Clinical medical sciences for undergraduate dental students in the United Kingdom and Ireland - a curriculum.

The technical aspects of dentistry need to be practised with insight into the spectrum of human diseases and illnesses and how these impact upon individuals and society. Application of this insight is critical to decision-making related to the planning and delivery of safe and appropriate patient-centred healthcare tailored to the needs of the individual. Provision for the necessary training is included in undergraduate programmes, but in the United Kingdom and Ireland there is considerable variation between centres without common outcomes. In 2009 representatives from 17 undergraduate dental schools in the United Kingdom and Ireland agreed to move towards a common, shared approach to meet their own immediate needs and that might also be of value to others in keeping with the Bologna Process. To provide a clear identity the term 'Clinical Medical Sciences in Dentistry' was agreed in preference to other names such as 'Human Disease' or 'Medicine and Surgery'. The group was challenged to define consensus outcomes. Contemporary dental education documents informed, but did not drive the process. The consensus curriculum for undergraduate Clinical Medical Sciences in Dentistry teaching agreed by the participating centres is reported. Many of the issues are generic and it includes elements that are likely to be applicable to others. This document will act as a focus for a more unified approach to the outcomes required by graduates of the participating centres and act as a catalyst for future developments that ultimately aim to enhance the quality of patient care.

Effects of NOS inhibition on the cardiopulmonary system and brain microvascular markers after intermittent hypoxia in rats.

We previously demonstrated that rats subjected to intermittent hypoxia (IH) by exposure to 10% O(2) for 4 h daily for 56 days in a normobaric chamber, developed pulmonary hypertension, right ventricular hypertrophy and wall-thickening in pulmonary arterioles, compared with normoxic (N) controls. These changes were greater in rats subjected to continuous hypoxia (CH breathing 10% O(2) for 56 days). Cerebral angiogenesis was demonstrated by immunostaining with glucose transporter 1 (GLUT1) antibody, in viable vessels, in CH and to a lesser degree in IH. In this study, adult Wistar rats were subjected to the same hypoxic regimes and given the nitric oxide synthase (NOS) inhibitor N(6)-nitro-L-arginine methyl ester (L-NAME) in drinking water (NLN, IHLN and CHLN regimes) to induce hypertension. There was significant systemic hypertension in NLN and IHLN rats, compared with N and IH, but surprisingly not in CHLN compared with CH. Hematocrit rose in all hypoxic groups (up to 79% in CHLN). There was no significant pulmonary hypertension in IHLN versus NLN rats, although there was asymmetric wall thickening in pulmonary arterioles. Cerebral GLUT1 immunoreactivity increased with L-NAME, with or without hypoxia, especially in CHLN rats, but conspicuously there was no evidence of angiogenesis in brains of IHLN compared with NLN rats. NOS blockade may attenuate the cerebral and pulmonary vascular changes of IH while augmenting cerebral angiogenesis in continuous hypoxia. However, whether cerebral effects are due to systemic hypertension or changes in cerebral nitric oxide production needs to be evaluated.

Circulating nitrite anions are a directly acting vasodilator and are donors for nitric oxide.

Inhaled nitric oxide (NO) is a pulmonary vasodilator, but also acts systemically, causing negative cardiac inotropic effects and a fall in systemic vascular resistance. Circulating metabolites of NO are presumed to be responsible. We questioned the role of nitrite anions and the manner in which they might contribute to these effects. Nitrite and nitrate anions coexist in blood, while circulating levels of dissolved NO are very low. Nitrate anions are not biologically active, but nitrite anions may have a biological role through the release of NO. In vitro, at 37 degrees C and in aerated Krebs bicarbonate solution, the steady-state concentration of dissolved NO was proportional to the concentration of NO in the gas. Nanomolar concentrations of dissolved NO coexisted with micromolar concentrations of nitrite anions. The idea of an equilibrium between the two in solution was also supported by the observed release of NO from nitrite anions in the absence of gas. With rings of precontracted pig pulmonary arteries (prostaglandin F(2alpha); 10 micromol/l), the steady-state concentration of dissolved NO causing 50% relaxation (EC(50)) was 0.84+/-0.25 nmol/l, corresponding to a gaseous concentration of 2.2 p.p.m. The EC(50) of nitrite was 4.5+/-0.7 micromol/l, a concentration normally found in plasma. The estimated concentration of dissolved NO derived from this nitrite was 4.5 pmol/l, some 100 times lower than would be needed to cause relaxation. The rate of exhalation of NO was increased and pulmonary vascular resistance was reduced by the addition of nitrite solution to the perfusate of isolated perfused and ventilated pig lungs, but only when millimolar concentrations were achieved. Thus circulating nitrite anions are a direct vasodilator, only being a carrier of effective amounts of "free" NO at higher than physiological concentrations.

The acute effects of dexfenfluramine on human and porcine pulmonary vascular tone and resistance.

STUDY OBJECTIVES: Treatment with anorectics has become an important aspect of care for the severely obese. One such anorectic, the phenylethylamine dexfenfluramine (dFen), has been associated with the development of pulmonary hypertension. It works by reducing the neuronal uptake of 5-hydroxytryptamine (5-HT; serotonin) through inhibition of the 5-HT transporter. In this study we investigated whether dFen has a direct vasoconstrictor action on human and porcine pulmonary vasculature. DESIGN: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10(-5) mol/L), or nitric oxide synthase (NOS) blockade (N(G)-nitro-L-arginine, 10(-5) mol/L). RESULTS: In the human study, 5-HT and dFen caused only limited increases in tension of isolated rings of PA. The concentration of dFen, 10(-4) mol/L, that was needed to increase tension was higher than that found normally in treated patients where peak levels are 3. 3 x 10(-7) mol/L. Other vasoconstrictors such as prostaglandin F(2)alpha, 10(-5) mol/L, and the thromboxane analog U46619, 10(-6) mol/L, produced far greater increases in tension. Ketanserin, 10(-4) mol/L, attenuated the constrictor response to 5-HT but had no effect on the constrictor response to dFen. Removal of the endothelium did not influence the response to dFen. In the isolated ventilated and perfused lungs, dFen caused an increase in PVR again only at a comparatively high concentration, 10(-4) mol/L. In the porcine study, dFen, 10(-4) mol/L, did not increase any PVR during normoxia or following NOS blockade. Small insignificant increases in PVR occurred during hypoxia and after cyclo-oxygenase blockade. CONCLUSION: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.

Role of nitric oxide synthase and cyclooxygenase in pulmonary vascular control in isolated perfused lungs of ferrets, rats and rabbits.

Dilator products of nitric oxide synthase (NOS) and cyclooxygenase (COX) may contribute to the low normal pulmonary artery pressure (Ppa). In isolated perfused lungs of ferrets, rabbits and rats we investigated this hypothesis by blockade of NOS with L-NAME (L-nitro-arginine methyl ester) and COX with meclofenamate. There were species differences. Inhibition of either enzyme caused little rise in Ppa in ferrets and rats but inhibition of both enzymes caused huge increases in Ppa. We suggest this might be due to intracellular connections between the excitatory pathways for NOS and COX dilators, such that inhibition of one enzyme leads to activation of the other. Impairment of these endothelial-based enzymes in pulmonary vascular disease might lead to severe pulmonary hypertension. By contrast, in rabbits, comparable doses of L-NAME lead to large rises in Ppa which were reversed rather than amplified by COX blockade. NO seems to protect against some pressor/oedema forming product of COX in this species.

Combined microlightguide spectrophotometry and microendoscopy for measurement of oxygen saturation in peripheral nerves.

Microlightguide measurements of the spectral composition of backscattered light may be used to determine local tissue oxygen saturation and monitor tissue perfusion using intravenous injection of fluorescein dye as a contrast agent. We have used a combination of microlightguide spectrophotometry and microendoscopy to measure intravascular oxygen saturation (HbSaO2%) and monitor blood flow in the sciatic nerve of 12 healthy male Sprague-Dawley rats. The microlightguide and endoscope combination is a relatively new measurement technique. The aims of this study were to determine whether microlightguide spectrophotometry and microendoscopy could be used to measure HbO2 and blood flow in peripheral nerves and to compare the measurements made using the flexible lightguide with the endoscope-lightguide combination. We found no significant difference between the two types of measurement over similar regions of the nerve. mean SaO2% values 77.1% (95% CI = 75.4-78.8) and 78.8% (95% CI = 77.5-80.1) respectively. During a period of hypoxia there was a similar fall in both arterial and nerve oxygen saturation. Following injection of fluorescein, the rate of increase in nerve fluorescence was used as a measure of perfusion. The combination of microlightguide spectrophotometry and microendoscopy allows the exact site of measurement to be directly visualized. The minimally invasive nature of this technique may allow its application to the study of peripheral nerves in human subjects in conditions such as diabetic neuropathy where vascular factors are thought to have an important role in aetiology.

Ionic currents in carotid body type I cells isolated from normoxic and chronically hypoxic adult rats.

Whole-cell recordings were used to investigate the effects of a 3-week period of hypoxia (10% O2) on the properties of K+ and Ca2+ currents in type I cells isolated from adult rat carotid bodies. Chronic hypoxia significantly increased whole-cell membrane capacitance. K+ current amplitudes were not affected by this period of hypoxia, but K+ current density was significantly reduced in cells from chronically hypoxic rats as compared with normoxically maintained, age-matched controls. K+ current density was separated into Ca2+-dependent and Ca2+-independent components by bath application of 200 microM Cd2+, which blocked Ca2+ currents and therefore, indirectly, Ca2+-dependent K+ currents. Ca2+-dependent K+ current density was not significantly different in control and chronically hypoxic type I cells. Cd2+-resistant (Ca2+-insensitive) K+ current densities were significantly reduced in type I cells from chronically hypoxic rats. Acute hypoxia (Po2 15-22 mmHg) caused reversible, selective inhibition of Ca2+-dependent K+ currents in both groups of cells and Ca2+-insensitive K+ currents were unaffected by acute hypoxia. Ca2+ channel current density was not significantly affected by chronic hypoxia, nor was the degree of Ca2+ channel current inhibition caused by nifedipine (5 microM). Acute hypoxia did not affect Ca2+ channel currents in either group. Our results indicate that adult rat type I cells undergo a selective suppression of Ca2+-insensitive, voltage-gated K+ currents in response to chronic hypoxia in vivo. These findings are discussed in relation to the known adaptations of the intact carotid body to chronic hypoxia.

Spread of HIV-1 to children in Cambodia.

PIP: Beginning November 1, 1995, children under 5 years of age, who were admitted to Kantha Bopha Hospitals and who were suspected tuberculosis cases, were screened for human immunodeficiency virus 1 (HIV-1) using enzyme-linked immunosorbent assay (ELISA). By January 31, 1997, 9026 children, 83% of the under 5-year-olds admitted, had been tested; 290 (3.2%) were positive. Serum samples from 205 children of the 236 seropositive children under the age of 18 months were tested for p24 antigen; 51 (25%) were positive. Mothers of 173 of the seropositive children were tested for antibodies to HIV; 170 were positive, which suggests that the main mode of acquisition of HIV-1 in the children was vertical transmission. If HIV-1 infection occurred only in the 54 seropositive children older than 18 months and in the 51 children younger than 18 months with detectable p24 antigen, the calculated prevalence of HIV-1 in children under 5 years old who were suspected of having tuberculosis when admitted to Kantha Bopha Children's Hospitals would be 1.2%. If the 17% not included in the test were all negative, the prevalence would be 1%. This is an underestimate because some of the children not tested could be positive and because some of the children tested had indeterminate HIV status. HIV testing was extended to all children admitted to the hospital; 715 were younger than 5 years of age, 596 of whom were suspected of having tuberculosis, and 119 of whom were not. The seroprevalences for the 2 subgroups were 3.2% and 0.8%, respectively. None of the 369 older children was seropositive. In 1996, the World Health Organization estimated a seroprevalence of 1.97% in adults 15-49 years old in Cambodia, the highest among Asian countries. The blood bank at Kantha Bopha found 211 (6.6%) HIV-1 seropositives among 3197 donors in 1995 and 211 (7.5%) among 2834 donors in 1996. Similar figures were seen at the National Transfusion Centre in Phnom Penh. A 1996 survey in Cambodia found an HIV-1 seroprevalence of 40.9% in prostitutes and 1.7% in pregnant women. The vertical transmission of HIV-1 to children may increase because the virus appears to have been introduced recently to Cambodia; this is indicated by lack of seropositivity in children older than 5 years of age.^ieng

Ca2+ channel currents in type I carotid body cells of normoxic and chronically hypoxic neonatal rats.

Whole-cell patch-clamp recordings were used to study voltage-gated Ca2+ channel currents in type I carotid body cells of young rats born and reared in normoxia or in a chronically hypoxic (CH) environment (10% O2). Currents activated at potentials of -40 mV and more positive, and typically peaked at 0 mV in both groups of cells. Steady-state inactivation curves were similar in the two populations. Ca2+ currents were significantly larger in CH type I cells, but this was accounted for by the increased size of CH cells: current density was similar in both cell types. Nifedipine (5 microM) always partially inhibited currents and Bay K 8644 (2-5 microM) always enhanced currents, indicating the presence of L-type channels. In a small number of cells from each group, the N-type channel blocker omega-conotoxin GVIA caused partial, irreversible inhibition, but in most cells was without discernible effect. These results indicate that type I cells possess L-type Ca2+ channels, that N-type are expressed in some cells and that non-L, non-N-type channels are also present. Furthermore, chronic hypoxia does not appear to cause specific adaptive changes in the properties of Ca2+ channels in type I cells.

Acute hypoxic ventilation, carotid body cell division, and dopamine content during early hypoxia in rats.

In a previous study, we showed that the acute hypoxic ventilatory response was blunted in anesthetized chronically hypoxic rats and was restored by blockade of the dopamine D2 receptor with domperidone. We now report observations made during 1-8 days of exposure to 10% O2 on the acute hypoxic ventilatory response and the effect of domperidone and relate them to dopamine content and cellular proliferation in the carotid body. Hypoxic exposure caused a parallel shift in the hypoxic response curve to higher levels of ventilation and arterial oxygen saturation. The greatest response occurred on day 1 and was unaffected by domperidone: dopamine content diminished and mitotic activity increased. By 8 days, hypoxic ventilation approached normal and was significantly augmented by domperidone; in the carotid body, dopamine levels had risen above the control level and mitoses had diminished. Thus the increase in ventilation was inversely related to carotid body dopamine content, which was depressed. The possibility of a causal relationship is discussed.

Antitussive and antibronchoconstriction actions of fenspiride in guinea-pigs.

Fenspiride is a nonsteroidal anti-inflammatory agent, which we have previously shown to have an in vivo antibronchoconstrictor action in guinea pigs. We have currently studied this action using the constrictors Substance P, neurokinin A, citric acid and capsaicin in anaesthetized guinea-pigs. Fenspiride has also been reported to produce a subjective improvement in cough in patients. We have used a conscious guinea-pig model of cough as a more definitive method to study the effect of fenspiride on capsaicin- and citric acid-induced cough. Aerosolized fenspiride (1 mg.mL-1) caused a 58% reversal of capsaicin-induced bronchoconstriction; and i.v. fenspiride (1mg.kg-1) a 45% reversal of citric acid induced bronchoconstriction. Substance P- and neurokinin A-induced bronchoconstriction were unaffected by 1 mg.kg-1 i.v. fenspiride. Aerosolized fenspiride (1, 3 and 10 mg.mL-1) administered for 4 min reduced citric acid (300 mM) induced cough, but 0.1 mg.mL-1 was without effect. Pretreatment with aerosolized fenspiride (10 mg.mL-1) caused a shift in the citric acid dose response curve to the right. For citric acid-induced cough, the duration of action of aerosolized fenspiride (10 mg.mL-1) was found to be 5 and 15 min post-treatment. Aerosolized capsaicin (30 microM) induced cough was also reduced by 3 and 10 mg.mL-1 aerosolized fenspiride, but no significant effect was found with 1 mg.mL-1. We conclude that aerosolized fenspiride reduces capsaicin- and citric acid-induced bronchoconstriction as well as induced cough in guinea-pigs in vivo. Whether a pathway common to both cough and bronchoconstriction is the site of action of fenspiride remains to be established. We postulate that fenspiride, acting as an antitussive and antibronchoconstrictor agent, would be beneficial in the clinical situation for those patients with hyperresponsive airways.

Occurrence of different genospecies of Borrelia burgdorferi sensu lato in ixodid ticks of Valais, Switzerland.

A total of 825 adult ticks (727 Ixodes ricinus, 72 Dermacentor marginatus and 26 Haemaphysalis punctata) was collected from vegetation in Valais (Switzerland) in 1987 to 1992. They were examined for the presence of Borrelia burgdorferi sensu lato, the etiologic agent of Lyme borreliosis. B. burgdorferi sensu lato was detected by indirect immunofluorescence assay, dark field microscopy and/or culture in 221 out of 727 I. ricinus (30.4%) and none in the other two species. From these 221 infected ticks we obtained 50 isolates. Indirect immunofluorescence assay and culture were used for all ticks but dark field examination has also been performed and compared to the two above mentioned methods for 231 I. ricinus. Indirect immunofluorescence assay and culture were used for all ticks but dark field examination has also been performed and compared to the two above mentioned methods for 231 I. ricinus. Indirect immunofluorescence was found the most efficient method for the detection of Borrelia in ticks with 54 positive out of 231, followed by dark field examination with 35 positive and culture with 12 isolates. We found no site free of Borrelia where I. ricinus is present. The rate of infection varied from 9.7 to 47.5%, as detected by the addition of the three methods. Typing of the 50 isolates revealed also a nonhomogeneous distribution of the Borrelia species. Based on the electrophoretic mobility of the OspA and B and immunostaining with species specific monoclonal antibodies (H3TS for B. burgdorferi sensu stricto, D6 for B. garinii and J8.3 for B. afzelii) 4 groups could be observed. Half of the isolates (n = 26) were typed as B. burgdorferi sensu stricto, 19 as B. garinii, 3 as B. afzelii and 2 as group VS116. This forth group formed of two isolates from one location is genetically distinct from the 3 former species described in Europe so far. The Borreliae of this group are unreactive with any of the three monoclonal antibodies used.

Effect of fenspiride on pulmonary function in the rat and guinea pig.

1. Fenspiride is an anti-inflammatory agent that may have a role in reversible obstructive airways disease. Small, but significant, improvements have been seen in airways function and arterial oxygen tension in patients with mild chronic obstructive pulmonary disease. These changes have been attributed to the anti-inflammatory properties of the drug. However, airways function can be improved by other means, e.g. improved ventilation/perfusion ratio or reduced airways resistance. The possibility that fenspiride may have actions other than anti-inflammatory was investigated in two animal species. 2. In the rat, actions on the pulmonary circulation were investigated in the isolated perfused lung, but fenspiride proved to be a poor pulmonary vasodilator, showing only a small reversal of the raised pulmonary artery pressure induced by hypoxia. 3. Ventilation was measured in the anaesthetized rat using whole-body plethysmography. Fenspiride caused no increase in ventilation or changes in arterial blood gases. However, a profound hypotensive action was observed with high doses. 4. The possibility that a decrease in airways resistance (R(aw)) might occur with fenspiride was investigated in anaesthetized guinea pigs. Capsaicin (30 mumol/l) was used to increase baseline R(aw) through bronchoconstriction. Fenspiride gave a dose-dependent partial reversal of the raised R(aw), and its administration by aerosol proved as efficacious as the intravenous route. In addition, the hypotensive side-effect found with intravenous injection was alleviated by aerosolized fenspiride.(ABSTRACT TRUNCATED AT 250 WORDS)

O2-sensitive K+ currents in carotid body chemoreceptor cells from normoxic and chronically hypoxic rats and their roles in hypoxic chemotransduction.

Carotid body-mediated ventilatory increases in response to acute hypoxia are attenuated in animals reared in an hypoxic environment. Normally, O2-sensitive K+ channels in neurosecretory type I carotid body cells are intimately involved in excitation of the intact organ by hypoxia. We have therefore studied K+ channels and their sensitivity to acute hypoxia (PO2 12-20 mmHg) in type I cells isolated from neonatal rats born and reared in normoxic and hypoxic environments. When compared with cells from normoxic rats, K+ current density in cells from hypoxic rats was significantly reduced, whereas Ca2+ current density was unaffected. Charybdotoxin (20 nM) inhibited K+ currents in cells from normoxic rats by approximately 25% but was without significant effect in cells from hypoxic rats. However, hypoxia caused similar, reversible inhibitions of K+ currents in cells from the two groups. Resting membrane potentials (measured at 37 degrees C using the perforated-patch technique) were similar in normoxic and hypoxic rats. However, although acute hypoxia depolarized type I cells of normoxic rats, it was without effect on membrane potential in type I cells from hypoxic animals. Charybdotoxin (20 nM) also depolarized cells from normoxic rats. Our results suggest that type I cells from chronically hypoxic rats, like normoxic rats, possess O2-sensing mechanisms. However, they lack charybdotoxin-sensitive K+ channels that contribute to resting membrane potential in normoxically reared rats, and this appears to prevent them from depolarizing (and hence triggering Ca2+ influx and neurosecretion) during acute hypoxia.

Acculturation and the initiation of breastfeeding.

Despite the fact that breastfeeding is the most appropriate form of nutrition for the healthy term infant, the rate of initiation in the U.S. is declining. One demographic factor associated with this low rate is ethnicity and so in this study we measured acculturation (one aspect of ethnicity) into the U.S. and its relationship to the successful initiation of breastfeeding in a sample of women recruited approximately 2 months prenatally in a U.S.-Mexico border city. Interviews were administered in English or Spanish by bilingual interviewers prenatally (n = 906), natally (n = 788), and postnatally (n = 715). Acculturation (measured with a 20 item instrument) was strongly related to the intent to (p < 0.001) or the successful initiation of breastfeeding (p < 0.001). Marital status (p = 0.014) and education (p = 0.002) were related to breastfeeding prenatally and natally. Initiation of breastfeeding was highest among those women least acculturated (52.9%) and lowest in those most acculturated (36.1%) indicating an inhibiting effect of acculturation. To improve the rate of initiation of breastfeeding in the U.S. (a national health goal) intervention programs must consider cultural factors.

Nitrogen balance, plasma free amino acid concentrations and urinary orotic acid excretion during long-term fasting in cats.

The purpose of this study was to ascertain the changes in nitrogen balance, plasma free amino acid concentrations, urinary orotic acid excretion and body weight during long-term fasting in adult obese cats. Results from eight cats that fasted rather than eat an unpalatable diet are reported. After 5 to 6 wk of weight loss, six of the eight cats developed signs of hepatic lipidosis, and the livers of all cats were severely infiltrated with lipids. Cats lost (mean +/- SE) 33.2 +/- 1.4% of their pre-fasting body weight. Mean nitrogen balance (+/- SE) was -547 +/- 54 mg.d-1.kg-2/3 for the first week, and then the net nitrogen losses decreased to a plateau (-303 +/- 52 mg.d-1.kg-2/3) after 4 wk. Fasting was associated with a decrease in plasma concentration of essential amino acids. When plasma amino acid concentrations were considered individually, concentrations of alanine, methionine, taurine, citrulline, arginine and tryptophan decreased the most (> or = 50%), whereas concentrations of glutamine, glutamate and ornithine significantly increased. Orotic acid was not detected in the urine during the fast. After 1 wk of fasting, obese cats had reduced nitrogen excretion, but not to the same extent as has been shown in obese humans or obese rats. It is suggested that the availability of several amino acids may become limiting for liver protein synthesis during fasting and that these deficiencies may contribute to the development of hepatic lipidosis. Orotic acid was not linked to hepatic lipidosis caused by fasting in cats.