Lack of association of apoE ε4 allele with insulin resistance

ApoE is a polymorphic protein involved in the metabolism of plasma lipoproteins; the ε4 allele was shown to be associated with coronary and aortic atherosclerosis in age-dependent fashion mediated by unknown mechanisms. This study was undertaken to assess whether the apoE isoforms in humans were associated with normal glucose tolerance and with metabolic and inflammatory risk factors of CVD. ApoE genotype was assessed in 365 individuals. Of those, 309 were studied in the postabsorptive conditions and 142 of them also underwent a 3h-OGTT; 56 additional subjects were studied by means of the insulin clamp in combination with [6,6-2H2] glucose infusion. ApoE genotype frequencies were similar to those previously reported and were not influenced by age and BMI. Fasting plasma glucose, insulin, FFA, the lipid profile, surrogate markers (HOMA-IR, OGTT-derived index) as well as the clamp-derived parameters or insulin sensitivity and insulin secretion were not different by apoE genotypes. Serum adipokines concentrations (leptin, adiponectin, resistin) and markers of inflammation (serum fasting hsCRP and MCP1/CCL2) were also not different by apoE genotypes. In the subgroup of young ε4 carriers which underwent the clamp procedure, a higher fasting endogenous glucose production was detected. ApoE genotype was not associated with insulin resistance or altered insulin secretion, and no abnormalities in the typical circulating endocrine, metabolic, and inflammatory features of the insulin resistance syndrome were detected.     

Rinderpest Virus Sequestration and Use in Posteradication Era

After the 2011 declaration of rinderpest disease eradication, we surveyed 150 countries about rinderpest virus stocks. Forty-four laboratories in 35 countries held laboratory-attenuated strains, field strains, or diagnostic samples. Vaccine and reagent production and laboratory experiments continued. Rigorous standards are necessary to ensure that stocks are kept under safe conditions.     

Multiple brain networks support processing speed abilities of patients with multiple sclerosis

Objectives: Many people affected by multiple sclerosis (MS) experience cognitive impairment, especially decreases in information processing speed (PS). Neural disconnection is thought to represent the neural marker of this symptom, although the role played by alterations of specific functional brain networks still remains unclear. The aim is to investigate and compare patterns of association between PS-demanding cognitive performance and functional connectivity across two MS phenotypes.

Methods: Forty patients with relapsing-remitting MS (RRMS) and 25 with secondary progressive MS (SPMS) had neuropsychological and MRI assessments. Multiple regression models were used to investigate the relationship between performance on tests of visuomotor and verbal PS, and on the verbal fluency tests, and functional connectivity of four cognitive networks, i.e. left and right frontoparietal, salience and default-mode, and two control networks, i.e. visual and sensorimotor.

Results: Patients with SPMS were older and had longer disease history than patients with RRMS and presented with worse overall clinical conditions: higher disease severity, total lesion volume, and cognitive impairment rates. However, in both patient samples, cognitive performance across tests was negatively correlated with functional connectivity of the salience and default-mode networks, and positively with connectivity of the left frontoparietal network. Only the visuomotor PS scores of the RRMS group were also associated with connectivity of the sensorimotor network.

Conclusions: PS-demanding cognitive performance in patients with MS appears mainly associated with strength of functional connectivity of frontal networks involved in the evaluation and manipulation of information, as well as the default mode network. These results are in line with the hypothesis that multiple neural networks are needed to support normal cognitive performance across MS phenotypes. However, different PS measures showed partially different patterns of association with functional connectivity. Therefore, further investigations are needed to clarify the contribution of inter-network communication to specific cognitive deficits due to MS.     

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV''s induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.     

Different patterns of technetium-99m sestamibi uptake in multiple myeloma

Technetium-99m 2-methoxyisobutylisonitrile (^99mTc-MIBI) has been proposed as a potential tracer in patients with multiple myeloma (MM). The aims of this study were to evaluate the incidence of various patterns of diffuse ^99mTc-MIBI uptake in patients with MM, to assess their relationship with clinical status and stage of disease, and to try to clarify the meaning of the diffuse bone marrow uptake of ^99mTc-MIBI. Thirty-nine consecutive patients with MM were studied. Twenty-nine of these patients had active disease (13 in stage I, ten in stage II, and six in stage III) and ten were in remission after chemotherapy. Anterior and posterior whole-body scans were obtained 10 min after i.v. injection of 555 MBq of ^99mTc-MIBI. The scans were classified as showing: pattern N, when only physiological uptake was present; pattern D, when diffuse bone marrow uptake was observed; pattern F, when areas of focal uptake of the radiotracer were evident; or pattern D+F, when both D and F patterns were observed. Diffuse bone marrow uptake was scored according to extension and intensity. Seven of the 39 patients (18%) showed pattern N, 18 (46%) pattern D, 2 (5%) pattern F, and 12 (31%) pattern D+F. Of the 32 patients with a positive ^99mTc-MIBI scan (i.e. showing pattern D, F or D+F), 29 (91%) had active disease. Only three patients in remission showed pattern D, but with a very low bone marrow uptake score. Both extension and intensity of diffuse bone marrow uptake correlated with the amount of the monoclonal component and the percentage of bone marrow plasma cells. The distribution of the ^99mTc-MIBI uptake patterns differed among patients in different stages of disease. Using as criteria for advanced stage the presence of either focal uptake (pattern F or D+F) or pattern D with a high score, high (90%) diagnostic accuracy was obtained. In conclusion, the patterns of ^99mTc-MIBI uptake in patients with MM are related to both the clinical status and the stage of disease. The presence of focal uptake or of intense diffuse bone marrow uptake suggests that the patient has active and advanced stage disease, while a negative scan in a patient with MM clearly indicates remission. Received 12 February and in revised form 16 April 1998     

A minimally invasive technique for surgical treatment of hallux valgus: simple, effective, rapid, inexpensive (SERI)

Purpose

Several bony and soft tissue procedures have been described for the treatment of hallux valgus, and currently mini-invasive surgical techniques are preferred in order to reduce surgical trauma, complications, time of surgery and to allow an earlier recovery. The aim of this study is to analyse a series of 1,000 consecutive cases of hallux valgus, surgically treated by the minimally invasive SERI technique, reporting results at mid-term follow-up.

Methods

We prospectively studied 641 patients (1,000 feet) with symptomatic hallux valgus surgically treated by SERI osteotomy. Inclusion criteria were: age between 20 and 65 years, reducible mild or moderate hallux valgus, HVA ≤ 40°, IMA ≤ 20°, and arthritis of the first metatarsophalangeal joint up to grade 2 according to the Regnauld classification.

Results

The American Orthopaedic Foot and Ankle Society (AOFAS) score rose from 46.8 ± 16.7 preoperatively to 89 ± 10.3 at last follow-up. Radiographic control at follow-up showed a complete healing of the osteotomy and remodelling of the metatarsal bone. Low rate of complication has been reported.

Conclusions

This study demonstrated that the SERI technique is effective in treating mild to moderate hallux valgus in terms of relief from symptoms and functional improvement. This technique allowed correction of the main parameters of the deformity, with durable clinical and radiographic results at a mid-term follow-up.

Electronic supplementary material

The online version of this article (doi:10.1007/s00264-013-1980-8) contains supplementary material, which is available to authorized users.     

Cardiac consequences of hypertension in hemodialysis patients

Hypertension in end-stage renal disease (ESRD) is an important risk factor for left ventricular hypertrophy (LVH), cardiac failure, coronary artery disease (CAD), and arrhythmia. LVH is generally considered an integrator of the long-term effects of hypertension and other cardiovascular (CV) risk factors and represents the strongest predictor of adverse CV outcomes in ESRD patients. The risk of heart failure is higher in patients with a history of hypertensive renal disease than in those with other diagnoses. Both coronary heart disease (CHD) and LVH predict congestive heart failure, which is often the ultimate cause of death in patients with cardiac ischemia or LVH. A history of long-standing hypertension is associated with ischemic heart disease both in cross-sectional and prospective studies in ESRD. Atrial fibrillation and ventricular arrhythmias are highly prevalent in dialysis patients and are implicated in mortality and sudden death in this population. Despite the lack of evidence from randomized controlled trials, it appears reasonable that interventions aimed at curbing the high CV mortality of ESRD should be targeted to both hypertension and LVH.