Synthesis procedure for routine production of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380).

2-[18F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380) was among the first subtype selective radioligands to visualise the in vivo distribution of alpha4beta2-containing neuronal nicotinic acetylcholine receptors (nAChRs) in human brain. We developed a one-pot synthesis for the preparation of 2-[18F]F-A-85380 in a commercially available TRACERlab FXF-N synthesis module. The synthesis comprises a nucleophilic substitution followed by hydrolysis of a t-butyloxycarbonyl (BOC)-protected intermediate. After formulation for intravenous application up to 20 G Bq 2-[18F]F-A-85380 were produced from a starting activity of 100 G Bq [18F]fluoride in 60 min with a specific activity of about 4.10(5)GBq/mmol and a mean radiochemical purity of more than 99%.     

Alterations in cholinergic and non-cholinergic neurotransmitter receptor densities in transgenic Tg2576 mouse brain with beta-amyloid plaque pathology.

Cholinergic deficits in Alzheimer's disease are accompanied by a number of alterations in other transmitter systems including glutamate, noradrenaline and serotonin, suggesting the involvement also of other neurotransmitter systems in the pathogenesis of the disease. To address the question whether beta-amyloid may contribute to these deficits, brain tissue from transgenic Tg2576 mice with Alzheimer plaque pathology at ages of 5 (still no significant plaque load) and 17 months (moderate to high cortical beta-amyloid plaque load) were examined for a number of cholinergic and non-cholinergic markers. Transgenic mice with no significant plaque load demonstrated reduced hemicholinium-3 (HCh-3) binding to choline uptake sites in anterior brain regions as compared to non-transgenic littermates, while in aged transgenic mice with high number of plaque deposits decreased HCh-3 binding levels were accompanied by increased vesicular acetylcholine transporter binding in selected cortical brain regions. In aged transgenic mice GABA(A), NMDA, AMPA, kainate, and beta-adrenergic as well 5-HT(1A)- and 5-HT(2A)-receptor binding levels were hardly affected, whereas alpha(1)- and alpha(2)-adrenoceptor binding was increased in selected cerebral cortical regions as compared to non-transgenic littermates. The development of changes in both cholinergic and non-cholinergic markers in transgenic Tg2576 mouse brain already before the onset of progressive plaque deposition provides in vivo evidence of a modulatory role of soluble beta-amyloid on cortical neurotransmission and may be referred to the deficits in learning and memory observed in these mice also before significant plaque load.     

Acute colonic pseudo-obstruction after caesarean section

Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie’s syndrome, is a rare condition associated with massive dilatation of the colon in the absence of any mechanical obstruction. Between 4 and 35% of all reported cases of ACPO have occurred in association with pregnancy or puerperium, with most of these occurring after caesarean sections. We present a case report of the successful management of a patient with ACPO.     

Novel 5-flucytosine-resistant clade of Candida dubliniensis from Saudi Arabia and Egypt identified by Cd25 fingerprinting

DNA fingerprinting of Candida dubliniensis isolates using the species-specific probe Cd25 previously showed that this species consists of two distinct groups, termed Cd25 group I and Cd25 group II. The present study investigated the population structure of 30 C. dubliniensis oral isolates from Saudi Arabia and Egypt using Cd25 fingerprinting and rRNA gene internal transcribed spacer region-based genotyping. Cd25 fingerprinting analysis of these isolates revealed two distinct populations, the first of which consisted of 10 closely related genotype 1 isolates (average similarity coefficient [S(AB)] value, 0.86). The second population of 20 isolates was much more heterogeneous (average S(AB) value, 0.35) and consisted of two distinct subpopulations, one of which consisted of genotype 3 isolates (n = 13) and the other of genotype 4 isolates (n = 7). A mixed dendrogram generated from the fingerprint data from the 30 Saudi Arabian and Egyptian isolates, 5 Israeli isolates, and 51 previously characterized international isolates (32 of Cd25 group I and 19 of Cd25 group II) revealed the presence of three distinct main clades. The first corresponded to the previously described Cd25 group I and contained all the Saudi Arabian, Egyptian, and Israeli genotype 1 isolates mixed with international isolates. The second clade corresponded to the previously described Cd25 group II and contained three Israeli isolates, one genotype 2 isolate, one genotype 3 isolate, and a genotype 4 variant isolate, which were mixed with international isolates. The third clade has not been described before and consisted solely of the 20 Saudi Arabian and Egyptian genotype 3 and 4 isolates identified in this study and a previously described genotype 4 Israeli isolate. All 20 Cd25 group III isolates exhibited high-level resistance to 5-flucytosine (MIC > or = 128 microg/ml), whereas all Cd25 group I and Cd25 group II isolates tested (10 Saudi Arabian and Egyptian, 16 Israeli, and 24 international) were susceptible to 5-flucytosine (MIC < or = 0.125 microg/ml). The results of this study show for the first time the presence of a novel 5-flucytosine-resistant clade of C. dubliniensis (Cd25 group III) that is predominant among isolates from Saudi Arabia and Egypt and absent from a previously characterized international collection of 98 isolates from 15 countries.     

Mutations underlying 3-Hydroxy-3-Methylglutaryl CoA Lyase deficiency in the Saudi population

Background  

3-Hydroxy-3-Methylglutaric aciduria (3HMG, McKusick: 246450) is an autosomal recessive branched chain organic aciduria caused by deficiency of the enzyme 3-Hydroxy-3-Methylglutaryl CoA lyase (HL, HMGCL, EC 4.1.3.4). HL is encoded by HMGCL gene and many mutations have been reported. 3HMG is commonly observed in Saudi Arabia.     

Differences in regional wash-in and wash-out time constants for xenon-CT ventilation studies

Xenon-enhanced computed tomography (Xe-CT) has been used to measure regional ventilation by determining the wash-in (WI) and wash-out (WO) rates of stable Xe. We tested the common assumption that WI and WO rates are equal by measuring WO-WI in different anatomic lung regions of six anesthetized, supine sheep scanned using multi-detector-row computed tomography (MDCT). We further investigated the effect of tidal volume, image gating (end-expiratory EE versus end-inspiratory EI), local perfusion, and inspired Xe concentration on this phenomenon. RESULTS: WO time constant was greater than WI in all lung regions, with the greatest differences observed in dependent base regions. WO-WI time constant difference was greater during EE imaging, smaller tidal volumes, and with higher Xe concentrations. Regional perfusion did not correlate with WI-WO. We conclude that Xe-WI rate can be significantly different from the WO rate, and the data suggest that this effect may be due to a combination of anatomic and fluid mechanical factors such as Rayleigh-Taylor instabilities set up at interfaces between two gases of different densities.     

Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.     

Plasma Free Fatty Acids and Metabolic Effect in Type 2 Diabetes,an Ancillary Study from a Randomized Clinical Trial

Most nutrition studies looking at the association of food with cardiometabolic markers rely on food frequency questionnaires, which are prone to recall bias. Pentadecanoic acid, heptadecanoic acid and trans-palmitoleic acid are fatty acids that are not synthesized endogenously but are obtained from the diet, particularly dairy, making them reasonable biomarkers of dairy consumption. We investigated the association of dairy fatty acid biomarkers with glycated hemoglobin (HbA1c) and cardiovascular risk factors in type 2 diabetes (T2D). In a clinical trial, 111 participants with T2D (age 58.5 ± 8.9 years, HbA1c 8.09 ± 0.96%) were randomized into three groups: a control group that maintained baseline dairy intake, a low-fat (LF) group that incorporated ≥3 servings/day of LF dairy and a high-fat (HF) group that incorporated ≥3 servings/day of HF dairy. We compared the fatty acids (FA) composition between the three groups at 24 weeks. Pentadecanoic acid and trans-palmitoleic acid increased in the HF group by 14.1% ± 5.4% and 17.5% ± 5.1%, respectively, but not in the control and LF groups (p = 0.0474 and p = 0.0025 for group-by-time interaction, respectively). Those increases were positively associated with changes in total cholesterol, very-low-density lipoprotein cholesterol VLDL-C and triglycerides but were not associated with changes in HbA1c from baseline to 24 weeks. These results suggest that the intervention was successful and that participants were likely compliant, which supports the validity of the main trial.     

Decomposing Racial and Ethnic Disparities in Nursing Home Influenza Vaccination

ObjectivesQuantify how observable characteristics contribute to influenza vaccination disparities among White, Black, and Hispanic nursing home (NH) residents.DesignRetrospective cohort.Setting and ParticipantsShort- and long-stay U.S. NH residents aged ≥65 years.MethodsWe linked Minimum Data Set (MDS) and Medicare data to LTCFocUS and other facility data. We included residents with 6-month continuous enrollment in Medicare and an MDS assessment between October 1, 2013, and March 31, 2014. Residents were classified as short-stay (<100 days in NH) or long-stay (≥100 days in NH). We fit multivariable logistic regression models to assess the relationships between 27 resident and NH-level characteristics and receipt of influenza vaccination. Using nonlinear Oaxaca-Blinder decomposition, we decomposed the disparity in influenza vaccination between White versus Black and White versus Hispanic NH residents. Analyses were repeated separately for short- and long-stay residents.ResultsOur study included 630,373 short-stay and 1,029,593 long-stay residents. Proportions vaccinated against influenza included 67.2% of White, 55.1% of Black, and 54.5% of Hispanic individuals among short-stay residents and 84.2%, 76.7%, and 80.8%, respectively among long-stay residents. Across 4 comparisons, the crude disparity in influenza vaccination ranged from 3.4 to 12.7 percentage points. By equalizing 27 prespecified characteristics, these disparities could be reduced 37.7% to 59.2%. Living in a predominantly White facility and proxies for NH quality were important contributors across all analyses. Characteristics unmeasured in our data (eg, NH staff attitudes and beliefs) may have also contributed significantly to the disparity.Conclusions and ImplicationsThe racial/ethnic disparity in influenza vaccination was most dramatic among short-stay residents. Intervening on factors associated with NH quality would likely reduce these disparities; however, future qualitative research is essential to explore potential contributors that were unmeasured in our data and to understand the degree to which these factors contribute to the overall disparity in influenza vaccination.     

Primary vitrectomy without scleral buckling for rhegmatogenous retinal detachment

Background: Pars planta vitrectomy has evolved as an alternative method in the treatment of more complicated rhegmatogenous retinal detachments. We report a series of patients who underwent primary vitrectomy with gas tamponade without the use of additional scleral buckling. Methods: A retrospective study of 53 patients with a follow-up of 6–45 months (mean 17.8 months) was carried out. Preoperative findings included unusual, multiple or large breaks, vitreous haemorrhage, proliferative vitreoretinopathy and bullous retinal detachment. Preoperative visual acuity was between light perception and 1.0, with 30% (16/53) of patients with 0.4 or better. Results: Retinal reattachment was achieved in 64% of cases (34/53) with one and in 92% (49/53) with one or more operations. Final visual acuity was between light perception and 1.0, with 41% (22/53) of patients with 0.4 or better. Cataract formation occurred in 86% (37/43) of all patients with a clear lens preoperatively. Macular pucker was noted in 11 % (6/53) and postoperative proliferative vitreoretinopathy causing redetachment in 6% (3/53). Conclusion: With primary vitrectomy, a high final anatomical success rate with few intraoperative complications can be achieved in more complicated forms of rhegmatogenous retinal detachment. The major drawback of the procedure is the high incidence of post-operative cataract formation.