Randomized,double‐blind,placebo‐controlled trial of sulindac in individuals at risk for melanoma

BACKGROUND:

Reduced melanoma risk has been reported with regular use of nonsteroidal anti‐inflammatory drugs (NSAIDs). However, the ability of NSAIDs to reach melanocytes in vivo and modulate key biomarkers in preneoplastic lesions such as atypical nevi has not been evaluated.

METHODS:

This randomized, double‐blind, placebo‐controlled trial of sulindac was conducted in individuals with atypical nevi (AN) to determine bioavailability of sulindac and metabolites in nevi and effect on apoptosis and vascular endothelial growth factor A (VEGFA) expression in AN. Fifty subjects with AN ≥4 mm in size and 1 benign nevus (BN) were randomized to sulindac (150 mg twice a day) or placebo for 8 weeks. Two AN were randomized for baseline excision, and 2 AN and BN were excised after intervention.

RESULTS:

Postintervention sulindac, sulindac sulfone, and sulindac sulfide concentrations were 0.31 ± 0.36, 1.56 ± 1.35, and 2.25 ± 2.24 μg/mL in plasma, and 0.51 ± 1.05, 1.38 ± 2.86, and 0.12 ± 0.12 μg/g in BN, respectively. Sulindac intervention did not significantly change VEGFA expression but did increase expression of the apoptotic marker cleaved caspase‐3 in AN (increase of 3 ± 33 in sulindac vs decrease of 25 ± 45 in the placebo arm, P = .0056), although significance was attenuated (P = .1103) after adjusting for baseline expression.

CONCLUSIONS:

Eight weeks of sulindac intervention resulted in high concentrations of sulindac sulfone, a proapoptotic metabolite, in BN but did not effectively modulate VEGFA and cleaved caspase‐3 expression. Study limitations included limited exposure time to sulindac and the need to optimize a panel of biomarkers for NSAID intervention studies. Cancer 2012. © 2012 American Cancer Society.     

Biofunctionalized magnetic nanoparticles for specifically detecting biomarkers of Alzheimer's disease in vitro

Magnetic nanoparticles biofunctionalized with antibodies against β-amyloid-40 (Aβ-40) and Aβ-42, which are promising biomarkers related to Alzheimer's disease (AD), were synthesized. We characterized the size distribution, saturated magnetizations, and stability of the magnetic nanoparticles conjugated with anti-Aβ antibody. In combination with immunomagnetic reduction technology, it is demonstrated such biofunctionalized magnetic nanoparticles are able to label Aβs specifically. The ultralow-detection limits of assaying Aβs in vitro using the magnetic nanoparticles via immunomagnetic reduction are determined to a concentration of ～10 ppt (10 pg/mL). Further, immunomagnetic reduction signals of Aβ-40 and Aβ-42 in human plasma from normal samples and AD patients were analyzed, and the results showed a significant difference between these two groups. These results show the feasibility of using magnetic nanoparticles with Aβs as reagents for assaying low-concentration Aβs through immunomagnetic reduction, and also provide a promising new method for early diagnosis of Alzheimer's disease from human blood plasma.     

Human cerebral asymmetries evaluated by computed tomography.

The handedness of seventy-five persons without evidence of neurological disease, was assessed with a standardised test. An analysis of the CT scans of the same persons was performed to determine (1) presence and lateralisation of frontal and occipital "petalia," (2) width of frontal and occipital lobes of each hemisphere, (3) direction of straight sinus deviation. Results suggest that handedness and cerebral asymmetries are independent variables. There were no significant differences between right-handers and non-right-handers. Also there were no significant differences between strongly left-handed and ambidextrous individuals, nor were there differences between right-handers with or without family history of left-handedness. Irrespective of handedness, left occipital "petalia" was more common than right (p < 0.01), right frontal petalia was more common than left (p < 0.01), and straight sinus deviation was more commonly toward the right. The study does not support the concept that cerebral "symmetry" or "reverse asymmetry" are associated with left-handedness or ambidexterity. The noted asymmetries are more likely to be direct correlates of cerebral language dominance, than of handedness. Furthermore, the possibility that outside forces acting on the bone contributes to the asymmetries cannot be excluded. CT scan may be of value as a direct predictor of cerebral dominance.     

Hepatotoxicity caused by Breynia officinalis

Breynia officinalis has the Chinese proprietary name, Chi R Yun, which means dizziness or vertigo for 7 d. In daily practice, it has been used to treat venereal diseases, contusion, heart failure, growth retardation and conjunctivitis in combination with other traditional Chinese medicines. Two hospital-based cases of Breynia officinalis poisoning have been reported to the Poison Control Center. Case 1 was a 43-y-old female who consumed a mixture of 1500 g lower stem and root of Ji Mu Ju in boiled water in a suicide attempt. Her AST reached 264 and ALT reached 2443. Case 2 was a 51-y-old female who consumed 20 pieces of lower stem and root of Ji Mu Ju stewed with meat and 100 ml of wine to treat chronic contact dermatitis. Her AST reached 3815 and ALT reached 6625. In both cases Breynia officinalis was identified as the cause of poisoning. Poisoning in humans involves the neurologic, gastrointestinal, hepatic, urinary and respiratory systems. Hepatotoxic effects have been reported for some Chinese herbal medicines, but not Breynia officinalis: Breynia officinalis poisoning causes hepatocellular liver injury rather than cholestatic liver injury.     

Bioisosteric replacement of the pyrazole 5-aryl moiety of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). A novel series of alkynylthiophenes as potent and selective cannabinoid-1 receptor antagonists

Replacing the conventional pyrazole 5-aryl substituent of 1 (SR141716A) with the 2-thienyl moiety appended with an appropriate alkynyl unit, a novel class of 5-(5-alkynyl-2-thienyl)pyrazole derivatives, behaving as highly potent CB1 receptor antagonists with good CB1/2 selectivity, was discovered, many of which, as typified by compound 18, showed significant weight reduction in diet-induced obese mouse model, thus pharmacologically validating that the bioisosteric replacement described above is viable. Also encouraging was the finding that a subtle structural modification of the newly developed series could result in a distinct difference in the intrinsic property, as demonstrated by compounds 12 (NA) and its methylated structural isomers 15 (PA) and 18 (IA). Moreover, current structure-activity relationship studies revealed that around the pyrazole 5-position of 1, a deep and flat crevice surrounded by a sequence of hydrophobic/aromatic residues as indicated by the CB1-receptor homology model might exist in the binding site.     

Intensity-modulated radiation therapy (IMRT) for meningioma

To assess the safety and efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of intracranial meningioma.

Forty patients with intracranial meningioma (excluding optic nerve sheath meningiomas) were treated using IMRT with the NOMOS Peacock system between 1994 and 1999. Twenty-five patients received IMRT after surgery either as adjuvant therapy for incomplete resection or for recurrence, and 15 patients received definitive IMRT after presumptive diagnosis based on imaging. Thirty-two patients had skull base lesions, and 8 had nonskull base lesions. The prescribed dose ranged from 40 to 56 Gy (median 50.4 Gy) at 1.71 to 2 Gy per fraction, and the volume of the primary target ranged from 1.55 to 324.57 cc (median 20.22 cc). The mean dose to the target ranged from 44 to 60 Gy (median 53 Gy). Follow-up ranged from 6 to 71 months (median 30 months). Acute and chronic toxicity were assessed using Radiation Therapy Oncology Group (RTOG) morbidity criteria and tumor response was assessed by patient report, examination, and imaging. Overall survival, progression-free survival, and local control were calculated using the Kaplan-Meier method.

Cumulative 5-year local control, progression-free survival, and overall survival were 93%, 88%, and 89%, respectively. Two patients progressed after IMRT, one locally and one distantly. Each was treated with IMRT after multiple recurrences of benign meningioma over many years. Both were found to have malignant meningioma at the time of relapse after IMRT, and it is likely their tumors had already undergone malignant change by the time IMRT was given. Defined normal structures generally received a significantly lower dose than the target. The most common acute central nervous system (CNS) toxicity was mild headache, usually relieved with steroids. One patient experienced RTOG Grade 3 acute CNS toxicity, and 2 experienced Grade 3 or higher late CNS toxicity, with one possible treatment-related death. No toxicity was observed with mean doses to the optic nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy.

IMRT is a promising new technology that is safe and efficacious in the primary and adjuvant treatment of intracranial meningiomas. A history of local aggression may indicate malignant degeneration and predict a poorer outcome. Toxicity data are encouraging, but the potential for serious side effects exists, as demonstrated by one possible treatment-related death. Larger cohort and longer follow-up are needed to better define efficacy and late toxicity of IMRT.     

Kawasaki disease in infants three months of age or younger.

BACKGROUND AND PURPOSE: Kawasaki disease (KD) is rare in infants < or =3 months of age. This study analyzed the features of KD in 25 infants < or =3 months of age treated from February 1994 to December 2004. METHODS: Basic characteristics, clinical, laboratory, echocardiographic, therapeutic, and follow-up data of the infants were obtained from chart records. RESULTS: There were 19 male and 6 female infants in this cohort. The frequency of the 5 principal clinical features was as follows: changes in lips and oral cavity, 84%; bilateral bulbar conjunctival injection without exudates, 80%; polymorphous exanthem, 68%; cervical lymphadenopathy, 28%; and changes in extremities, 24%. Six infants (24%) fulfilled criteria for KD including fever which persists for 5 or more days with at least 4 of the principal clinical criteria, and the remaining infants were classified as having incomplete KD (all of whom showed coronary involvement). Coronary artery dilatation was found in 20 infants (80%). One infant developed a medium-size aneurysm (5.2 mm), while the others had only coronary arterial ectasia or small aneurysms. Coronary artery aneurysms regressed within 1-year follow-up in all but one infant. No fatal or recurrent case was observed during the study period. CONCLUSIONS: Infants < or =3 months of age with KD usually presented with incomplete clinical features. A high proportion of coronary artery involvement was observed in this series. Echocardiography should be considered in very young infants with unexplained prolonged fever who do not present all of the principal clinical features of KD.     

(−)Epigallocatechin-3-gallate inhibits the spontaneous firing of rat locus coeruleus neuron

(−)Epigallocatechin-3-gallate (EGCG), a tea catechin, has been known to cause many biological actions, such as anxiolytic and hypotensive effects in behavioral studies. However, to date, few reports investigate its neuronal modulation. In this study, intracellular recording was used to test the neuronal modulation of different catechins on locus coeruleus (LC) neuron, which has been demonstrated to be affected by cardiovascular function regulation and stressful events. Several catechins (1–1000 μM) were tested, including: (−)catechin (C), (−)catechingallate (CG), (−)epicatechin (EC), (−)epicatechin-3-gallate (ECG), (−)epigallocatechin (EGC) and EGCG. The results showed that catechins EC, ECG, EGC and EGCG could inhibit the spontaneous firing of the LC neurons; furthermore, these catechins show potency and efficacy in the order of EGCG > ECG > EC ≈ EGC. Among the tested catechins, EGCG was the most potent in inhibiting LC's spontaneous firing with IC₅₀ of 20.5 μM. This caused us to further examine the EGCG's desensitization and tolerance properties. When continuously administering EGCG at 1–300 μM for 20 min, no acute desensitization appeared. However, repeated applications of 300 μM EGCG at 5 min each time showed different results. The second and third applications induced less responses compared to that of the first application, suggesting a development of tolerance towards EGCG in inhibiting LC neuronal activity. Our data suggest that EGCG can inhibit LC neuron's spontaneous firing in a dose-dependent manner, with developed tolerance only when high concentration of EGCG is repeatedly applied.     

Rapid identification of Salmonella serovars in feces by specific detection of virulence genes, invA and spvC, by an enrichment broth culture-multiplex PCR combination assay.

In order to make a rapid and definite diagnosis of Salmonella enteritis in children, an enrichment broth culture-multiplex PCR combination assay was devised to identify Salmonella serovars directly from fecal samples. Two pairs of oligonucleotide primers were prepared according to the sequences of the chromosomal invA and plasmid spvC genes. PCR with these two primers would produce either one amplicon (from the invA gene) or two amplicons (from the invA and spvC genes), depending on whether or not the Salmonella bacteria contained a virulence plasmid. The fecal sample was diluted 10- to 20-fold into gram-negative enrichment broth and incubated to eliminate inhibitory compounds and also to allow selective enrichment of the bacteria. One or two amplicons were obtained, the expected result if Salmonella bacteria were present. The detection limit of this PCR was about 200 bacteria per reaction mixture. The primers were specific, as no amplification products were obtained with 18 species and 22 isolates of non-Salmonella bacteria tested which could be present in the feces or cause contamination. In contrast, when 23 commonly seen Salmonella serovars (38 isolates) were tested, all were shown to carry the invA gene and seven concomitantly harbored the spvC gene of the virulence plasmid. This assay was applied to the diagnosis of Salmonella enteritis in 57 children who were suffering from mucoid and/or bloody diarrhea. Of the 57 children, 38 were PCR positive and 22 were culture positive. There were two culture-positive samples that were not detected by PCR. Thus, this PCR assay showed an efficiency of 95% (38 of 40), which is much higher than the 60% (24 of 40) by culture alone. Not only is this method more sensitive, rapid, and efficient but it will cause only an incremental increase in the cost of stool processing, since enrichment cultivation of fecal samples from diarrheal patients using gram-negative enrichment broth is a routine practice for identification in many diagnostic microbiology laboratories. This PCR method, therefore, has clinical application.