Pharmacokinetics of varying doses of nicotinamide and tumour radiosensitisation with carbogen and nicotinamide: clinical considerations.

Plasma concentrations, after administration of varying doses of nicotinamide, were measured in CBA male mice using a newly-developed high performance liquid chromatography assay. In all dose groups, peak levels were observed within the first 15 min after an i.p. administration of 0.1, 0.2, 0.3 or 0.5 mg g-1 of nicotinamide. There was a clear dose-dependent increase in plasma concentration with increasing dose, with almost a five-fold lower concentration (1.0 vs 4.9 mumol ml-1) achieved with a dose of 0.1 mg g-1 compared with 0.5 mg g-1, respectively. The half-life of nicotinamide increased from 1.4 h to 2.2 h over the dose range (P < 0.01). Comparisons with previous pharmacokinetic data in humans show that clinically-relevant oral doses of 6 and 9 g in humans give plasma levels slightly higher than those achieved at 1 h with doses of 0.1 to 0.2 mg g-1 in mice. Tumour radiosensitisation with carbogen alone, and with carbogen combined with varying doses of nicotinamide (0.05 to 0.5 mg g-1), was investigated using a 10-fraction in 5 days X-ray schedule. Relative to air-breathing mice, a statistically significant increase in sensitisation was observed with both a local tumour control and with an in vivo/in vitro excision assay (P < or = 0.007). With the local control assay, a trend was observed towards lower enhancement ratios (ERs) with decreasing nicotinamide dose (from 1.85 to 1.55); carbogen alone was almost as effective as when combined with 0.1 mg g-1 of nicotinamide. With the excision assay, ERs for carbogen combined with nicotinamide increased with decreased levels of cell survival. At a surviving fraction of 0.02, enhancement ratios of 1.39-1.48 were obtained for carbogen plus 0.1 to 0.3 mg g-1 of nicotinamide. These were lower than those seen with the two higher doses of 0.4 to 0.5 mg g-1 (ERs = 1.63-1.69).     

Normal splenic function in children with the nephrotic syndrome

Children with the idiopathic nephrotic syndrome (NS) are known to be susceptible to bacterial infections. A recent report suggested that splenic hypofunction may be responsible for this immunological defect. We assessed splenic function by counting the circulating pocked red blood cells (PkRBCs) using interference phase contrast microscopy. PkRBCs are removed by the spleen, so that normal eusplenic individuals have less than 2% PkRBCs while asplenics have 15%–30%. Intermediate values are seen in hyposplenism. Thirty-three measurements of PkRBCs were made in 19 children with NS (mean age 7.5±0.8 years). PkRBCs were normal in all children tested (range 0–0.8%), including two patients with bacterial peritonitis associated with relapse. Thus we were unable to find evidence of hyposplenism in children with NS.     

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.