Evaluation of remote OMFS assessments in the era of pandemic COVID-19 control measures.

Pandemic COVID-19 has put unprecedented pressure on NHS providers to offer non face-to-face consultation. This study aims to assess acceptability of patients and clinicians towards teleconsultation in oral and maxillofacial surgery compared with an expected face-to-face assessment. 340 telephone clinic patient episodes were surveyed over the initial 7-week period of pandemic-related service restriction. Appointment outcomes from a further 420 telephone consultations were additionally scrutinised. A total of 59.1% of patients expressed a strong preference for teleconsultation with only 13.1% stating a moderate or strong preference for face-to-face assessment. Diagnostic accuracy was highlighted as a concern for both clinicians and patients due to inherent inability to conduct a traditional clinical examination, notable in 43.5% of qualitative comments. Logistical concerns, communications needs and other individual circumstances formed the other emerging themes. The majority of remote consultations (59.5%) were outcomed as requiring further review. A total of 29.3% of patients were discharged. These findings suggest that the increasing use of remote follow-up in carefully selected subgroups can facilitate efficient and acceptable healthcare delivery. Although 'in-person' clinical appointments will continue to be regarded as the default safe and gold standard management modality, OMFS departments should consider significant upscaling of teleconsultation services.

Common dental features and craniofacial development of three siblings with Ter Haar syndrome.

BACKGROUND: Ter Haar syndrome is a rare genetic syndrome with <30 cases reported worldwide. There is nothing within the published literature regarding the dental development and dental features of these patients. CASE REPORT: This case series examines three patients with Ter Haar syndrome and tracks their dental development and identifies common dental and skeletal features. FOLLOW-UP: All three patients received dental treatment and regular follow-up at Great Ormond Street Hospital Dental Department. CONCLUSION: These patients have many common dental and craniofacial features which poses the question as to whether these features are due to Ter Haar syndrome.

Nitric oxide fails to confer endogenous antiarrhythmic cardioprotection in the primate heart in vitro.

BACKGROUND AND PURPOSE: The role of nitric oxide (NO) in cardiac pathophysiology remains controversial. According to data from several studies using rat and rabbit isolated hearts, NO is an endogenous cardioprotectant against reperfusion-induced ventricular fibrillation (VF). Thus, if cardiac NO production is abolished by perfusion with L-N(G)-nitro-L-arginine methylester (L-NAME) (100 microM) there is a concomittant increase in the incidence of reperfusion-induced VF, with L-NAME's effects on NO and VF prevented by L- (but not D-) arginine co-perfusion. To make a better estimate of the clinical relevance of these findings, 100 microM L-NAME was tested in primate hearts under similar conditions. EXPERIMENTAL APPROACH: Marmoset (Callithrix jaccus) hearts, isolated and perfused, were subjected to 60 min left regional ischaemia followed by 10 min reperfusion in vitro. The ECG was recorded and NO in coronary effluent measured by chemiluminescence. KEY RESULTS: L-NAME (100 micro M) decreased NO in coronary effluent throughout ischaemia and reperfusion (e.g. from 3720+/-777 pmol min(-1) g(-1) in controls to 699+/-98 pmol min(-1) g(-1) after 5 min of ischaemia) and, during ischaemia, lowered coronary flow and reduced heart rate, actions identical to those seen in rat and rabbit hearts. However, the incidence of reperfusion-induced VF was unchanged (20%, with or without L-NAME). CONCLUSIONS AND IMPLICATIONS: A species difference exists in the effectiveness of endogenous NO to protect hearts against reperfusion-induced VF. The present primate data, which presumably take precedence over rat and rabbit data, cast doubt on the clinical relevance of NO as an endogenous, antiarrhythmic, cardioprotectant.

An assessment of deprivation as a factor in the delays in presentation, diagnosis and treatment in patients with oral and oropharyngeal squamous cell carcinoma.

This study explores the relationship between deprivation and patient and professional delays in presentation and treatment of oral and oropharyngeal squamous cell carcinoma. The cohort comprised 559 consecutive previously untreated patients presenting to the Regional Maxillofacial Unit, Liverpool from 1 January 1992 to 31 December 2002. All had primary surgery. The head and neck database was searched together with a review of casenotes. Deprivation was scored using the Index of Multiple Deprivation 2000 (IMD 2000) from patient post codes. PATIENT DELAY: Similar numbers of patients presented to general dental and general medical practitioners. The predominant presenting symptom was either an ulcer or swelling and 38% had symptoms for 3 or more months. Patients with shorter duration of symptoms tended to be smokers, drinkers, with lower gum and floor of mouth tumours, and more advanced disease. Primary health professional, patient age, gender, marital status, and deprivation showed no obvious correlation with patient delay. PROFESSIONAL DELAY: For 78% of patients a referral letter from GPs and GDPs was sent to the MFU on the same day as the primary consultation. There was on average about 3 weeks from referral to definitive diagnosis and about another 3 weeks before having surgery. Professional delay was shorter in patients with more advanced tumours and for patients living in the most deprived of wards. Deprivation did not seem to significantly lengthen presentation or referral however it may be that it is associated with more rapidly growing tumours.

Integrin-dependent control of translation: engagement of integrin alphaIIbbeta3 regulates synthesis of proteins in activated human platelets.

Integrins are widely expressed plasma membrane adhesion molecules that tether cells to matrix proteins and to one another in cell-cell interactions. Integrins also transmit outside-in signals that regulate functional responses of cells, and are known to influence gene expression by regulating transcription. In previous studies we found that platelets, which are naturally occurring anucleate cytoplasts, translate preformed mRNA transcripts when they are activated by outside-in signals. Using strategies that interrupt engagement of integrin alphaIIbbeta3 by fibrinogen and platelets deficient in this integrin, we found that alphaIIbbeta3 regulates the synthesis of B cell lymphoma 3 (Bcl-3) when platelet aggregation is induced by thrombin. We also found that synthesis of Bcl-3, which occurs via a specialized translation control pathway regulated by mammalian target of rapamycin (mTOR), is induced when platelets adhere to immobilized fibrinogen in the absence of thrombin and when integrin alphaIIbbeta3 is engaged by a conformation-altering antibody against integrin alphaIIbbeta3. Thus, outside-in signals delivered by integrin alphaIIbbeta3 are required for translation of Bcl-3 in thrombin-stimulated aggregated platelets and are sufficient to induce translation of this marker protein in the absence of thrombin. Engagement of integrin alpha2beta1 by collagen also triggered synthesis of Bcl-3. Thus, control of translation may be a general mechanism by which surface adhesion molecules regulate gene expression.

Bronchiolitis obliterans with organizing pneumonia (BOOP) heralding anti-Jo-1-positive polymyositis.

We report a 51-year-old man who presented with 3 weeks of polyarthritis with fever, nonproductive cough, bibasilar crackles, tachypnea, and hypoxia. Initial laboratory data showed an increased erythrocyte sedimentation rate, rheumatoid factor, and anti-Jo-1 antibody. Imaging studies showed bilateral lower lobe infiltrates of the lung. A transbronchial biopsy specimen revealed characteristic findings for bronchiolitis obliterans organizing pneumonia (BOOP). About 6 months later, he developed profound proximal muscle weakness with a dramatic increase in creatine phosphokinase and aldolase and a further elevation of anti-Jo-1. Muscle biopsy specimen findings were consistent with polymyositis.This represents an unusual case in which BOOP occurred at the onset of an illness initially suggestive of rheumatoid arthritis (RA). The anti-Jo-1-positivity led to close follow up and later discovery of evolution into polymyositis. BOOP can be an early feature of polymyositis as well as RA.

Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.

Circulating human platelets lack nuclei, cannot synthesize mRNA, and are considered incapable of regulated protein synthesis. We found that thrombin-activated, but not resting, platelets synthesize Bcl-3, a member of the IkappaB-alpha family of regulatory proteins. The time- and concentration-dependent generation of Bcl-3 in platelets signaled by thrombin was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol-3-kinase, indicating that it occurs via a specialized translational control pathway that involves phosphorylation of the inhibitory protein 4E-BP1. After its synthesis in activated platelets Bcl-3 binds to the SH3 domain of Fyn (p59(fyn)), a Src-related tyrosine kinase. This, along with its expression in anucleate cells, suggests that Bcl-3 has previously unrecognized functions aside from modulation of transcription. We also demonstrate that platelets synthesize and secrete numerous proteins besides Bcl-3 after they adhere to fibrinogen, which mediates adhesion and outside-in signaling of these cells by engagement of alphaIIb/beta3 integrin. Taken together, these data demonstrate that regulated synthesis of proteins is a signal-dependent activation response of human platelets.

Nitric oxide supplementation or synthesis block--which is the better approach to treatment of heart disease?

Nitric oxide (NO) released from endothelium mediates the vasodilatation caused by numerous autacoids. Nitric oxide can also be exogenous in that some drugs used in cardiovascular disease are NO donors (e.g. glyceryl trinitrate, sodium nitroprusside and isosorbide mononitrate used in angina). However, the notion that NO is a cardiac protectant, whose mimicry or supplementation is desirable, has recently been questioned by data that suggest it is an innocent bystander in some conditions, and even a pathological mediator of dysfunction in others. This important issue is discussed by Mike Curtis and Ravinder Pabla who suggest it is necessary to reappraise the role of NO modulation in cardiac pharmacotherapy.

Effect of endogenous nitric oxide on cardiac systolic and diastolic function during ischemia and reperfusion in the rat isolated perfused heart.

Nitric oxide (NO) protects the heart against some forms of reperfusion-associated dysfunction (e.g. arrhythmias). Its role in protecting against other types of dysfunction is controversial. NO ameliorates polymorphonuclear cell-induced exacerbation of stunning. Here, whether endogenous NO protects against contractile dysfunction in a polymorphonuclear cell-free model has been tested. Isolated rat hearts (n = 6 per group) were perfused with Krebs solution for 15 min. They were then perfused with test solution: Krebs, or Krebs containing 100 microM NG-nitro-L-arginine methyl ester (L-NAME) (a concentration shown previously to significantly reduce NO content in coronary effluent), 100 microM L-NAME plus 10 mM L-arginine (the latter shown previously to be sufficient to surmount the effect of L-NAME), or 10 mM L-arginine alone. After 10 min of this, the hearts were subjected to 60-min normothermic global ischemia followed by reperfusion with the same test solution as before. A time-matched (sham) group was perfused continuously with Krebs. L-NAME hastened the onset of ischemic contracture (P < 0.05) and increased its peak value from 67.8 +/- 4.6 mmHg to 93.0 +/- 4.9 mmHg (P < 0.05). Both effects were prevented by co-perfusion with 10 mM L-arginine. Initially, reperfusion exacerbated diastolic contracture, but diastolic pressure at a constant ventricular volume fell from 112 +/- 27 mmHg to 73 +/- 19 mmHg between the 5th and 60th min of reperfusion in drug-free hearts, indicative of recovery from diastolic stunning. This recovery was not exacerbated or lessened by perfusion with L-NAME or L-arginine. Left ventricular developed pressure increased from 42 +/- 2 mmHg to 106 +/- 18 mmHg in controls between 5 and 30 min after the start of reperfusion, the latter value being indistinguishable from that in the sham group. At this time, the value in the L-NAME group was similar (78 +/- 18 mmHg). This indicated complete recovery from systolic stunning in both groups 30 min after the start of reperfusion. However, earlier after the start of reperfusion, there had been zero pressure development in the L-NAME group (P < 0.05 v the control group). This was associated with severe impairment of recovery of coronary flow, e.g. of only 18% of the mean coronary flow in controls 5 min after the start of reperfusion (P < 0.05). At 30 min after the start of reperfusion (when systolic function had recovered in the L-NAME group), flow recovery had increased in this group to 96% of the mean control values. The impairment in rates of recovery of systolic function and coronary flow in the L-NAME group were each prevented by coperfusion with L-arginine (P < 0.05). In conclusion, endogenous NO may delay the onset and reduce the magnitude of ischemic contracture but despite this, appears not to facilitate early recovery from systolic and diastolic stunning as a result of any direct action in the myocardium. The beneficial effect it does possess in this polymorphonuclear cell-free preparation is transient and results from mediation of rapid recovery of coronary flow during reperfusion.

Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus non-neuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart.

Nitric oxide (NO) is an endogenous protectant against reperfusion-induced ventricular fibrillation (VF) in the rat isolated heart. Here, the following were investigated: (1) the tissue source of cardioprotective NO using a novel inhibitor (7-nitro indazole; 7-NI) of the neuronal form of NO synthase (NOS) and direct detection of coronary effluent NO by chemiluminescence; and (2) the species dependence by comparing rat and rabbit hearts. Perfusion with modified Krebs solution was followed by 60 min left regional ischemia and 10 min reperfusion. 7-NI (1 microM) increased the incidence of VF from 0% to 60% in rat hearts (n = 10; P < 0.05). Co-perfusion with L-arginine (1 mM) reduced VF incidence to 20% (P:N.S. v controls). The inactive analog of 7-NI (6-amino indazole: 6-AI) had no pro-fibrillatory activity. Neither 7-NI nor 6-AI affected coronary flow or recovery of flow during reperfusion. 7-NI reduced basal coronary effluent NO levels to below the limit of detection (< 1 pmol), but a massive increase in NO levels occurred when L-arginine was co-perfused with 7-NI. Although 7-NI had no effect on basal coronary flow and, by implication, resting NO release, it was found, in separate studies, to antagonise substance P-induced vasodilatation and NO release, suggesting that its neuronal selectivity is lost in the presence of an exogenously administered activator of endothelial NOS in rat hearts. In rabbit hearts, in contrast, 7-NI had no effect on VF or NO levels. However, in rabbit hearts the isozyme non-selective NO synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), increased VF incidence from 0 to 50% (P < 0.05) and, during the first minute of reperfusion, reduced NO levels from 4929 +/- 893 to 2505 +/- 483 pmol/min/g (P < 0.05) and recovery of coronary flow by 22% (P < 0.05). Each of these effects were prevented by L-arginine co-perfusion. These data indicate a role for basally released NO as an endogenous antifibrillatory cardioprotectant in rat and rabbit isolated heart and indicate that the tissue source (neuronal in rat but not in rabbit heart) is species-dependent.

Nitric oxide attenuates neutrophil-mediated myocardial contractile dysfunction after ischemia and reperfusion.

With the knowledge of NO as an antiadhesion molecule, we performed studies to investigate the effects of NO on postischemic polymorphonuclear leukocyte (PMN)-medicated myocardial contractile dysfunction. Studies were performed with isolated perfused rat hearts subjected to 20 minutes of global ischemia and 45 minutes of reperfusion. Human PMNs (50 million) were infused over the first 5 minutes of reperfusion, and the recovery of left ventricular function was compared with baseline values. Infusion of PMNs alone (n = 10) led to a 61% reduction in left ventricular developed pressure (LVDP) and a 57% reduction in the pressure-rate product (PRP) at 45 minutes of reperfusion. Infusion of an NO donor, CAS-754 (n = 9), resulted in 80.2 +/- 6.7% recovery of LVDP and 77.0 +/- 8.6% recovery of PRP. Treatment with L-arginine (2.5 mmol/L, n = 10) resulted in a similar improvement in the postischemic contractile state of the heart. In contrast, NG-nitro-L-arginine methyl ester (L-NAME) treatment (250 mumol/L, n = 10) resulted in an exacerbation of contractile dysfunction, as evidence by a 93% reduction in LVDP at 45 minutes of reperfusion and a 91% reduction in PRP. The deleterious effects of L-NAME were prevented by L-arginine coperfusion. We failed to observe any cardioprotective effects when NO or L-arginine was administered to hearts subjected to 25 minutes of ischemia and 45 minutes of reperfusion in the absence of PMNs. In conclusion, PMN-mediated myocardial contractile dysfunction is attenuated by NO and exacerbated by blockade of NO synthesis.

An endogenous protectant effect of cardiac cyclic GMP against reperfusion-induced ventricular fibrillation in the rat heart.

1. After a period of myocardial ischaemia, reperfusion of the myocardium can elicit cardiac arrhythmias. Susceptibility to these arrhythmias declines with time, such that a preceding period of more than approximately 40 min ischaemia is associated with few reperfusion-induced arrhythmias. We have tested the hypothesis that this decline in susceptibility occurs, in part, because of protection by endogenous guanosine 3':5'-cyclic monophosphate (cyclic GMP). 2. Rat isolated hearts were subjected to 60 min left regional ischaemia followed by reperfusion (n = 10 per group). Methylene blue (20 microM), a soluble guanylate cyclase inhibitor, raised the incidence of reperfusion-induced ventricular fibrillation (VF) from 10% in control hearts to 80% (P < 0.05). This effect of methylene blue was abolished by co-perfusion with zaprinast (100 microM), a phosphodiesterase inhibitor which, in the rat heart, is cyclic GMP-specific (specific for the type-V phosphodiesterase isozyme). 3. Methylene blue reduced cyclic GMP levels in the ischaemic, non-ischaemic and reperfused myocardium (P < 0.05) to 50 +/- 10, 52 +/- 12 and 70 +/- 7 fmol mg-1 tissue wet weight, respectively from control values of 143 +/- 38, 147 +/- 43 and 156 +/- 15 fmol mg-1. Co-perfusion with zaprinast prevented this effect, and cyclic GMP levels were actually elevated (P < 0.05) to 366 +/- 102, 396 +/- 130 and 293 +/- 22 fmol mg-1 in ischaemic, non-ischaemic and reperfused myocardium, respectively. Zaprinast by itself also elevated cyclic GMP content. Cyclic AMP levels were not affected by zaprinast or methylene blue. 4. In conclusion, when endogenous cardiac cyclic GMP synthesis is reduced, susceptibility to reperfusion-induced VF after sustained ischaemia is substantially increased. The effect is prevented by inhibiting cyclic GMP degradation. Therefore cyclic GMP appears to be an endogenous intracellular cardioprotectant, and its actions may account for the low susceptibility to VF normally encountered in hearts reperfused after sustained ischaemia.

Effects of NO modulation on cardiac arrhythmias in the rat isolated heart.

It has been proposed that NO may function as an endogenous cardioprotectant. We have investigated whether modulation of NO levels (detected in coronary effluent by chemiluminescence) by a blocker of its synthesis, by supplementation of its precursor, and by administration of an NO donor can influence reperfusion arrhythmias in the isolated rat heart. Rat hearts were perfused with modified Krebs' solution and subjected to 5, 35, or 60 minutes of left regional ischemia followed by 10 minutes of reperfusion. NG-Nitro-L-arginine methyl ester (L-NAME), which blocks NO synthase, increased the incidence of reperfusion-induced ventricular fibrillation (VF) from 5% in the control condition to 35% after 60 minutes of ischemia (n = 20, P < .05). The profibrillatory effect of L-NAME was prevented in hearts coperfused with 1 or 10 mmol/L L-arginine (an NO precursor) but persisted in hearts coperfused with D-arginine (1 mmol/L). L-NAME did not increase VF susceptibility in hearts reperfused after 5 or 35 minutes of ischemia. L-NAME caused sinus bradycardia (264 +/- 10 versus 309 +/- 5 bpm in control groups, P < .05) and reduced coronary flow before ischemia (6.2 +/- 0.6 versus 9.2 +/- 0.6 mL.min-1.g-1 tissue in controls, P < .05). L-NAME reduced coronary effluent NO levels after 60 minutes of ischemia; during the first minute of reperfusion, values were reduced from 1457 +/- 422 to 812 +/- 228 pmol.min-1.g-1 (P < .05). This effect was prevented by coperfusion with L-arginine (10,344 +/- 1730 pmol.min-1.g-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function.

In the present study a novel nitric oxide (NO) donor, CAS-1609, was utilized as a means of coronary NO replenishment in a canine model of myocardial ischemia-reperfusion. Administration of CAS-1609 (1.25 mg iv) 10 min before reperfusion, followed by a 1 mg/h intracoronary infusion throughout the 4.5-h reperfusion period, resulted in significant improvement in postischemic transmural myocardial blood flow (0.66 +/- 0.09 vs. 0.37 +/- 0.08 ml.min-1.g-1 for saline vehicle, P < 0.05). Dogs receiving NO supplementation also exhibited a significant recovery of myocardial contractility after 4.5 h of reperfusion (30 +/- 2% area ejection fraction vs. 22 +/- 2% for saline vehicle, P < 0.05). Moreover, myocardial necrosis as a percentage of the area at risk was reduced from 28.9 +/- 4.3% in the saline group to 8.5 +/- 2.6% in the CAS-1609 group (P < 0.01), while ischemic zone myeloperoxidase activity, indicative of neutrophil infiltration, was also attenuated by 70% with NO therapy. Injection of acetylcholine and nitroglycerin into the left circumflex coronary artery revealed a significant impairment of vasodilator responses in the saline vehicle dogs at 2 h of reperfusion. However, dogs treated with the NO donor demonstrated postischemic vasodilator responses which were similar to baseline (P = not significant vs. baseline). These studies demonstrate that intracoronary administration of NO significantly augments postischemic coronary blood flow and contractile function following ischemia and reperfusion. In addition, NO therapy reduces coronary vascular injury, attenuates myocardial necrosis, and reduces neutrophil infiltration. The cardioprotective actions of intracoronary NO administration may be related to the potent antineutrophil actions of NO.

Cobalt uptake enables identification of capsaicin- and bradykinin-sensitive subpopulations of rat dorsal root ganglion cells in vitro.

A novel modification of the stimulated cobalt uptake technique has been used to identify rat dorsal root ganglion cells expressing capsaicin and bradykinin receptors. The technique involves incubating intact dorsal root ganglia in vitro in a modified Krebs solution in which cobalt chloride has been substituted for calcium. Activation of dorsal root ganglion cells by capsaicin or bradykinin in the presence of the cobalt ions results in cobalt influx into the excited cells. Histochemical methods were then used to visualize the intracellular accumulation of cobalt, and labelled cells were counted and characterized. Capsaicin (2 microM) or bradykinin (500 nM) applied for 20 min induced cobalt uptake in 13.8 +/- 0.6 and 9.6 +/- 0.5% of neuronal profiles in dorsal root ganglia (L4), respectively, a significantly larger number than stained in control ganglia (in the absence of agonists: 1.8 +/- 0.7%). The longest diameter of the soma of stained dorsal root ganglion cells following capsaicin and bradykinin perfusion were significantly different from each other and from the non-labelled population (17.5 +/- 0.7 and 24.5 +/- 0.2 microns for capsaicin; 23.2 +/- 0.9 and 25.5 +/- 0.4 microns for bradykinin; labelled and non-labelled cells, respectively). The distribution of cell diameters revealed that while capsaicin-sensitive cells were exclusively small-sized, bradykinin-sensitive cells were predominantly small and medium sized. The selective bradykinin-2 receptor antagonist HOE-140 (5.0 microM) blocked the bradykinin-induced staining (2.16 +/- 0.02%) but not that of capsaicin. The bradykinin-1 agonist [des-Arg9]-bradykinin did not induce any significant increase in stained cells over the control number (2.2 +/- 0.7%).(ABSTRACT TRUNCATED AT 250 WORDS)