4-4-(Anilinomethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-ylbenzoic acid derivatives as potent anti-gram-positive bacterial agents.

A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibitory concentration (MIC), a bactericidal effect in time-kill assays, moderate inhibition of biofilm formation as well as biofilm destruction, and a bactericidal effect against stationary phase cells representing non-growing persister cells. Multistep resistance assays showed a very low tendency for S. aureus and Enterococcus faecalis to develop resistance through mutation. Additionally, in vivo mouse model studies showed no harmful effects at doses up to 50 mg/kg using 14 blood plasma organ toxicity markers or TUNEL assay in liver and kidney. Investigations into the mode of action by performing macromolecular synthesis inhibition studies showed a broad range of inhibitory effects, suggesting targets that have a global effect on bacterial cell function.

Synthesis and antimicrobial studies of hydrazone derivatives of 4-[3-(2,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid and 4-[3-(3,4-difluorophenyl)-4-formyl-1H-pyrazol-1-yl]benzoic acid.

Microbial resistance to antibiotics is an unresolved global concern, which needs urgent and coordinated action. One of the guidelines of the Centers for Disease Control and Preventions (CDC) to combat antibiotic resistance is the development of new antibiotics to treat drug-resistant bacteria. In our effort to find new antibiotics, we report the synthesis and antimicrobial studies of 30 new pyrazole derivatives. These novel molecules have been synthesized by using readily available starting materials and benign reaction conditions. Some of these molecules have shown activity with MIC values as low as 0.78 µg/mL against four bacterial strains; Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Acinetobacter baumannii. Furthermore, active molecules are non-toxic to mammalian cell line.

Effects of substance use screening and brief intervention on health-related quality of life.

PURPOSE: Screening, brief intervention, and referral to treatment interventions have been shown to positively impact alcohol use. These programs utilize motivational interviewing techniques in an effort to reduce risky substance use among those at elevated risk of developing a disorder. However, there is a dearth of research assessing positive impacts above and beyond changes in alcohol use. This study examines potential benefits of brief interventions, utilizing motivation interviewing, on mental and physical quality of life. METHODS: The present quasi-experimental study examined changes in health-related quality of life among individuals presenting at urban emergency departments. The analyses included the use of propensity score matching to minimize potential biases resulting from differences between groups at baseline. RESULTS: The results indicated that the intervention group experienced significant increases in perceptions of mental health over those of the comparison group, regardless of changes in substance use. CONCLUSIONS: These findings have implications for practice, as they suggest that brief substance abuse interventions delivered in the emergency department settings may have effects beyond those targeted by the intervention. Specifically, brief substance abuse interventions may positively impact mental health, thus enhancing the quality of life among targets of the intervention.

A qualitative study of the meaning of oral health and self-care for 40 Dunedin residents living on lower incomes.

BACKGROUND AND OBJECTIVES: This project extends studies of oral health cultures for lower income families by identifying the participants' meaning of oral health self-care, barriers to its attainment, and suggestions for its improvement. METHODS: Forty open-ended interviews were conducted with Dunedin residents purposively selected from a variety of ages, backgrounds and ethnicities. Transcribed interviews were analysed thematically. RESULTS: Five key themes emerged: (1) oral health understandings for self and wider family groups; (2) the complexity of understanding cost in relation to oral self-care; (3) oral self-care tools and daily oral health routines; (4) relationships with oral health workers and the meaning of good and bad care provision; and (5) the State's involvement in oral health. CONCLUSIONS: Participants valued good oral health and were knowledgeable about it, but cost was the primary barrier to care.

Blood pressure regulation in the three-toed sloth, Bradypus variegatus.

The aim of this study was to elucidate the role of the baroreflex in blood pressure control in sloths, Bradypus variegatus, since these animals show labile levels in this parameter. Unanesthetized cannulated sloths were positioned in an experimental chair and the arterial catheter was coupled to a strain gauge pressure transducer. Blood pressure was monitored before, during and after the administration of phenylephrine (0.0625 to 4 microg/kg) and sodium nitroprusside (0.0625 to 2 microg/kg), bringing about changes in mean blood pressure from +/-30 mmHg in relation to control values. The relation between heart rate changes due to blood pressure variation was estimated by linear regression analysis. The slope was considered the reflex baroreceptor gain. The results (means+/-SD) showed that the reflex baroreceptor gain was -0.3+/-0.1 bpm/mmHg (r=0.88) to phenylephrine and -0.5+/-0.1 bpm/mmHg (r=0.92) to sodium nitroprusside, denoting a reduced reflex baroreceptor gain when compared with other mammals, suggesting that in sloths the baroreceptors are minimally involved in the buffering reflex response to these drugs. These findings suggest that the labile blood pressure could be influenced or be a result of this lowering in the reflex baroreceptor gain.

Fecal estradiol and progesterone metabolite levels in the three-toed sloth (Bradypus variegatus).

The present study was carried out to assess the possibility of measuring fecal steroid hormone metabolites as a noninvasive technique for monitoring reproductive function in the three-toed sloth, Bradypus variegatus. Levels of the estradiol (E2) and progesterone (P4) metabolites were measured by radioimmunoassay in fecal samples collected over 12 weeks from 4 captive female B. variegatus sloths. The validation of the radioimmunoassay for evaluation of fecal steroid metabolites was carried out by collecting 10 blood samples on the same day as defecation. There was a significant direct correlation between the plasma and fecal E2 and P4 levels (P < 0.05, Pearson's test), thereby validating this noninvasive technique for the study of the estrous cycle in these animals. Ovulation was detected in two sloths (SL03 and SL04) whose E2 levels reached 2237.43 and 6713.26 pg/g wet feces weight, respectively, for over four weeks, followed by an increase in P4 metabolites reaching 33.54 and 3242.68 ng/g wet feces weight, respectively. Interestingly, SL04, which presented higher levels of E2 and P4 metabolites, later gave birth to a healthy baby sloth. The results obtained indicate that this is a reliable technique for recording gonadal steroid secretion and thereby reproduction in sloths.

Fecal estradiol and progesterone metabolite levels in the three-toed sloth (Bradypus variegatus)

The present study was carried out to assess the possibility of measuring fecal steroid hormone metabolites as a noninvasive technique for monitoring reproductive function in the three-toed sloth, Bradypus variegatus. Levels of the estradiol (E2) and progesterone (P4) metabolites were measured by radioimmunoassay in fecal samples collected over 12 weeks from 4 captive female B. variegatus sloths. The validation of the radioimmunoassay for evaluation of fecal steroid metabolites was carried out by collecting 10 blood samples on the same day as defecation. There was a significant direct correlation between the plasma and fecal E2 and P4 levels (P < 0.05, Pearson's test), thereby validating this noninvasive technique for the study of the estrous cycle in these animals. Ovulation was detected in two sloths (SL03 and SL04) whose E2 levels reached 2237.43 and 6713.26 pg/g wet feces weight, respectively, for over four weeks, followed by an increase in P4 metabolites reaching 33.54 and 3242.68 ng/g wet feces weight, respectively. Interestingly, SL04, which presented higher levels of E2 and P4 metabolites, later gave birth to a healthy baby sloth. The results obtained indicate that this is a reliable technique for recording gonadal steroid secretion and thereby reproduction in sloths.

Cardiovascular responses to locomotor activity and feeding in unrestrained three-toed sloths, Bradypus variegatus

Heart rate (HR) and systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure were recorded by biotelemetry in nine conscious unrestrained sloths for 1 min every 15 min over a 24-h period. The animals were allowed to freely move in an acoustically isolated and temperature-controlled (24 ± 1ºC) experimental room with light-dark cycle (12/12 h). Behavior was closely monitored through a unidirectional visor and classified as resting (sitting or suspended), feeding (chewing and swallowing embauba leaves, Cecropia adenops), or locomotor activity around the tree trunk or on the room floor. Locomotor activity caused statistically significant increases in SBP (+8 percent, from 121 ± 22 to 131 ± 18 mmHg), DBP (+7 percent, from 86 ± 17 to 92 ± 10 mmHg), MBP (+8 percent, from 97 ± 19 to 105 ± 12 mmHg), and HR (+14 percent, from 84 ± 15 to 96 ± 15 bpm) compared to resting values, indicating a possible major influence of the autonomic nervous system on the modulation of cardiac function during this behavior. During feeding, the increase in blood pressure was even higher (SBP +27 percent, from 119 ± 21 to 151 ± 21 mmHg; DBP +21 percent, from 85 ± 16 to 103 ± 15 mmHg; MBP +24 percent, from 96 ± 17 to 119 ± 17 mmHg), while HR remained at 14 percent (from 84 ± 15 to 96 ± 10 bpm) above resting values. The proportionally greater increase in blood pressure than in HR during feeding suggests an increase in peripheral vascular resistance as part of the overall response to this behavior.

Cardiovascular responses to locomotor activity and feeding in unrestrained three-toed sloths, Bradypus variegatus.

Heart rate (HR) and systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure were recorded by biotelemetry in nine conscious unrestrained sloths for 1 min every 15 min over a 24-h period. The animals were allowed to freely move in an acoustically isolated and temperature-controlled (24 +/- 1 degree C) experimental room with light-dark cycle (12/12 h). Behavior was closely monitored through a unidirectional visor and classified as resting (sitting or suspended), feeding (chewing and swallowing embauba leaves, Cecropia adenops), or locomotor activity around the tree trunk or on the room floor. Locomotor activity caused statistically significant increases in SBP (+8%, from 121 +/- 22 to 131 +/- 18 mmHg), DBP (+7%, from 86 +/- 17 to 92 +/- 10 mmHg), MBP (+8%, from 97 +/- 19 to 105 +/- 12 mmHg), and HR (+14%, from 84 +/- 15 to 96 +/- 15 bpm) compared to resting values, indicating a possible major influence of the autonomic nervous system on the modulation of cardiac function during this behavior. During feeding, the increase in blood pressure was even higher (SBP +27%, from 119 +/- 21 to 151 +/- 21 mmHg; DBP +21%, from 85 +/- 16 to 103 +/- 15 mmHg; MBP +24%, from 96 +/- 17 to 119 +/- 17 mmHg), while HR remained at 14% (from 84 +/- 15 to 96 +/- 10 bpm) above resting values. The proportionally greater increase in blood pressure than in HR during feeding suggests an increase in peripheral vascular resistance as part of the overall response to this behavior.

Postnatal development of the reproductive system in the grey short-tailed opossum, Monodelphis domestica.

Postnatal phenotypic sex differentiation has been investigated in a laboratory marsupial, Monodelphis domestica, as part of a larger study to resolve apparent discrepancies between eutherian and marsupial mammals. These include the formation of sex-specific structures in marsupials prior to gonadal differentiation and the retention in both sexes of structures which are sex-specific in eutherians. The time-course and nature of differentiation was investigated in 131 specimens ranging in age from the day of birth to 56 days. Patent wolffian ducts extend to the urogenital sinus in both sexes at birth, while müllerian ducts are identified on day 1 and grow in a cranio-caudal direction to reach the urogenital sinus on day 6. The male müllerian duct shows signs of regression at its cranial end on day 10 and throughout its length on day 12; its lumen has completely disappeared by day 15. By this time the epididymis and vas deferens have developed from the wolffian duct; their histological differentiation occurs between days 26 and 56. Prostatic buds are identifiable in tissue surrounding the male urethra on day 14. In the female, the wolffian duct is larger than the müllerian duct until day 14; thereafter the wolffian duct begins to regress at its cranial end, disappearing by day 17, whereas the müllerian duct begins to enlarge, converging with its fellow at the urogenital sinus by day 19. Lateral vaginae, vaginal culs-de-sac, uteri and oviducts have differentiated from the müllerian ducts by day 25. Gonads of both sexes are elongated in shape at birth, attached along the medial aspect of the large mesonephroi in the abdominal cavity. However, from day 3 onwards the testis becomes more rounded than the ovary. Degeneration of the male mesonephros begins about day 10 and is almost completed by day 19; the female mesonephros is still relatively large at day 14 though it too has almost disappeared by day 19. By postnatal day 13 the abdominal phase of testis descent is underway and the inguinal phase begins at day 15. Testes have reached the scrotal sac by day 24 and achieve their final position at the base of the scrotum by day 28. In summary, postnatal reproductive tract development and gonadal descent has been examined in this important biomedical model, where differentiation of the wolffian and müllerian ducts takes place after gonadal differentiation, according to the normal eutherian pattern.

The role of androgens in development of the scrotum of the grey short-tailed Brazilian opossum ( Monodelphis domestica).

In eutherian mammals, sex differentiation is initiated by expression of the testis-determining gene on the Y chromosome. Subsequent phenotypic development of the reproductive tract and genitalia depends on the production of hormones by the differentiated testis. In marsupials the mechanisms of phenotypic development may vary from this pattern, as differentiation of the scrotal primordia has been shown to occur before that of the gonad. Thus, the development of the scrotum in the marsupial has been regarded as an androgen-independent process. We have sought to clarify the ontogeny of scrotal development and the appearance of androgen receptor immunoreactivity by examining Monodelphis domesticaembryos/pups from 1 day prior to birth until 2 days after birth. We have also used immunocytochemistry to determine the expression of the key steroidogenic enzyme 3beta-hydroxysteroid dehydrogenase as an indicator of when the developing gonad may be capable of synthesizing androgens. Expression of this enzyme was first detected in the gonads and adrenals of both sexes 1 day prior to birth and before the appearance of scrotal bulges. Androgen receptor immunoreactivity was detected in the scrotal anlagen of male opossum pups as early as 1 day following birth. This finding is significantly earlier than previous reports and coincides with the appearance 1 day after birth of distinct scrotal bulges. Androgen receptor immunoreactivity was also observed in the genital tubercles of male pups, but not female pups, 2 days after birth. These results suggest that androgens may play an important role in the development of the male genitalia at a much earlier stage than that indicated by previously published work and that scrotal development in this species may not be androgen-independent.

Circadian rhythms in blood pressure in free-ranging three-toed sloths (Bradypus variegatus).

Blood pressure (BP) profiles were monitored in nine free-ranging sloths (Bradypus variegatus) by coupling one common carotid artery to a BP telemetry transmitter. Animals moved freely in an isolated and temperature-controlled room (24 degrees C) with 12/12-h artificial light-dark cycles and behaviors were observed during resting, eating and moving. Systolic (SBP) and diastolic (DBP) blood pressures were sampled for 1 min every 15 min for 24 h. BP rhythm over 24 h was analyzed by the cosinor method and the mesor, amplitude, acrophase and percent rhythm were calculated. A total of 764 measurements were made in the light cycle and 721 in the dark cycle. Twenty-four-hour values (mean +/- SD) were obtained for SBP (121 +/- 22 mmHg), DBP (86 +/- 17 mmHg), mean BP (MBP, 98 +/- 18 mmHg) and heart rate (73 +/- 16 bpm). The SBP, DBP and MBP were significantly higher (unpaired Student t-test) during the light period (125 +/- 21, 88 +/- 15 and 100 +/- 17 mmHg, respectively) than during the dark period (120 +/- 21, 85 +/- 17 and 97 +/- 17 mmHg, respectively) and the acrophase occurred between 16:00 and 17:45 h. This circadian variation is similar to that observed in cats, dogs and marmosets. The BP decreased during "behavioral sleep" (MBP down from 110 +/- 19 to 90 +/- 19 mmHg at 21:00 to 8:00 h). Both feeding and moving induced an increase in MBP (96 +/- 17 to 119 +/- 17 mmHg at 17:00 h and 97 +/- 19 to 105 +/- 12 mmHg at 15:00 h, respectively). The results show that conscious sloths present biphasic circadian fluctuations in BP levels, which are higher during the light period and are mainly synchronized with feeding.

Circadian rhythms in blood pressure in free-ranging three-toed sloths (Bradypus variegatus)

Blood pressure (BP) profiles were monitored in nine free-ranging sloths (Bradypus variegatus) by coupling one common carotid artery to a BP telemetry transmitter. Animals moved freely in an isolated and temperature-controlled room (24ºC) with 12/12-h artificial light-dark cycles and behaviors were observed during resting, eating and moving. Systolic (SBP) and diastolic (DBP) blood pressures were sampled for 1 min every 15 min for 24 h. BP rhythm over 24 h was analyzed by the cosinor method and the mesor, amplitude, acrophase and percent rhythm were calculated. A total of 764 measurements were made in the light cycle and 721 in the dark cycle. Twenty-four-hour values (mean ± SD) were obtained for SBP (121 ± 22 mmHg), DBP (86 ± 17 mmHg), mean BP (MBP, 98 ± 18 mmHg) and heart rate (73 ± 16 bpm). The SBP, DBP and MBP were significantly higher (unpaired Student t-test) during the light period (125 ± 21, 88 ± 15 and 100 ± 17 mmHg, respectively) than during the dark period (120 ± 21, 85 ± 17 and 97 ± 17 mmHg, respectively) and the acrophase occurred between 16:00 and 17:45 h. This circadian variation is similar to that observed in cats, dogs and marmosets. The BP decreased during "behavioral sleep" (MBP down from 110 ± 19 to 90 ± 19 mmHg at 21:00 to 8:00 h). Both feeding and moving induced an increase in MBP (96 ± 17 to 119 ± 17 mmHg at 17:00 h and 97 ± 19 to 105 ± 12 mmHg at 15:00 h, respectively). The results show that conscious sloths present biphasic circadian fluctuations in BP levels, which are higher during the light period and are mainly synchronized with feeding

Sloth biology: an update on their physiological ecology, behavior and role as vectors of arthropods and arboviruses.

This is a review of the research undertaken since 1971 on the behavior and physiological ecology of sloths. The animals exhibit numerous fascinating features. Sloth hair is extremely specialized for a wet tropical environment and contains symbiotic algae. Activity shows circadian and seasonal variation. Nutrients derived from the food, particularly in Bradypus, only barely match the requirements for energy expenditure. Sloths are hosts to a fascinating array of commensal and parasitic arthropods and are carriers of various arthropod-borne viruses. Sloths are known reservoirs of the flagellate protozoan which causes leishmaniasis in humans, and may also carry trypanosomes and the protozoan Pneumocystis carinii.

Sloth biology: an update on their physiological ecology, behavior and role as vectors of arthropods and arboviruses

This is a review of the research undertaken since 1971 on the behavior and physiological ecology of sloths. The animals exhibit numerous fascinating features. Sloth hair is extremely specialized for a wet tropical environment and contains symbiotic algae. Activity shows circadian and seasonal variation. Nutrients derived from the food, particularly in Bradypus, only barely match the requirements for energy expenditure. Sloths are hosts to a fascinating array of commensal and parasitic arthropods and are carriers of various arthropod-borne viruses. Sloths are known reservoirs of the flagellate protozoan which causes leishmaniasis in humans, and may also carry trypanosomes and the protozoan Pneumocystis carinii

A randomised comparison and economic evaluation of laparoscopic-assisted hysterectomy and abdominal hysterectomy.

OBJECTIVES: To determine the safety, cost effectiveness and effect on quality of life of laparoscopic-assisted vaginal hysterectomy (LAVH) compared with total abdominal hysterectomy (TAH) in the management of benign gynaecological disease. DESIGN: Randomised controlled trial and economic evaluation. SETTING: Three hospitals in the West of Scotland. PARTICIPANTS: Two hundred women scheduled for an abdominal hysterectomy for benign gynaecological disease. MAIN OUTCOME MEASURES: Conversion rate of LAVH to TAH, complication rates, NHS resource use and costs, quality of life using EuroQol 5 D visual analogue scale, and achievement of milestones. RESULTS: The overall incidence of operative complications was 14% in the TAH group and 8% in the LAVH group, with an 8% conversion rate. Length of operation was significantly greater in the women having LAVH at 81 +/- 30 min vs 47 +/- 16 min (P < 0.001). There was no difference in analgesic requirements between the groups although there was a significantly shorter hospital stay for those having LAVH. The rate of post-surgery recovery, satisfaction with operation and quality of life at four weeks post-operative were similar in the two groups of women. LAVH was significantly more expensive than TAH and remained more expensive for all but the most extreme scenario. CONCLUSIONS: This study demonstrates that despite the decreased length of hospital stay, LAVH is more expensive than TAH. In addition, recovery following operation and patient satisfaction were not affected by the route chosen. It is unlikely that LAVH represents an efficient use of NHS resources.

Pharmacological analysis of extracellular dopamine and metabolites in the striatum of conscious as/agu rats, mutants with locomotor disorder.

The as/agu rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in the substantia nigra and lower extracellular levels of dopamine. The animal could represent a model of some human locomotor disorders. High-potassium medium evoked a 460% rise of dopamine levels in control rats but double this in mutants. Amphetamine increased extracellular dopamine by 710% in controls and 1480% in mutants. Clorgyline produced a small increase of dopamine levels in controls but an 1170% increase in mutants. The uptake inhibitor nomifensine increased dopamine levels by 910% in controls but only 270% in mutants. After treatment with benserazide plus L-DOPA, an acute injection of L-DOPA evoked a release of dopamine which was twice as large in the as/agu rats compared with controls. The results show reduced extracellular dopamine in as/agu rats when the locomotor disorder is apparent, but there has been little loss of tyrosine hydroxylase. The responses to drugs are qualitatively different from those obtained using 6-hydroxydopamine.Overall, the effects of compounds affecting aminergic neurons suggest that one possible mechanism for the neuronal abnormality in as/agu rats is a defective regulation of dopamine release from striatal terminals.

Correctable visual impairment in stroke rehabilitation patients.

BACKGROUND: after stroke, visual impairment may exacerbate the impact of other impairments on overall disability and negatively influence rehabilitation. OBJECTIVE: to examine the visual status of patients after stroke and determine whether this can be improved by simple interventions. DESIGN: prospective study. SETTINGS: stroke rehabilitation unit in a Belfast teaching hospital. SUBJECTS: 77 consecutive patients admitted for rehabilitation after acute stroke. METHODS: full optometric and ophthalmic assessment within 2 weeks of admission. RESULTS: of 70 patients with glasses, 19 did not have their glasses in hospital before prompting and 18 had glasses in unacceptable condition. Twenty patients had impaired visual acuity (6/12 or worse) with existing glasses (if helpful); 11 of these improved to better than 6/12 with refractive correction. CONCLUSIONS: stroke professionals need to enquire about patients' spectacles and assess their condition. Patients with reduced visual acuity in the absence of significant non-refractive disease should be referred to an optometrist: in this series 14% of patients had visual impairment which benefited from refractive correction.

An update on the physiology of two- and three-toed sloths.

Physiological and pharmacological research undertaken on sloths during the past 30 years is comprehensively reviewed. This includes the numerous studies carried out upon the respiratory and cardiovascular systems, anesthesia, blood chemistry, neuromuscular responses, the brain and spinal cord, vision, sleeping and waking, water balance and kidney function and reproduction. Similarities and differences between the physiology of sloths and that of other mammals are discussed in detail.