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Background: Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders., Methods: Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells., Findings: Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent-albeit limited-evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism., Interpretation: Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets., Funding: Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw-Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD)., Methods: The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies., Results: We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD., Interpretation: Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis., (© 2016 American Neurological Association.)

Unlabelled: A telephone survey was used to assess adequacy of pain control after third molar removal in a series of three audits. After each audit, factors contributing to failure to control pain adequately and poor patient compliance with our analgesic regimen were identified. Changes in practice were then introduced to remedy areas of weakness and improve outcome. Despite an apparently sound protocol for the prescription of analgesics for patients having third molar surgery, the first audit revealed that 53% of patients experienced moderate to severe pain. After the introduction of written patient instructions to clarify the use of post-operative analgesics, the second audit demonstrated that 86% had their pain managed successfully. After subsequently increasing the post-operative Ibuprofen doses from 400 mg to 600 mg, the third audit showed that 96% of patients had satisfactory pain control. The use of clinical audit with an evidence-based analgesic regimen and clear, written patient instruction has improved post-operative pain control., Clinical Relevance: This paper demonstrates the usefulness of clinical audit for the monitoring and improvement of pain control and analgesic prescribing regimens following oral surgery, which in turn may improve patient experience and outcome.

We aimed to find out whether improved preoperative assessment and surgical planning with cone beam computed tomography (CT) could reduce damage to the inferior alveolar nerve when high risk impacted mandibular third molars are extracted. We recorded the presence or absence of postoperative neuropathy after extraction of 200 lower third molars in 185 patients (where cone beam CT had shown contact between the nerve and root) after treatment in the oral surgery department of King's College Hospital. All patients had had cone beam CT of the teeth after panoramic radiography had indicated increased risk of injury to the nerve during extraction. Experienced oral surgeons did all the operations and postoperative reviews. Patients reported temporary alteration of sensation after operation in 12% of teeth but it resolved in all cases and no patient reported permanent loss of sensation. Permanent sensory disturbance in the distribution of the inferior alveolar nerve after third molars have been removed can be eliminated in high risk cases if operations are planned carefully (including cone beam CT), and the procedure is done by a skilled surgeon who has an appreciation of the anatomy of the nerve and roots, and an insight into the mechanical effect of their surgical manipulation. The incidence of permanent neurosensory dysfunction in this study was zero even though all teeth were intimately related to the inferior alveolar canal., (Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

In a randomised, double-blind placebo-controlled single-centre study we compared the efficacy and safety of 0.75% levobupivacaine (without vasoconstrictor) with 2% lignocaine (with adrenaline 1:80,000) and with placebo for postoperative pain relief in 93 patients having day surgery under general anaesthesia for the removal of impacted mandibular third molars. Premedication and preoperative analgesics were not prescribed, although a short-acting opioid analgesic agent was allowed if required during the anaesthetic procedure. Patients were asked to keep a diary card for 2 days after discharge from hospital. The primary endpoint was the number of patients who requested analgesia within 2 h of completion of the operation. In total, 16 (53%) of patients given levobupivacaine requested analgesia compared with 22 (71%) given lignocaine and 23 (72%) given placebo. Patients given levobupivacaine had lower maximum visual analogue pain scores (VAS) and took longer to request rescue medication (P=0.045 compared with lignocaine). Fewer patients after levobupivacaine n=20 (7%) than after lignocaine n=7 (23%) or placebo n=5 (16%) experienced adverse events. Levobupivacaine seems to be a suitable alternative local anaesthetic to lignocaine with adrenaline for pain control after oral operations.

The lingual nerve is sometimes injured during the surgical removal of an impacted mandibular third molar. The level of sensory recovery was studied in 10 patients who underwent external neurolysis of the lingual nerve. The mean time from third molar surgery to neurolysis was 13.5 months (range 9-24 months). Seven of the 10 patients showed significant improvement, three patients regaining normal sensation. Three patients showed no improvement. These results show that external neurolysis should be considered for patients with altered sensation in the distribution of the lingual nerve.

Objective: An audit study which examines patient's opinions on the efficiency of two analgesic regimes prescribed to them following dento-alveolar surgery in our Day Unit., Design: Single centre prospective study., Setting: Oral Surgery Day Case Unit, Subjects: One-hundred-and-seventy-four adults undergoing routine dento-alveolar surgery under general anaesthetic were asked to assess their pain control (on a five point scale) 1 hour after surgery, at discharge from hospital and at 24 and 48 hours post-operatively. Post-operatively, patients received ibuprofen 400 mg three times daily for five days or two tablets of paracetamol 500 mg with codeine 30 mg six hourly for 5 days if they were allergic to aspirin or were asthmatics sensitive to aspirin. Patients were not given local anaesthesia intra or post-operatively., Results: Completed records were obtained for 161 (93%) patients. Ibuprofen was apparently adequate in controlling pain for 147 out of 161 patients but on further questioning 42 of these patients took supplemental analgesics and self-prescribed paracetamol or a paracetamol combination. Thirteen patients who were prescribed paracetamol with codeine had adequate pain control and did not take supplemental analgesics. One patient did not require any analgesics post-operatively, Conclusion: Telephone contact with patients 24 and 48 hours post-surgery provides a valuable assessment of pain control following discharge from a day surgery unit. Ibuprofen offered satisfactory control of pain for 65% (95) of patients who underwent routine dento-alveolar surgery. Discharge prescriptions must be given with verbal and written instructions to ensure that patients take the correct dose and self-prescription is within safe doses.

Objective: To investigate patients considered to have experienced allergic reactions to local anaesthetics administered for dental treatment., Setting: Dental facility within a general hospital., Procedure: Skin and intra-oral challenge tests., Results: No patients were found to be allergic to lignocaine or prilocaine. The most likely causes of the adverse reactions were found to be psychogenic., Conclusion: Although allergy to lignocaine (and the other amide anaesthetic agents used in dentistry) is known to be extremely rare, it continues to be suggested as a cause when adverse reactions to dental injections occur. Psychogenic reactions are the main causes of untoward events, and some can be alarming. A smaller proportion of adverse responses can be attributed to (avoidable) intravascular injections. Adverse reactions can be reduced if injections are administered carefully.

Objective: To compare the effectiveness of direct access referrals with standard letter referrals, and also assess the impact of the direct access system on the primary care provider, secondary sector and from the patients perspective., Design: Surgical and anaesthetic guidelines were agreed and 12 general dental practitioners were recruited to participate in the study. Each practitioner was given 100 envelopes which contained randomly allocated 50 direct and 50 standard referrals. For direct referrals, GDPs completed a pre-operative assessment and obtained an operation date by telephone from the day case unit while the patient was in the surgery. The clinical history sheet was faxed to the day unit and the radiographs posted. The only contact the patient had with the hospital was on the day of surgery. Standard referral patients were referred in the traditional way with a referral letter being sent to an out-patient clinic. Evaluation of the effectiveness of the direct referral system versus standard letter method were made via completion of questionnaires by the patients, dental practitioners, hospital clinicians, day case anaesthetist and co-ordinator., Setting: The study was carried out over 2 years commencing in 1997 at the Oral Surgery Day Case Unit at Manchester Royal Infirmary., Results: A greater number of direct access referrals (409; 90%) were treated in comparison with (312; 75%) standard referrals (P < 0.001). Eighty nine per cent of direct access records were adequate pre-operatively. More than 70% of dentists and hospital clinicians preferred the direct access referral method. Sixty-three per cent of standard letter patients were satisfied with their mode of referral compared with 87% of direct access patients., Conclusions: Given appropriate guidelines dental practitioners are able to refer directly to oral surgery day case operation lists. This has proved to be the favoured method of referral for dental practitioners, the secondary sector and patients.

This paper considers the adverse effects that a patient may suffer as a result of anticipating an injection of dental local anaesthetic. Although most of these are extremely rare (a testimony to good technique), the dental practitioner should be aware of the possibility of their occurrence and of ways to deal with them.

Research into improving local anaesthetic agents and methods of delivering them in dental practice has been very slow. This article describes some of the progress that is being made in these areas.

The effects of extraneural and intramuscular applications of l-adrenaline on peripheral nerve function were examined. Change in the compound action potential was monitored until a complete conduction block was obtained if it occurred within 100 min. Extraneural application of 0.5 ml l-adrenaline to an isolated segment of the sciatic nerve of the rat in three concentrations of 1:100,000; 1:10,000, and 1:2,000 resulted in complete conduction block within 8 min. However, intramuscular injections of similar concentrations resulted in concentration dependent neural blockades with the highest concentration causing conduction blockade in 27.1 +/- 8.0 min.

It has been suggested that small doses of opioid drugs given prior to surgery can reduce postoperative pain. This study was designed to compare the effectiveness of a paracetamol/codeine combination and paracetamol alone in preventing the pain following surgical removal of impacted third molar teeth under general anaesthesia. Analysis of the results showed no statistical differences between treatment groups when compared with placebo. We suggest that the opioids may not be the best drugs available to prevent the moderate to severe pain present following some oral surgery procedures.

Paraesthesia and anaesthesia of the mental nerve may result from a variety of pathological conditions, and in persistent cases of orofacial sensory disturbance thorough clinical assessment, including CT scanning, is vital to exclude underlying systemic or neoplastic disease. This paper presents three patients with right mental nerve dysfunction, and reviews the aetiology of mental nerve paraesthesia and anaesthesia.

The incidence of altered lingual nerve sensation following lower third molar removal was examined in 150 cases where a broad retractor was used to retract the lingual flap and compared with 150 cases where a more conventional Howarth's periosteal elevator was employed. This study supports the view that a broad retractor employed to protect the lingual nerve during lower third molar surgery produces significantly less altered lingual nerve sensation at 1 month than a Howarth's periosteal elevator used for the same purpose.

Results of analgesic studies obtained using experimental pain are often not comparable with those obtained from clinical studies. This may be because anxiety, which plays an important role in the pain experience, may not be evoked by experimentally induced pain. The aim of this study is to measure the level of anxiety induced by the submaximum effort tourniquet technique, which produces pain similar in quality to clinical pain. The mean time that subjects tolerated the pain from the tourniquet was 14.94 minutes. Systolic blood pressure and heart rate increased. Visual analogue scale measures of anxiety showed an overall increase during the experiment but were highly erratic individually. This study suggests that the submaximum effort tourniquet technique is incapable of inducing the same type of anxiety experienced with clinical pain.

A double-blind clinical study was designed to compare the efficacy and safety of intramuscular and oral ketorolac, a new non-steroidal anti-inflammatory analgesic with that of diclofenac and placebo for patients undergoing removal of impacted mandibular third molar teeth. Results showed that both analgesic preparations were more effective than placebo (p = 0.0029) and that ketorolac provided a similar degree of pain relief to that of diclofenac. It is concluded that ketorolac is important new addition to the available intra-muscular NSAID preparations.

The effect of intravenous midazolam on the somatosensory evoked potentials (SEP's) elicited from median nerve stimulation was investigated in a study on 20 volunteers. SEP's were recorded from contralateral scalp before and at 5, 30, and 60 min after drug administration. Relative amplitudes of the early components (N18-N20) were essentially stable, while relative amplitudes of the late components (N50-P90, P90-N160, N160-P250 and P250-N380) were reduced significantly after midazolam administration and had not returned to baseline 60 min after administration. Given the correlation between late SEP amplitude and subjective reports of experimental pain, the data support the possibility that administration of midazolam in conscious sedation doses may have some effect on pain in addition to its better documented sedative and amnesic properties.

The effect of midazolam sedation on late evoked potentials (EPs) elicited from painful stimulation of the median nerve was investigated in 20 human volunteers. EPs were recorded from the contralateral scalp at baseline and at 5, 30, and 60 min post-midazolam infusion. Relative amplitudes of the late EPs were significantly reduced after intravenous midazolam infusion and did not return to normal during the 60 min of the experiment. Given the correlation between EP amplitude and subjective reports of experimental pain, the data support the suggestion that midazolam may have some analgesic effect.

In a randomised, double-blind, cross-over study on 20 healthy human volunteers, the effect of intravenous midazolam on pain tolerance using the 'submaximum effort tourniquet technique' is described. Intravenous midazolam administered in conscious sedation doses was found to significantly reduce the affective and motivational component of the pain experience.

Twenty healthy volunteers entered a study to assess cardiopulmonary responses, as measured by pulse oximetry, following changes in posture in the dental chair and the administration of Diazemuls (diazepam) in doses sufficient to instill sedation (up to a maximum dose of 20 mg) in the volunteers to a degree such that ptosis was seen. The results indicate that SaO2 values remained above 95 per cent throughout the study. It is concluded that although changes in SaO2 and pulse rate do occur, these differences are not important in healthy individuals, although they may be more serious in patients with pre-existing cardiopulmonary disease.

Injuries to the inferior alveolar or lingual nerve are recognised complications of third molar surgery. In a prospective study, permanent damage was found to be significantly related to bone removal using a surgical drill. The Howarth periosteal elevator may not provide adequate protection to the lingual nerve when a surgical drill is used.

When injecting into a blood vessel (for example during intravenous sedation) it is essential to aspirate blood into the syringe prior to drug administration to ensure that the tip of the needle is lying within a vein. By the same token, when the injection is intended to be extravascular it would appear to be wise to ensure that no blood is aspirated into the syringe before drug delivery. This procedure is employed routinely by medical and nursing staff, but is not universally accepted by dentists prior to the administration of dental local anaesthetics.

This study was undertaken to investigate whether plain lidocaine, 3% plain mepivacaine and 3% prilocaine with felypressin were suitable epinephrine-free local anesthetic solutions for use in periodontal ligament anesthesia as alternatives to lidocaine with 1:80,000 epinephrine. Two hundred and seven patients received one of the four test solutions via a periodontal ligament injection and the success rate of anesthesia was confirmed using an electric pulp stimulator. Although neither mepivacaine nor prilocaine were as effective as lidocaine with epinephrine, the success rates of these three solutions were not statistically different. A single periodontal ligament injection of any of the solutions tested resulted in a low incidence of anesthesia. The success rate of lidocaine without epinephrine was consistently poor.

Non-steroidal anti-inflammatory analgesics are commonly prescribed to out-patients who have undergone oral surgical procedures, since they are said to provide excellent pain relief for mild to moderate pain, allied with minimal side-effects. One hundred patients were entered into a randomised clinical trial to compare the efficacy of a simple non-steroidal analgesic with that of a combination analgesic compound following the removal of lower third molars under local anaesthesia. Pain scores were measured for patients post-operatively by means of a verbal rating scale for 3 days and data were analysed using the Mann-Whitney U-test. Results suggest that this combination product offers no advantages (but shows definite disadvantages) when compared to an effective non-steroidal anti-inflammatory product.

It is essential to know the pattern of facial skin temperatures in normal subjects to be able to objectively assess differences in cases of nerve injury. Thirty healthy adults were selected at random to investigate the pattern of facial temperature using liquid crystal thermography and an electronic thermocouple system. The highest temperature of the face was in the forehead area (c, 34 degrees C) and the lowest (c. 32 degrees C) in the cheek area. If ambient temperature and humidity are controlled in a draught-free environment, symmetry of the facial skin temperature can be maintained. It is concluded that measurements of facial skin temperature may be used to investigate and assess lesions of peripheral branches of cranial nerves supplying the face.