Relative sensitivity and specificity of salivary and serum cotinine in identifying tobacco-smoking status of self-reported nonsmokers and smokers of tobacco and/or marijuana

Serum and salivary cotinine levels were measured in 327 smoking and nonsmoking participants in a study of the health effects of marijuana with and without tobacco. These individuals had no reason to misrepresent their current tobacco-smoking status. The sensitivity, specificity, and predictive values positive and negative of the cotinine levels in distinguishing self-reported current tobacco smokers from nonsmokers was high (88-100%) and essentially the same for both fluids. Agreement between self-report and cotinine levels was not influenced by the presence or absence of marijuana smoking. A good correlation was found between serum and salivary cotinine levels in self-reported tobacco smokers (r = 0.84, p less than 0.001). Mean average levels were 279 +/- 144 ( +/- standard deviation) ng/ml for serum and 360 +/- 195 ng/ml for saliva. In a separate group of seven tobacco smokers, cotinine levels in saliva were found to be essentially independent of salivary flow rate. An analogous relationship has been observed by others for various compounds that are filtered to saliva from the blood. This may explain the close relationship observed between serum and salivary cotinine levels, and the observation made by others that the half-life of salivary cotinine is similar to that of serum cotinine.     

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.     

Bexarotene and erlotinib for aerodigestive tract cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity. PATIENTS AND METHODS: In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non-small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective. RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%. CONCLUSION: The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.     

Managing Obesity in Primary Care: Breaking Down the Barriers

Several Australian obesity management guidelines have been developed for general practice but, to date, implementation of these guidelines has been shown to be inadequate. In this review, we explore the barriers to obesity treatment and propose a four-stage plan to manage individuals with obesity in general practice using a framework of a multidisciplinary team.Funding: Novo Nordisk.     

Circadian periodicity and other clinical features of biliary pain.

We studied the time of onset and other clinical features of biliary pain in 54 patients living in Northern Italy. All patients had cholelithiasis documented by ultrasonography. The time of onset of pain followed a circadian periodicity with its peak occurring at 9:30 p.m. The typical biliary pain was steady, mostly localized in the right upper quadrant of the abdomen or the epigastrium, lasted over 1 h, and required analgesics for relief. The pain was not related to meals or body position. What precipitates biliary pain is still an enigma.     

FBXO28 causes developmental and epileptic encephalopathy with profound intellectual disability

Chromosome 1q41‐q42 deletion syndrome is a rare cause of intellectual disability, seizures, dysmorphology, and multiple anomalies. Two genes in the 1q41‐q42 microdeletion, WDR26 and FBXO28, have been implicated in monogenic disease. Patients with WDR26 encephalopathy overlap clinically with those with 1q41‐q42 deletion syndrome, whereas only one patient with FBXO28 encephalopathy has been described. Seizures are a prominent feature of 1q41‐q42 deletion syndrome; therefore, we hypothesized that pathogenic FBXO28 variants cause developmental and epileptic encephalopathies (DEEs). We describe nine new patients with FBXO28 pathogenic variants (four missense, including one recurrent, three nonsense, and one frameshift) and analyze all 10 known cases to delineate the phenotypic spectrum. All patients had epilepsy and 9 of 10 had DEE, including infantile spasms (3) and a progressive myoclonic epilepsy (1). Median age at seizure onset was 22.5 months (range 8 months to 5 years). Nine of 10 patients had intellectual disability, which was profound in six of nine and severe in three of nine. Movement disorders occurred in eight of 10 patients, six of 10 had hypotonia, four of 10 had acquired microcephaly, and five of 10 had dysmorphic features, albeit different to those typically seen in 1q41‐q42 deletion syndrome and WDR26 encephalopathy. We distinguish FBXO28 encephalopathy from both of these disorders with more severe intellectual impairment, drug‐resistant epilepsy, and hyperkinetic movement disorders.     

Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: An fMRI study

Background: Ornithine transcarbamylase deficiency (OTCD) is an X‐linked urea cycle disorder characterized by hyperammonemia resulting in white matter injury and impairments in working memory and executive cognition. Objective: To test for differences in BOLD signal activation between subjects with OTCD and healthy controls during a working memory task. Design, setting and patients: Nineteen subjects with OTCD and 21 healthy controls participated in a case‐control, IRB‐approved study at Georgetown University Medical Center. Intervention: An N‐back working memory task was performed in a block design using 3T functional magnetic resonance imaging. Results: In subjects with OTCD we observed increased BOLD signal in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) relative to healthy age matched controls. Conclusions: Increased neuronal activation in OTCD subjects despite equivalent task performance points to sub‐optimal activation of the working memory network in these subjects, most likely reflecting damage caused by hyperammonemic events. These increases directly relate to our previous finding of reduced frontal white matter integrity in the superior extents of the corpus callosum; key hemispheric connections for these areas. Future studies using higher cognitive load are required to further characterize these effects. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Uric acid and incident chronic kidney disease in dyslipidemic individuals

Background: Elevated uric acid (UA) is a recognized risk factor for chronic kidney disease (CKD). This study aimed to investigate whether this association exists in dyslipidemic patients receiving multifactorial treatment.

Methods: An observational study conducted in Greece including 1,269 dyslipidemic individuals followed-up in a lipid clinic for ≥3 years. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI equation and CKD was defined as ≤60?mL/min/1.73 m². The correlation was assessed between UA levels and the CKD risk after adjusting for potential confounding factors, after defining the following UA quartiles: Q1: ?6?mg/dL.

Results: After excluding patients with baseline eGFR <60?mL/min/1.73 m², gout and those taking UA-lowering drugs, 1,095 individuals were eligible; of those, 91% and 69% were treated with statins and anti-hypertensive drugs, respectively. During their follow-up (6 years; IQR?=?4–10), 11.9% of the subjects developed CKD, whereas the median annual eGFR decline was 0.69?mL/min/1.73 m² (IQR?=?0.45–2.33). Multivariate analysis showed that baseline UA levels (HR?=?1.26; 95% CI?=?1.09–1.45, p?=?.001), female gender (HR?=?1.74; 95% CI?=?1.14–2.65, p?=?.01), age (HR?=?1.10; 95% CI?=?1.07–1.12, p?p?=?.03), cardiovascular disease (HR?=?1.62; 95% CI?=?1.02–2.58, p?=?.04), decreased baseline renal function (eGFR <90?mL/min/1.73 m²) (HR?=?2.38; 95% CI?=?1.14–4.81, p?=?.02), and low-density lipoprotein cholesterol reduction (HR?=?0.995; 95% CI?=?0.991–0.998, p?=?.01) were associated with incident CKD. Additionally, patients with UA ≥6?mg/dL exhibited a higher risk of incident CKD compared with those in the lowest UA quartile (HR?=?2.01; 95% CI?=?1.11–3.65, p?=?.02).

Conclusion: Higher UA levels are correlated with a higher risk of incident CKD in dyslipidemic individuals taking multifactorial treatment.     

Hyperphosphatemia and phosphate binders: effectiveness and safety

In patients with kidney dysfunction hyperphosphatemia is more evident as renal failure progresses. It is related to increased FGF-23 levels, secondary hyperparathyroidism, and accelerated progressive vascular calcification. In CKD patients advanced coronary artery calcification is strongly associated with future cardiovascular events, cardiovascular death, and all-cause mortality. Apart from the above, phosphate per se is suspected as a causal risk factor for CKD progression. Keeping serum phosphorus within the target values are linked to improvement in life expectancy. A low phosphate diet, an efficient dialysis removal of phosphate load, and the administration of phosphate binders are the main recommended steps to control hyperphosphatemia. Calcium-based phosphate binders can lead to a positive calcium balance, hypercalcaemia, parathyroid gland suppression, adynamic bone disease, and coronary artery and aortic calcification. On the other hand Sevelamer hydrochloride and Lanthanum carbonate has been shown to be effective, safe and useful therapeutic tools for hyperphosphatemia. When prescribe pharmacological agents, one must take into account the large increase in health-care expenditure and the choice of phosphate binder should be individualized.