Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction

Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available ¹³C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding ¹³C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including ¹³C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing ¹³C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.     

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Beta2-Microglobulin

Among the uremic toxins in the "middle molecule" range, beta2-microglobulin (β2-M) is certainly one of the most frequently studied compounds. Its serum level increases with the progression of chronic kidney disease, to reach very high concentrations in patients with end-stage kidney disease. It is the major protein component of dialysis-related amyloidosis, a dramatic complication which results from high extracellular concentration and posttranslational modification of β2-M and a number of other promoters of amyloid fibril formation and deposition in osteo-articular tissues. Effective removal of β2-M can be achieved with highly effective hemodialysis and hemodiafiltration techniques but predialysis session serum levels cannot be normalized. The prevalence and severity of β2-M amyloidosis appear to have decreased in the last 20 years, although its occurrence may simply be delayed.     

Laboratory diagnosis of pulmonary embolism: value of increased levels of plasma D-dimer and thrombin--antithrombin III complexes

Plasma D-dimer (DD) and thrombin--antithrombin III complex (TAT) were measured with ELISAs in 99 patients investigated by 102 ventilation--perfusion lung scintigraphy because of suspected pulmonary embolism. High-probability lung scan was associated with increased DD (more than 500 ng/ml) and TAT (more than 4.1 ng/ml) levels (sensitivity of 100 and 70%, respectively). The corresponding figures of specificity were 81 and 42%. In the 56 patients with low-probability or indeterminate probability scans, 31 (55%) had DD concentrations of less than 500 ng/ml. These preliminary data suggest that a plasma DD concentration of less than 500 ng/ml might rule out the diagnosis of pulmonary embolism in suspected patients with an inconclusive lung scanning.     

Acoustic rhinometry in nasal provocation test in perennial allergic rhinitis

Acoustic rhinometry is one method to evaluate nasal geometry by an acoustic reflection technique. The aim of this study was to investigate the changes in acoustic rhinometry after nasal provocation in patients with exclusively perennial allergic rhinitis. In 19 patients, acoustic rhinometry and active anterior rhinomanometry were performed before and after nasal provocation test. There was a statistically significant nasal flow reduction measured by active anterior rhinomanometry after nasal provocation (p < 0.05) and a median symptom score of four points, both indicating a positive response to nasal provocation. On the other hand, there was no statistically significant change in the values of acoustic rhinometry after nasal provocation (p > 0.05). In patients with exclusively perennial allergic rhinitis, acoustic rhinometry does not seem to significantly change after nasal provocation. In contrast, active anterior rhinomanometry values decreased significantly after nasal provocation. The presented results indicate that acoustic rhinometry does not seem to be a diagnostic method superior to active anterior rhinomanometry in this context.     

Dopamine in models of alcoholic acute pancreatitis.

Acute oedematous pancreatitis and acute haemorrhagic pancreatitis were studied using the low pressure duct perfusion models of alcoholic pancreatitis in cats. After creating either form over 24 hours, each pancreas was histologically graded and assigned an inflammatory score (0-16; absent-severe). Urinary trypsinogen activation peptide concentrations were also used as a measure of severity. Using the model of acute haemorrhagic pancreatitis, it was previously shown that low dose dopamine (5 micrograms/kg.m) reduced the inflammatory score at 24 hours and that this effect was mediated by a reduction in pancreatic microvascular permeability acting via dopaminergic and beta adrenergic receptors. Further studies were conducted and are reported here. In experiment 1 different doses of dopamine in established alcoholic acute haemorrhagic pancreatitis were studied. In group 1 control cats (no dopamine), the inflammatory score was 10.5 (interquartile range (IQR)4). In groups 2, 3, and 4, haemorrhagic pancreatitis was induced. Twelve hours later dopamine was infused for six hours, in the doses of 2 micrograms/kg.min, 5 micrograms/kg.min, and 50 micrograms/kg.min respectively. The inflammatory score in group 2 was 7 (IQR 0.5, p < 0.05 v group 1), in group 3 it was 7 (IQR 2, p < 0.05 v group 1), and in group 4 it was 7 (IQR 4, p < 0.05 v group 1). This was matched by significantly lower levels of urinary tripsinogen activation peptide at 24 hours. In experiment 2 (group 5) we tried to reduce microvascular permeability further by combining dopamine with antihistamines, but there was no improvement in the inflammatory score. As oedematous pancreatitis is the commoner and milder form of acute pancreatitis in clinical practice, in experiment 3 we looked at the effect of dopamine in this model. In group 6 control cats (no treatment), the inflammatory score was 7 (IQR 3, p < 0.05 v group 1). In group 7 cats given dopamine (5 micrograms/kg.min for six hours) from 12 hours after the onset of actue oedematous pancreatitis, the inflammatory score was reduced to 4(IQR 2, p < 0.05 v group 6). This was matched by a significant reduction in the 24 hour urinary tripsin activation peptide concentration.     

The course of rehabilitation in patients with locked-in syndrome]

On the basis of observations of the course taken by 5 patients with so-called Locked-in Syndrome (LIS), the level of functional performance that can be achieved by long-term rehabilitation notwithstanding very severe initial symptoms is set out. The priority measures in the early phases of the condition and the particular problems of long-term rehabilitation are summarized in a checklist. Technical aids to ameliorate communication are dealt with in some detail. Special importance is attributed to patient-centered psychotherapeutic support and to family involvement.     

Acute hypercalcemia, pancreatic duct permeability, and pancreatitis in cats

We investigated the effects of hypercalcemia on pancreatic duct permeability and pancreatitis in cats. Acute hypercalcemia was maintained by an infusion of calcium gluconate; controls received saline solution. Chronic hypercalcemia was maintained by diet and by vitamin D and dihydrotachysterol injections. Portal venous blood was analyzed for large dextran molecules that had been perfused through the pancreatic duct. In a separate group of hypercalcemic animals, we perfused the duct with activated pancreatic enzymes to induce acute pancreatitis. After 24 hours of hypercalcemia, dextrans were detected in the portal venous blood of 6 of 11 hypercalcemic and none of the 6 control animals (p less than 0.05). After 12 hours of hypercalcemia, dextrans were detected in all 7 hypercalcemic and 1 of 7 control animals (p less than 0.001). The degree of pancreatic inflammation was greater in the 12-hour animals than in the controls (p less than 0.001). After 14 days of hypercalcemia, however, there were no differences in dextran permeability or pancreatitis in experimental or control animals. Our results indicate that acute hypercalcemia increases the permeability of the pancreatic duct to molecules the size of pancreatic enzymes. This could be important in the pathogenesis of acute pancreatitis associated with hypercalcemic states.