Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis

Reduced generation of multiple motile cilia (RGMC) is a novel chronic destructive airway disease within the group of mucociliary clearance disorders with only few cases reported. Mutations in two genes, CCNO and MCIDAS, have been identified as a cause of this disease, both leading to a greatly reduced number of cilia and causing impaired mucociliary clearance. This study was designed to identify the prevalence of CCNO mutations in Israel and further delineate the clinical characteristics of RGMC. We analyzed 170 families with mucociliary clearance disorders originating from Israel for mutations in CCNO and identified two novel mutations (c.165delC, p.Gly56Alafs*38; c.638T>C, p.Leu213Pro) and two known mutations in 15 individuals from 10 families (6% prevalence). Pathogenicity of the missense mutation (c.638T>C, p.Leu213Pro) was demonstrated by functional analyses in Xenopus. Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%). Consistent with these findings, we demonstrate that CCNO expression is present in murine ependyma and fallopian tubes. CCNO is mutated more frequently than expected from the rare previous clinical case reports, leads to severe clinical manifestations, and should therefore be considered an important differential diagnosis of mucociliary clearance disorders.     

Paracetamol overdose as a result of dental pain requiring medical treatment - two case reports

Two cases of unintentional paracetamol overdose are presented. Over a one month period these patients presented to an Accident and Emergency (A&E) department with symptoms of paracetamol toxicity, following the ingestion of large quantities of analgesia for the self treatment of dental pain. In one case the patient had no access to a dentist. Both patients required admission under the care of the medical on-call team and required anti-toxicity treatment to prevent permanent liver injury. Subsequent referrals were made to the oral and maxillofacial surgery team who provided emergency dental treatment and advice on further dental care. This paper highlights the significant signs and symptoms of paracetamol overdose about which dental practitioners should be aware. It also describes the management principles required to prevent potentially life threatening liver damage. Discussion is also made of the potential impact on patients struggling to cope with pulpal pain without access to a general dental practitioner.     

Pigmented thymic carcinoids: a clinicopathological and immunohistochemical study of two cases.

Two cases of pigmented thymic carcinoids are presented. The patients were two men, 32 and 47 years of age. The two patients were asymptomatic and the tumor was discovered on routine chest radiographic evaluation. The tumors were treated by surgical excision in both patients. Grossly, they presented as tan-white tumors without evidence of necrosis or hemorrhage or any visible pigmentation. Histologically, the tumors were characterized by a monotonous proliferation of tumor cells arranged in a trabecular or nesting pattern. The tumor cells showed moderate amounts of pale eosinophilic cytoplasm, round to oval nuclei, and inconspicuous nucleoli. Mitotic activity varied from three to eight per 10 high-power fields. In addition, both tumors showed prominent areas of intra- and extracellular dark pigment deposition. The pigment reacted positively with the Fontana-Masson stain and was negative for iron stain. Immunohistochemical studies performed in one case showed immunoreactivity of the tumor cells for chromogranin, Leu 7, and keratin. Synaptophysin and P53 immunostains were negative. Clinical follow-up was obtained in one patient who was alive and well 10 years after surgical resection. The presence of abundant melanin pigment in thymic carcinoids highlights an important pitfall for diagnosis in these tumors that should be taken into consideration in the evaluation of anterior mediastinal lesions.     

Effects of exposure to gas cooking in childhood and adulthood on respiratory symptoms, allergic sensitization and lung function in young British adults

BACKGROUND: There is evidence that people who use gas for cooking have reduced lung function and experience more respiratory symptoms than those who use other fuels for cooking. OBJECTIVES: To study the effect of the presence of a gas cooker in the home, during both childhood and adulthood, on respiratory symptoms, allergic sensitization and ventilatory function among young adults. METHODS: A sample of 1449 young adults born in Britain 3-9 March 1958, who have been followed from birth to ages 7, 11, 16, 23 and 33 years, were examined at home at age 34-35 years. FEV1 and FVC were measured before and 20 min after inhalation of 400 microg salbutamol, and skin prick tests performed with three allergen extracts (grass, Der p 1 and cat). An interview on respiratory symptoms and indoor environmental exposures was included. RESULTS: No association was found between gas cooking in childhood or adulthood and incidence or prognosis of asthma/wheeze, allergic sensitization or current severity of respiratory symptoms. Subjects who currently used gas for cooking had a significantly reduced FEV1 (- 70 mL, 95% CI +/- 56) but not FVC (- 35 mL, 95% CI +/- 61) compared with those who used electricity for cooking. This reduction in FEV1 was concentrated among men and current asthmatics. CONCLUSION: The use of gas for cooking is unlikely to be a major influence on respiratory morbidity in young adults.     

Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims.

BACKGROUND: The serotonin deficiency hypothesis of suicide has been important heuristically. Few studies have directly examined the brainstem dorsal raphe nucleus (DRN) serotonin neurons. We determined the number and morphometry of DRN serotonergic neurons in suicide victims (n = 7) compared to controls (n = 6). METHODS: Brainstems were collected at autopsy, fixed and cryoprotected. Tissue was sectioned, stained for Nissl and processed with an antiserum that cross-reacts with tryptophan hydroxylase. All DRN neurons were identified, counted and analyzed every 1000 microns. Neuron morphometry was characterized by soma area (micron 2), sphericity, perimeter, length and density (neurons per mm3). RESULTS: Neuron number and density was higher in suicide victims (1,780 +/- 127 neurons/mm3) than controls (1,349 +/- 68). The DRN volume did not differ between groups (66 +/- 9 mm3 for controls vs. 67 +/- 5 mm3 for suicides). Mean neuronal area and sphericity did not differ between suicides and controls. The total number and the density of DRN neurons did not correlate with age. CONCLUSIONS: The finding of an increased number of neurons indicates that impaired serotonergic transmission found in association with serious suicide attempts is not due to fewer neurons.     

Intra-articular tenoxicam improves postoperative analgesia in knee arthroscopy

PURPOSE: Non Steroidal Anti-inflammatory drugs have a well documented benefit in the relief of postoperative pain. This study was designed to compare the analgesic effect of intra-articular tenoxicam 20 mg with intravenous tenoxicam on postoperative pain in 88 patients undergoing day case knee arthroscopy. METHODS: A prospective, double blind, randomized trial was performed. All patients received a standard general anesthetic. Patients in group A received 20 mg tenoxicam made up to 40 ml with normal saline intra-articularly (ia) and 2 ml normal saline i.v. Patients in group B received 40 ml normal saline intra-articularly and 2 ml, 20 mg of tenoxicam, i.v. RESULTS: Both groups of patients were similar with respect to age, weight, sex and tourniquet inflation time. Patients receiving ia tenoxicam had lower pain scores (at rest and upon movement) at 30, 60, 120 and 180 min postoperatively (0.8+/-0.2 vs. 2.5+/-0.2 at rest and 1.24+/-0.2 vs. 3.4+/-0.2 at movement at 60 min; P< 0.0001). Fewer patients required additional analgesia in the first four hours postoperatively (33% vs. 84%; P<0.00001) and the time to first analgesia (23.7+/-11.2 vs. 9.4+/-0.6; P<0.02) was longer in those receiving ia tenoxicam. CONCLUSION: Intra-articular tenoxicam provides superior postoperative analgesia and reduces postoperative analgesic requirements compared with i.v. tenoxicam in patients undergoing day case knee arthroscopy.