Tau immunoreactivity and SDS solubility of two populations of paired helical filaments that differ in morphology

To further understand the processes that lead to the formation of neurofibrillary tangles from paired helical filaments (PHF) in Alzheimer brains, we studied two morphologically distinct fractions of PHF separated on sucrose density gradient. In a fraction with mostly short and non-aggregated PHF, the majority of filaments could be solubilized in SDS. In a fraction containing primarily PHF aggregated into clusters or bundles, sometimes resembling neurofibrillary tangles, filaments were less soluble in SDS. Immunogold labelling with a panel of tau-immunoreactive antibodies demonstrated that N-terminal epitopes of tau were preserved in the short filaments, but were reduced or absent in aggregated filaments. In contrast, C-terminal epitopes were present in both fractions. Furthermore, the accessibility of the microtubule-binding domain to immunolabelling was markedly impaired in short and non-aggregated filaments compared to aggregated filaments. These results are consistent with proteolytic degradation of the N-terminal epitopes and preservation of the C-terminal epitopes and the microtubule-binding domain of tau in the aggregated filaments. Partial proteolysis may be involved in the generation of aggregated PHF in neurofibrillary tangles.     

Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.     

Diagnosis and management of the patulous eustachian tube.

OBJECTIVE: The patulous eustachian tube (ET) seems to be caused by a longitudinal concave defect in the mucosal valve at the superior aspect of its anterolateral wall and causes troublesome autophony of one's own voice and breathing sounds. Patulous ET reconstruction was evaluated to analyze whether submucosal graft implantation to fill in the concavity within the patulous tubal valve may produce lasting relief of symptoms. STUDY DESIGN: Prospective trial. SETTING: Tertiary referral center, ambulatory surgery. PATIENTS: Fourteen ETs in 11 adults with 1 or more years of confirmed continuous patulous ET symptoms refractory to medical care. INTERVENTION: Endoluminal patulous ET reconstruction was performed in 14 separate cases using a combined endoscopic transnasal and transoral approach under general anesthesia. A submucosal flap was raised along the anterolateral wall of the tubal lumen up to the valve and mobilized superiorly off of the basisphenoid. The pocket was filled with autologous cartilage graft or Alloderm implant, restoring the normal convexity and competence to the mucosal lumen valve. MAIN OUTCOME MEASURE: Autophony symptoms were scored as 1) complete relief; 2) significant improvement, satisfied; 3)significant improvement, dissatisfied; 4) unchanged; or 5)worse. RESULTS: All 14 cases reported immediate complete relief of autophony. Results with an average follow-up of 15.8 months are as follows: 1 (7%) case had complete relief; 5 (36%) had significant improvement, satisfied; 7 (50%) had significant improvement, dissatisfied; and 1 (7%) was unchanged. There were no complications. Correlation between patulous ET and other conditions was strongest with previous tubal dysfunction. Autophony of voice, but not breathing sounds, was also found to be experienced by 17 (94%) of 18 patients with superior semicircular canal dehiscence syndrome and could be easily mistaken for patulous ET autophony. CONCLUSION: Patulous ET seems to be caused by a concave defect in the tubal valve's anterolateral wall. Submucosal graft implantation to restore the normal convexity to the valve wall seems to provide lasting relief of symptoms. Long-term study is needed. It is important to differentiate between the autophony of semicircular canal dehiscence syndrome and patulous ET.     

An internet survey of 2,596 people with fibromyalgia

Background  

This study explored the feasibility of using an Internet survey of people with fibromyalgia (FM), with a view to providing information on demographics, sources of information, symptoms, functionality, perceived aggravating factors, perceived triggering events, health care utilization, management strategies, and medication use.     

The resurgence of tuberculosis in the Republic of Ireland: Perceptions and reality

Tuberculosis remained a very significant cause of death in Ireland until the mid-20th century and still occupies a prominent position in the folk memory. As I show with reference to recent Irish media coverage, the global resurgence of tuberculosis is therefore viewed with concern in Ireland. Using data collated by the Health Protection Surveillance Centre between 1998 and 2005 however, I show that the recent increase in tuberculosis incidence in Ireland is less than is popularly perceived. This increase is largely associated with economic immigrants attracted to Ireland by the ‘Celtic Tiger’ economic boom, but there is little evidence to suggest that this has had a negative impact on the Irish-born population. Drug resistance is still a small but growing problem. Whilst vigilance is required, it is argued that the recent increase does not at present indicate a likely return to the situation in the mid-20th century.     

Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder.

BACKGROUND: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroimaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-depressives (MDD), bipolar-depressives (BD) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BD extend to depressed subjects with MDD. METHODS: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [(11)C]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). RESULTS: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BD and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. CONCLUSIONS: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BD.     

Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance-Associated Protein 2

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.     

Pituitary volume in teenagers with first-presentation borderline personality disorder

This study used magnetic resonance imaging to examine pituitary gland volume (PGV) in teenage patients with a first presentation of borderline personality disorder (BPD). No difference in PGV was observed between healthy controls (n = 20) and the total BPD cohort (n = 20). However, within the BPD cohort, those exposed to childhood trauma (n = 9) tended to have smaller pituitaries (− 18%) than those with no history of childhood trauma (n = 10). These preliminary findings suggest that exposure to childhood trauma, rather than BPD, per se, might be associated with reduced PGV, possibly reflecting hypothalamic–pituitary–adrenal axis dysfunction.