Semisynthesis of Antitrypanosomal p-Quinone Analog Possesing the Komaroviquinone Pharmacophore.

A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.

Ultrasonic control of neurite outgrowth direction.

This study investigated a method to control neurite outgrowth direction using ultrasound vibration. An ultrasound cell culture dish comprising a glass-bottom culture surface and a glass disc with an ultrasound transducer was fabricated, and undifferentiated neuron-like PC12 cells were grown on the dish as an adherent culture. The 78 kHz resonant concentric flexural vibration mode of the dish was used to quantitatively evaluate the neurite outgrowth direction and length. Time-lapse imaging of cells was performed for 72 h under ultrasound excitation. Unsonicated neurites grew in random directions, whereas neurite outgrowth was circumferentially oriented during ultrasonication in a power-dependent manner. The neurite orientation correlated with the spatial gradient of the ultrasound vibration, implying that neurites tend to grow in directions along which the vibrational amplitude does not change. Ultrasonication with 30 Vpp for 72 h increased the neurite length by 99.7% compared with that observed in unsonicated cells.

Adhesive cell patterning technique using ultrasound vibrations.

This paper investigated an ultrasound vibration cell patterning technique. The ultrasound cell culture dish consisted of a culture dish with a glass bottom and a glass disc with a piezoelectric ring that generated a resonance flexural vibration mode on the bottom of the dish. The growth of HeLa cells on the dish was observed under ultrasound excitation for 24 h. Large ultrasound vibrations on the dish inhibited the cell growth. The acoustic field was predicted with finite element analysis and it was found that the cell growth depended strongly on both the acoustic field in the culture medium and the vibration distribution of the dish. The ultrasound vibrations did not affect the viability of the cells, and the cell growth could be controlled by the flexural vibration of the cultured dish.

Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.

Effects of chronic khat use on cardiovascular, adrenocortical, and psychological responses to stress in men and women.

BACKGROUND: Khat is a psychostimulant plant widely used in Africa and its use has been growing rapidly in Europe and North America. OBJECTIVES: We investigated effects of chronic khat (Catha edulis) use on cardiovascular, adrenocortical, and psychological responses to acute stress. METHODS: Chronic khat users and nonusers were compared on physiological measures and mood reports in a cross-sectional, mixed design. Measurements were conducted during 24-hour ambulatory monitoring and during a laboratory session. A total of 152 participants (58 women) were recruited by flyers posted around Sana'a University campus and the surrounding community in Sana'a, Yemen. Salivary cortisol and self-report measures were collected during a 24-hour ambulatory period prior to a lab testing session. In addition, blood pressures (BP), salivary cortisol, and mood measures were assessed during rest and in response to acute mental stress. RESULTS: Khat users exhibited enhanced evening and attenuated morning cortisol levels, reflecting a blunted diurnal pattern of adrenocortical activity compared to nonusers. Khat users reported greater negative affect during the ambulatory period and during the laboratory session. In addition, they exhibited attenuated BP responses to stress. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These novel results demonstrate altered adrenocortical activity and increased dysphoric mood among khat users. The extent to which these associations are due to effects of chronic khat use per se or instead reflect predisposing risk factors for khat use is yet to be determined.

Circulating leptin levels are associated with increased craving to smoke in abstinent smokers.

The adipocyte hormone leptin regulates satiety and energy expenditure. Recent evidence suggests that leptin is associated with increased craving for alcohol and with shorter length of abstinence during alcohol treatment. This study examined leptin's associations with craving for cigarettes and smoking relapse among smokers interested in cessation. Participants (32 smokers; 14 women) attended a laboratory session 24h following their designated quit day where circulating leptin levels and craving for smoking were assessed. Other measures of withdrawal symptoms, affect, physical symptoms, as well as neuroendocrine and cardiovascular measures were collected before and after performing two stress tasks (public speaking and cognitive tasks). High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. Circulating leptin levels were not related to cardiovascular and neuroendocrine measures, responses to acute stressors, or to smoking relapse. These results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence.

Psychoses, PTSD, and depression in Somali refugees in Minnesota.

INTRODUCTION: Initial clinical observation of Somali patients seen at a busy inner-city community clinic (CUHCC) suggested that, in addition to the expected pictures of Posttraumatic Stress Disorder (PTSD) and depression previously seen in the clinic's Southeast Asian refugee population from 1980 to 2000, there was an unusually high number of young Somali men presenting with acute psychotic disturbances. OBJECTIVES: The aim of this study of health care utilization of Somali refugees (N = 600) seen in the mental health unit of the clinic from 2001 to 2009 was to investigate the major patterns of psychiatric disorders in this outpatient population and compare these findings with a cohort of non-Somali patients (N = 3,009) seen at the same outpatient clinic during the years 2007-2009. If the results supported the initial clinical observations that the rate of psychoses was higher among young Somali men than non-Somali men attending CUHCC clinic, then several areas of further research would recommend itself. First, since this study was not a study of prevalence of mental illness in the Somali community, the next step would be to undertake a study of community prevalence of mental illness among different age and gender cohorts. Second, further research should look into likely causative and contributory risk factors to explain the development of psychoses among Somali young men. METHODS: Somali and non-Somali patients were diagnosed according to DSM-IV-R criteria. Main outcome measures (diagnoses, age cohort, sex) were analyzed by Chi-square tests. Patterns of illness and adjustment varied significantly by age and gender cohorts, reflecting the relevance of age and gender at time of trauma on different trauma and loss experiences and cultural and religious shaping of subsequent adjustment and symptoms. RESULTS: The study confirmed that almost half of the Somali male patients are under age 30, 80% of whom presented with psychoses, compared with the rate of psychosis (13.7%) in the non-Somali control group of same-aged males at the clinic. The older male, and the majority of Somali female patients, show predominantly depressive and PTSD symptomatology. CONCLUSIONS: War trauma experienced in childhood, early malnutrition from famines, head trauma, and excess Khat use in male adolescents provide partial explanations for the large number of young psychotic Somali men seen in the clinic from 2001 to 2009.

Michael addition-elimination mechanism for nucleophilic substitution reaction of cycloalkenyl iodonium salts and selectivity of 1,2-hydrogen shift in cycloalkylidene intermediate.

Reactions of cyclohexenyl and cyclopentenyl iodonium salts with cyanide ion in chloroform give cyanide substitution products of allylic and vinylic forms. Deuterium-labeling experiments show that the allylic product is formed via the Michael addition of cyanide to the vinylic iodonium salt, followed by elimination of the iodonio group and 1,2-hydrogen shift in the 2-cyanocycloalkylidene intermediate. The hydrogen shift preferentially occurs from the methylene rather than the methine beta-position of the carbene, and the selectivity is rationalized by the DFT calculations. The Michael reaction was also observed in the reaction of cyclopentenyliodonium salt with acetate ion in chloroform. The vinylic substitution products are ascribed to the ligand-coupling (via lambda3-iodane) and elimination-addition (via cyclohexyne) pathways.

Elimination-addition mechanism for nucleophilic substitution reaction of cyclohexenyl iodonium salts and regioselectivity of nucleophilic addition to the cyclohexyne intermediate.

The reaction of 4-substituted cyclohex-1-enyl(phenyl)iodonium tetrafluoroborate with tetrabutylammonium acetate gives both the ipso and cine acetate-substitution products in aprotic solvents. The isomeric 5-substituted iodonium salt also gives the same mixture of the isomeric acetate products. The reaction is best explained by an elimination-addition mechanism with 4-substituted cyclohexyne as a common intermediate. The cyclohexyne formation was confirmed by deuterium labeling and trapping to lead to [4 + 2] cycloadducts and a platinum-cyclohexyne complex. Cyclohexyne can also be generated in the presence of some other mild bases such as fluoride ion, alkoxides, and amines, though amines are less effective bases for the elimination. Kinetic deuterium isotope effects show that the anionic bases induce the E2 elimination (k(H)/k(D) > 2), while the amines allow formation of a cyclohexenyl cation in chloroform to lead to E1 as well as S(N)1 reactions (k(H)/k(D) approximately 1). Bases are much less effective in methanol, and methoxide was the only base to efficiently afford the cyclohexyne intermediate. Nucleophiles react with the cyclohexyne to give regioisomeric products in the ratio dependent on the ring substituent. The observed regioselectivity of nucleophilic addition to substituted cyclohexynes is rationalized from calculated LUMO populations, which are governed by the bond angles at the acetylenic carbons: The less deformed carbon has a higher LUMO population and is preferentially attacked by the nucleophile.