that oxidative stress may be increased in the CNS in healthy individuals with PD-associated LRRK2 mutations. Further, TAC may decrease in the CNS with the progression of PD, and when cognitive impairment is present regardless of the presence or absence of PD.

Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress.

Age-associated declines in protein homeostasis mechanisms (“proteostasis”) are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone-mediated autophagy, and its associations with indicators of oxidative stress (8-hydroxy-2′-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (ρ = –0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (ρ = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (ρ = –0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of ρ values: –0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8-isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain.

Aβ anti-idiotypic antibodies are present in intravenous immunoglobulin and are produced in mice following its administration

Abstract The effects of intravenous immunoglobulin (IVIG) products were recently examined in patients with Alzheimer’s disease (AD). Although encouraging results were obtained in pilot studies, later trials produced negative results. The rationale for these studies was that IVIG contains antibodies to amyloid-beta (Aβ). However, if Aβ anti-idiotypic antibodies (antibodies which bind to anti-Aβ antibodies) are present in IVIG or induced by its administration, these antibodies could potentially reduce its neuroprotective effects in AD. The objective of this study was to determine if IVIG contained such antibodies. Enzyme-linked immunosorbent assays (ELISAs) measured specific binding of IVIG Gamunex to purified human anti-Aβ IgG. The mean concentration of its Aβ anti-idiotypic antibodies in four experiments was 1.85 μg/mL (18.5 μg/g IgG; range = 1.82–1.89 μg/mL [18.2–18.9 μg/g IgG]), and their mean percentage of specific binding was 72.2% (range = 68.3–75.3%). We then performed ELISAs to determine if antibodies to purified human anti-Aβ were produced in C57BL/6 mice injected with the IVIG product Gammagard in an earlier study. After subtracting the expected immune response to normal human immunoglobulins, the median concentrations of these antibodies were 15.6 ng/mL (range = 1.2–108.2 ng/mL) in pre-treatment sera and 2419.4 ng/mL (range = 327.4–8478.4 ng/mL) in post-treatment sera. These results indicate that specific Aβ anti-idiotypic antibodies are detectable in IVIG and may be induced in mice by its administration. The presence of Aβ anti-idiotypic antibodies in IVIG products might decrease neuroprotective effects of their anti-Aβ antibodies in AD.

Middle Eastern Rhinoplasty: Relationship of the Nasal Spine and Caudal Septum to Tip Projection and Columellar-Labial Angle

Objective To measure the anterior nasal spine length (ANSL) and septal caudal extension (SCE), as well as assess the strength of association between these variables and tip projection in the Middle Eastern nose. Our secondary aim was to assess if columellar-labial angle (CLA) or columellar-spinal angle (CSA) vary as a function of ANSL and/or SCE. Study Design/Setting Prospective single institutional study. Subjects Middle Eastern primary rhinoplasty patients without nasal trauma or prior endonasal surgical history. Methods Photographic and intraoperative caliper measurements were used to determine Goode ratio (GR), CLA, CSA, ANSL, and SCE. Associations between numeric variables were examined with scatterplots, including use of LOWESS curves and Pearson correlation coefficients. Linear regression models were used for predicting quantitative variables (GR, CLA, CSA). Logistic regression models were used for predicting overprojection status based on GR. Results In total, 102 patients met inclusion criteria (82 females, 20 males). Mean ANSL and SCE were 8.6 mm and 14.9 mm, respectively; ANSL and SCE had a strong positive association with each other. SCE and ANSL were found to have low predictability for GR, CLA, or CSA. Conclusion Determinations of projection status using the GR method do not appear to be related to ANSL or SCE values in our Middle Eastern study group. Relationships of absolute columellar-labial or columellar-spinal angles are likely more complex than isolated value implications of SCE or ANSL.