Mechanics of facial growth in young patients.

AIM: The aim of this work is to focus on the impact of occlusion on facial development. METHODS: Literature was searched using Medline, Embase and Cochrane Library. The key words and mesh used were bone remodelling, facial growth, masticatory muscles, children. Only articles written in English were included in the study. CONCLUSION: Disturbances in the harmonious interplay of the masticatory muscles may result in facial alteration and asymmetries. If not treated, the dysplastic pattern of growth continues and worsens with time.

Self-sampling to increase participation in cervical cancer screening: an RCT comparing home mailing, distribution in pharmacies, and recall letter.

BACKGROUND: We performed a multicentre randomised controlled trial to evaluate the effect on participation in organised screening programmes of a self-sampling device mailed home or picked up at a pharmacy compared with the standard recall letter. METHODS: Women aged 30-64 non-responding to screening invitation were eligible. Response rate to first invitation ranged from 30% to 60% between centres. The control was the standard reminder letter to undergo the test used by the programme (Pap test in three centres and HPV DNA test in three other centres). Home mailing of the self-sampler was preceded by a letter with a leaflet about HPV. The analysis was intention-to-treat. RESULTS: In all, 14 041 women were randomised and recruited: 5012 in the control arm, 4516 to receive the self-sampler at home, and 4513 to pick up the self-sampler at a pharmacy. Participation was 11.9% in the control, 21.6% (relative participation: 1.75; 95% CI 1.60-1.93) in home, and 12.0% (relative participation: 0.96; 95% CI 0.86-1.07) in the pharmacy arms, respectively. The heterogeneity between centres was high (excess heterogeneity of that expected due to chance, i.e., I(2), 94.9% and 94.1% for home and pharmacy arm, respectively). The estimated impact on the overall coverage was +4.3% for home mail self-sampling compared with +2.2% for standard reminder. CONCLUSIONS: Home mailing of self-sampler proved to be an effective way to increase participation in screening programmes, even in those with HPV as primary testing. Picking up at pharmacies showed effects varying from centre to centre.

Use of a high-risk human papillomavirus DNA test as the primary test in a cervical cancer screening programme: a population-based cohort study.

OBJECTIVE: To present the results of the first 2 years of a human papillomavirus (HPV) test-based screening programme outside the research context. DESIGN: Population-based cohort study. SETTING: A cervical service screening programme in Italy. POPULATION: Women aged 25-64 years invited to screening from April 2009 to April 2011. METHODS: Eligible women were invited to undergo an HPV test: those with a negative HPV test went on to the next screening episode; those with a positive HPV went on to triage with a Pap smear. Women with positive cytology (i.e. positive for atypical squamous cells of undetermined significance or worse, ASC-US+) were referred to colposcopy, whereas those with negative cytology were referred to repeat HPV testing 1 year later. MAIN OUTCOME MEASURES: Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+. RESULTS: Participation increased compared with the previous Pap programme (60.6 versus 43.9%). The HPV positivity rate was 7.0; 39.6% of Pap smears were scored as positive, and therefore 2.8% of the women screened were referred for immediate colposcopy. The compliance of women who scored positive for HPV and negative for Pap for repeat HPV testing at 12 months was 78.6%, and the HPV positivity rate was 56.6%. The overall referral rate to colposcopy was 4.6%. The overall detection rate for CIN2+ was 4.5 versus 1.5% of the Pap programme (25-34 years, 8.2%; 35+ years, 3.6%). CONCLUSIONS: Compared with the traditional Pap test, the HPV programme recorded a higher response to invitation and an increased DR for CIN2+. The most critical aspects were the reading of cytology in women that were positive for HPV and the increased workload at colposcopy.

The direct effect of insulin on barosensitive neurones in the nucleus tractus solitarii of rats.

The present investigation was designed to determine the direct effect of insulin on the spontaneous discharge of barosensitive neurones in the nucleus tractus solitarii (NTS) of rats anaesthetized with urethane. Microinjection of 20 nl insulin (10 IU/ml) into NTS decreased the spontaneous discharge of 38 of the 52 units studied (73.1%), and this decrease was augmented by increasing the concentration to 40 IU/ml. Microinjections of insulin vehicle, glucose, hydralazine or phenylephrine did not elicit significant changes in the spontaneous discharge of NTS barosensitive neurones. These results demonstrate that insulin inhibits the spontaneous discharge of barosensitive NTS neurones. They suggest that insulin increases sympathetic nervous activity via a central neural mechanism and may play a role in the modulation of cardiovascular information within the NTS.

Reflex cardiovascular responses to somatic stimulation in spontaneously hypertensive rats.

OBJECTIVES: This study aimed to test whether the cardiovascular responses to somatic stimulation in spontaneously hypertensive rats (SHR) were enhanced compared with those in normotensive Wistar-Kyoto (WKY) rats, and to examine any role of the impaired baroreflex function in the hypertensive rats. METHODS: Experiments were done in anaesthetized SHR (n = 34) and WKY (n = 31). Baroreceptor reflexes were assessed by continuous infusion of incremental doses (5-30 microg/kg per min) of phenylephrine over a 3 min infusion period. Cardiovascular responses to sciatic nerve stimulation (5 s trains, 1 ms pulse duration, 400 microA intensity) were studied before and after baroreceptor deactivation. The latter was achieved either by carotid occlusion and cutting the vagi and aortic nerves (SHR, n = 28 and WKY rats, n = 27), or by complete baroreceptor denervation (SHR, n = 6 and WKY rats, n = 4). RESULTS: We confirmed that baroreceptor sensitivity was significantly lower in SHR (0.40 +/- 0.05 ms/mmHg) than in WKY rats (0.90 +/- 0.04 ms/mmHg). Sciatic nerve stimulation elicited significantly greater increases in mean arterial pressure (MAP) and in heart rate in SHR than in WKY rats (+32.5 +/- 1.9 mmHg versus +20.2 +/- 1.1 mmHg and +13.5 +/- 1.5 bpm versus +8.0 +/- 1.1 bpm, respectively). Following baroreceptor deactivation, the responses to the same sciatic nerve stimulation of MAP and heart rate in SHR (+38.5 +/- 2.4 mmHg and +15.5 +/- 1.5 bpm) were still significantly greater than those in WKY rats (+29.5 +/- 1.3 mmHg and +11.6 +/- 1.2 bpm). CONCLUSIONS: These results show that cardiovascular responses to sciatic nerve stimulation are increased in SHR compared to WKY rats, and that this increased reactivity to somatic stimuli in hypertensive rats does not depend upon the impairment in baroreflex function demonstrated in this strain.

Insulin sensitivity and glucose effectiveness estimated by the minimal model technique in spontaneously hypertensive and normal rats.

This study was performed to compare glucose metabolism in anaesthetised spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) in an attempt to clarify whether this animal model of hypertension approximates the insulin-resistant state seen in human hypertension. With this aim the minimal model of glucose kinetics was applied to glucose and insulin data derived from a 12-sample, 120 min intravenous glucose tolerance test (IVGTT) performed in ten SHR and nine WKY rats under pentobarbital anaesthesia. This method provided two metabolic indices: the glucose effectiveness, S(G), which quantifies the ability of glucose per se to enhance its rate of disappearance and to inhibit hepatic glucose production, and the insulin sensitivity, S(I), which measures the ability of insulin to enhance plasma glucose disappearance and to inhibit hepatic glucose production. Systolic and diastolic arterial pressures in the SHR group were significantly higher (P < 0.0005) than in the WKY group. Mean S(G) and S(I) estimates from the SHR group (S(G) = 16.2 (+/- 2.0) x 10(-2) dl x min(-1) x kg(-1) and S(I) = 12.5 (+/- 1.9) x 10(-4) dl x min(-1) x kg(-1) (microU ml(-1))(-1)) were not significantly different (P > 0.05) from mean estimates that characterised the WKY group (S(G) = 13.1 (+/- 1.5) x 10(-2) dl x min(-1) x kg(-1) and S(I) = 15.8 (+/- 4.3) x 10(-4) dl x min(-1) x kg(-1) (microU ml(-1))(-1)). This result is in contrast with reported findings from humans in which insulin sensitivity is significantly reduced in the presence of hypertension.

Influence of GABAergic mechanisms on baroreceptor inputs to nucleus tractus solitarii of rats.

The firing frequency of baroreceptive neurons in the nucleus tractus solitarii (NTS) during microiontophoretic application of muscimol, a gamma-aminobutyric acid (GABA)A agonist, or baclofen, a GABAB agonist, was monitored in anesthetized rats. Muscimol decreased the spontaneous discharge of 69 of 73 (94.5%) NTS baroreceptive neurons without affecting the remaining four neurons (5.5%). The statistical comparison on a bin-by-bin basis of the peri-R wave interval histograms of the discharge of each NTS neuron showed that the inhibitory action of muscimol was always exerted on the whole neuronal discharge independently of its correlation to the cardiac cycle. Baclofen inhibited 60 of 73 (82.2%) NTS neurons without affecting the remaining 13 neurons (17.8%). In 31 of 60 (51.7%) neurons inhibited by baclofen, this substance significantly affected only pulse-synchronous peaks of neuronal discharge without significant inhibition of the neuronal firing between cardiac cycle-related peaks. Fifty-eight of 73 (79.5%) NTS neurons studied were inhibited by both muscimol and baclofen, 11 neurons (15%) only by muscimol, 2 neurons (2.7%) only by baclofen, and 2 neurons (2.7%) were unaffected by both substances. These results demonstrate that both GABAA and GABAB receptors mediate inhibition of the spontaneous discharge in the great majority of the NTS baroreceptive neurons studied and suggest different functions of the two types of GABA receptors in influencing baroreceptor inputs to the NTS.

Cardiovascular effects of microinjection of atrial natriuretic factor (ANF) in the nucleus tractus solitarii of spontaneously hypertensive rats.

The effects on mean arterial pressure (MAP) and heart rate (HR) of unilateral microinjections of atrial natriuretic factor (ANF) into discrete sites of the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHR) were compared with those observed in normotensive Wistar-Kyoto rats (WKY). NTS sites were identified to be involved in cardiovascular control on the basis of the bradycardia and hypotension elicited by microinjections of 20 nl of 0.1 M L-glutamate. Microinjection of 20 nl of 10(-7) M ANF into 38 NTS 'cardiovascular sites' in rats of the SHR strain decreased MAP (-8.7 +/- 1.8 mmHg) and HR (-7.8 +/- 1.9 bpm) in 9 sites (24%), but caused no changes in the remaining 29 sites (76%). In WKY rats 35 cardiovascular sites within the NTS were studied. In 18 sites (51%) ANF microinjections induced a decrease in MAP (-15.1 +/- 1.9 mmHg) and in HR (-18.1 +/- 3.9 bpm), whereas the remaining 17 sites (49%) were unaffected. The decreased responsiveness of the NTS to ANF in the SHR animals could play a role in the development and/or maintenance of the elevated arterial blood pressure in genetically hypertensive rats.

GABAB receptor-mediated mechanisms in the RVLM studied by microinjections of two GABAB receptor antagonists.

The cardiovascular effects of microinjections of two gamma-aminobutyric acid (GABA) antagonists specifically acting on GABAB receptors, 2-hydroxy-saclofen (2-OH-S) and CGP-35348, into vasopressor sites of rostral ventrolateral medulla (RVLM) were studied in rats anesthetized with urethan. Bilateral microinjection of 2-OH-S induced significant increases in mean arterial pressure (MAP) and heart rate (HR) in 21 of 26 RVLM vasopressor sites (81%); average increases obtained in the 26 sites studied were +25.2 +/- 3.0 mmHg and +12.7 +/- 2.1 beats/min. Bilateral microinjection of CGP-35348 induced significant increases in MAP and HR in 10 of 12 RVLM sites (83%). Average increases in the 12 sites studied were +27.6 +/- 3.9 mmHg and +14.6 +/- 2.5 beats/min. Sixteen rats received unilateral electrolytic lesions of one RVLM. Microinjections of either 2-OH-S or CGP-35348 into vasopressor sites within the intact RVLM significantly antagonized the depressor responses observed after injections of baclofen (20 pmol) into the same sites, whereas both GABAB antagonists did not affect the depressor response induced by microinjection of muscimol (5 pmol). These results suggest a tonic inhibitory mechanism within the RVLM mediated by GABAB receptors involved in central cardiovascular regulation.

Neuronal and cardiovascular responses to ANF microinjected into nucleus ambiguous.

Effects of microinjection of atrial natriuretic factor (ANF) into cardioinhibitory sites in the nucleus ambiguous (NA) or on single vagal cardioinhibitory neurons (VCN) were investigated in urethan-anesthetized rats. Sites containing cardioinhibitory neurons were identified by observing a marked and reproducible bradycardia in response to microiontophoretically applied (20-40 nA) or microinjected (20 nl) 0.1 M L-glutamate. In 35 of the 40 (87.5%) cardioinhibitory sites identified by microinjection of glutamate, ANF (20 nl of 10(-7) M) decreased heart rate (HR; -47.1 +/- 2.5 beats/min). No responses were elicited in the other five sites. In animals paralyzed and artificially ventilated, the HR effects of ANF were not significantly different before and after muscle paralysis. Microinjections of 10 nl of 10(-7) M ANF caused excitation of 19 of 21 VCN (90%), which was followed by a decrease in HR (-20.8 +/- 2.3 beats/min); no neuronal or cardiovascular responses were elicited by ANF in the remaining two VCN. Bilateral vagotomy or atropine sulfate (1 mg/kg iv) abolished cardiac slowing without affecting neuronal activation, whereas propranolol (2 mg/kg iv) did not affect either response to ANF. These results suggest that ANF is a neuromediator involved in the excitation of cardioinhibitory neurons in the NA.

Actions of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone on single neurones of the mesencephalic reticular formation in the rat.

The effects of microinjections of 3 alpha,5 alpha-tetrahydrodeoxycorticosterone (3 alpha-THDOC) on single neurones of the mesencephalic reticular formation (MRF) were investigated in rats anaesthetized with urethan. Microinjections of approximately 100 nl of 0.5-2 microM 3 alpha-THDOC inhibited firing of 105 of 112 neurones (94%). Microinjections of approximately 100 nl of 100-250 nM of 3 alpha-THDOC did not alter neuronal activity, but in 52 of 68 cases (76%) it potentiated the inhibitory action of microiontophoretically applied gamma-aminobutyric acid (GABA). The 3 beta-isomer of tetrahydrodeoxycorticosterone did not elicit any changes in neuronal firing. The effects of 3 alpha-THDOC were reversibly antagonized by microiontophoretically applied bicuculline. This 'in vivo' study supports the hypothesis that 3 alpha-THDOC may function as endogenous modulator of GABAA-mediated inhibition in various physiopathological conditions.

Neuronal and cardiovascular responses to ANF microinjected into the solitary nucleus.

The effect on single-unit activity, arterial pressure, and heart rate of a microinjection of atrial natriuretic factor (ANF) into 78 histologically verified sites in the nucleus tractus solitarii (NTS) was investigated in rats. Injections of 50 nl of 10(-7) M ANF excited 34 neurons (44%), mainly localized at the level of the obex, inhibited 15 (19%), and had no effect on the remaining 29 (37%). The increase in firing frequency of the 34 excited neurons was always followed by a decline in mean arterial pressure [MAP, -10.6 +/- 1.8 (SE) mmHg; P less than 0.01] and heart rate [HR, -9.6 +/- 3.1 (SE) beats/min; P less than 0.05]. When injections of ANF caused either no effect or inhibition of single-unit activity, no changes in either MAP or HR were observed. Single units excited by injections of ANF were also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading. Control injections of an inactive peptide analogue of ANF or of vehicle never produced any effects on neuronal firing frequency or on MAP and HR. Similar results were obtained from animals paralyzed and artificially ventilated. These results support the hypothesis that ANF plays a role in the chemical transmission of baroreceptor information within the NTS.

Effects of intraoral mechanoreceptor stimulation on reticular formation neurones, in the rabbit.

The effects of intraoral mechanoreceptor stimulation on the firing rate of single neurones of the brain stem reticular formation (RF) were investigated in rabbits. 30% of RF neurones responded to periodontal mechanoreceptor stimulation; 16% to mucosal mechanoreceptor stimulation and 6% to both types of stimuli. Periodontal stimulation induced mainly inhibitory effects localized within the mesencephalic and rostral pontine RF. Among periodontal afferents incisors were the most widely represented. The effects of mucosal mechanoreceptor stimulation were predominant in the medullary and pontine RF and they were mainly excitatory. The present results support the hypothesis that brain stem RF neurones can be recruited into regulating mastication and biting also by stimulation of intraoral mechanoreceptors.

Effects of corticosterone on neurones of the locus coeruleus, in the rat.

The effects of microelectrophoretic application of corticosterone (CS) on single neurones of the locus coeruleus (LC) were investigated in rats under urethane anaesthesia. Ejecting currents generally ranged from 10 to 60 nA. CS produced an excitatory effect in 73% of the neurones and no effect in 27%. The prevailingly excitatory effects induced by CS on LC neurones may be related to the regulation of those complex events, which constitute the 'stress response'.

Effects of corticosterone on neurons of reticular formation in rats.

The effects of microelectrophoretic application of corticosterone (CS) on single neurons of the brain stem reticular formation (RF) were investigated and then compared with the effects produced on the same neurons by intravenous administration of CS. The experiments were done in two groups of rats, one anesthetized with urethan and the other with pentobarbital sodium because these anesthetics cause different increases of basal concentration of plasma CS. Microelectrophoretic application of CS to neurons in the caudal portion of RF caused primarily excitatory effects, whereas inhibitory effects were observed in neurons of the rostral portion of the RF. The intravenous injection of CS (5 micrograms/100 g body wt) always produced the same effects as microelectrophoretic application. Under our experimental conditions the increase in plasma CS concentration produced by the intravenous injection of CS was found to be within the physiological range for the rat. The different anatomical distribution of units within the RF responding with either excitation or inhibition may be related to functional differences of the two RF areas.

Effect of microelectrophoretically applied corticosterone on raphe neurones in the rat.

The effect of microelectrophoretic application of corticosterone (CS) on single neurones of raphe nuclei (RN) were investigated in rats under urethane anaesthesia. Ejecting currents generally ranged from 5 to 40 nA. CS produced an excitatory effect in 61% and no effect in 39% of the neurones. None of the 54 neurones studied was inhibited by CS. These quite homogeneous data support the hypothesis that RN are involved in the regulation of most of the nervous functions in which glucocorticoid hormones have been implicated.

Actions of microelectrophoretically applied glucocorticoid hormones on reticular formation neurones in the rat.

The effects of microelectrophoretic application of hydrocortisone (HC) and corticosterone (CS) on single neurones of the brainstem reticular formation (RF) were investigated in rats under urethane anaesthesia. Ejecting currents generally ranged from 5 to 20nA. HC and CS behaved similarly in that they produced an excitatory effect in 26% and 24% of the neurones, respectively, an inhibition in 15% and 17% and no effect in 59% of neurones. The excitatory effects predominated in the caudal portion of the FR and the inhibitory effects in the rostral RF. The different distribution of the effects may be related to functional differences between the two RF areas.