CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Public awareness, attitudes, beliefs, and behaviors regarding the role of pharmacists as immunizers.

Vaccine coverage is below desired levels in Canada, despite National Advisory Committee on Immunization recommendations. One solution to improve coverage is to offer vaccines in pharmacies. We explore the awareness, attitudes, beliefs, and behaviors of the general public in four communities in Nova Scotia (NS) and New Brunswick (NB) about the changing role of pharmacists as immunizers. Adult members of the public were invited to complete an online survey through advertisements in print and online, and through e-mail lists at local universities. Immunization status among participants (n = 985) varied across vaccines with slightly more than one-half of the participants (51.8%) reporting receipt of a seasonal influenza vaccine last year, 38.0% reporting receipt of the meningococcal C or ACWY vaccine, and 77.7% reporting receipt of the pertussis vaccine. Despite variable self-reported receipt of vaccines, the pervasive belief that participants were not at risk of getting vaccine-preventable diseases, and a lack of awareness about which vaccines are recommended for adults, participants in this study held vaccine-positive beliefs. Participants, especially those who had previously been vaccinated in a pharmacy (39.0%), were supportive of the inclusion of pharmacists as immunizers although nearly one-half of the participants would feel more comfortable getting vaccinated by a pharmacist if another practitioner recommended it to them. While cost threatens to be a barrier to pharmacists as immunizers, this study suggests that they are well-positioned to improve vaccine coverage and to communicate recommendations and other vaccine-related information to the public.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

Anatomic variations of the paranasal sinuses in the general pediatric population.

BACKGROUND: The prevalence of sinuses' anatomic variations in the healthy pediatric population has not been studied. The study describes the prevalence of known anatomic variations with regard to gender and age in this population. METHODS: A single academic institute observational cohort study. A total of 200 head CT scans were reviewed, subdivided into five equal age subgroups (0-4.99; 5-7.99; 8-10.99; 11-13.99; 14-17 years), with an equal male to female ratio. Different subgroups were randomly assigned to two senior residents (100 CTs each). A senior rhinologist and radiologist were randomly selected to review 100 CTs each. Consensus was reached after a joint review. Each CT was evaluated for the presence of sinuses and the following variations: deviated septum, frontoethmoidal, infraorbital, posterior-ethmoid cells (Kuhn, Haller, and Onodi cells, respectively) and concha bullosa. Definitions were made according to the European Position on Rhinosinusitis 2012. RESULTS: Gender did not affect sinus development or anatomical variations. The frontal and sphenoid sinuses were significantly less developed in the 0-4.99 years group. The point prevalence of concha bullosa and deviated septum significantly increased with age. The point prevalence of Haller cells demonstrated borderline significance among age groups, with children 0-4.99 demonstrating the lowest point prevalence. A significant association was found between the existence of Haller cells to Kuhn and Onodi cells. CONCLUSIONS: Anatomical variations should be expected in the pediatric population. Familiarity with their point prevalence and associations may assist pediatric endoscopic sinus surgery planning.

Motivation for participating in phase 1 vaccine trials: Comparison of an influenza and an Ebola randomized controlled trial.

INTRODUCTION/HYPOTHESIS: Recruitment of participants into phase 1 vaccine clinical trials can be challenging since these vaccines have not been used in humans and there is no perceived benefit to the participant. Occasionally, as was the case with a phase 1 clinical trial of an Ebola vaccine in Halifax, Canada, during the 2014-2016 West African Ebola virus outbreak, recruitment is less difficult. In this study, we explored the motivations of participants in two phase 1 vaccine trials that were concurrently enrolling at the same centre and compared the motivations of participants in a high-profile phase 1 Ebola vaccine trial to those in a less high-profile phase 1 adjuvanted seasonal influenza vaccine study. METHODS: An online survey which included participants' prior experience with clinical trials, motivations to participate (including financial incentives), and demographic information was developed to examine the motivations of healthy participants in two phase 1 clinical vaccine trials conducted at the Canadian Center for Vaccinology in Halifax, Nova Scotia. Participants were invited via email to complete the online survey. Readability and clarity were assessed through pilot testing. RESULTS: A total of 49 (55.7%) of 88 participants of the two studies completed the survey (22 [55%] of 40 participants from the Ebola vaccine study and 27 [56.3%] of 48 from the adjuvanted influenza vaccine study). Motivations that were most frequently ranked among participants' top three in both trials were (1) wanting to contribute to the health of others, (2) wanting to participate in something important, (3) wanting to contribute to the advancement of science, and (4) wanting to receive an incentive such as money or a tablet. CONCLUSIONS/RECOMMENDATIONS: Although media attention and financial compensation were more often cited by Ebola vaccine trial participants as a reason to participate, both altruistic and self-interested factors were important motivations for participants in their decision to participate in a phase 1 vaccine clinical trial.

Pre-existing Symptoms and Healthcare Utilization Prior to Diagnosis of Neuroendocrine Tumors: A SEER-Medicare Database Study.

The incidence and prevalence of neuroendocrine tumors (NETs) are continually increasing. While it is known that NET symptoms often predate diagnosis, their prevalence and impact on resource utilization and costs are largely unknown. We identified 9,319 elderly patients diagnosed with NETs between 1/2003 and 12/2011 from the Surveillance, Epidemiology and End Results (SEER)-Medicare. We examined the patients' conditions potentially associated with NET, resource utilization and costs during the year before diagnosis. We found that NET patients were more likely to have diagnoses of hypertension (63.8% vs. 53.3%), abdominal pain (22.2% vs. 7.6%), heart failure (11.7% vs. 8.0%), diarrhea (5.8% vs. 1.8%), peripheral edema (5.4% vs. 3.8%) and irritable bowel syndrome (1.2% vs. 0.5%) compared to the non-cancer control group. They also had much higher resource utilization including number of outpatient visits (mean: 22.1 vs. 17.2), percentage with ER visits (20.9% vs. 11.6%), and hospitalizations (28.4% vs. 17.0%). Similarly, NET patients incurred significantly higher total (mean: $14602 vs. $9464), outpatient (mean: $5987 vs. $4253), and inpatient costs (mean: $8615 vs. $5211). This first population-based study on the pre-diagnosis symptoms and healthcare utilization found that NET patients were more likely to have certain conditions and incur higher resource utilizations and costs.

Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.

Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus. Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels, previously described as "fork and bracket" signs. Genome-wide linkage analysis identified a single ~1.5 Mbp disease-associated locus on chromosome 22q13.33. Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1). SBF1 missense mutations were shown to underlie Charcot-Marie-Tooth (CMT) type 4B3 disease, a rare autosomal recessive subtype of CMT4. The novel SBF1 null mutation highlights distinct severe phenotypic manifestations, broadening the clinical spectrum of SBF1-related neuropathies: cerebellar and pyramidal signs evident in the first months of life with peripheral polyneuropathy emerging only toward the end of the first decade, together with unique MRI findings.

Intravenous opioid drug abuse as an independent risk factor for supraglottic squamous cell carcinoma-A case-control study.

OBJECTIVES: Intravenous opioid drug abuse (IVDA) was previously correlated with laryngeal cancer. However, discrimination of this correlation by anatomical subsites has not yet been described. In this study, we aim to further establish the association between IVDA and laryngeal squamous cell carcinoma (SCC) and to indicate the laryngeal subsites that are predisposed for this correlation. DESIGN: A retrospective matched case-control study. SETTING AND PARTICIPANTS: Patients diagnosed with supraglottic SCC (SG-SCC) between 1996 and 2016 treated in a tertiary academic referral centre were enrolled to the case group. The control group comprised of matched patients diagnosed with glottis SCC (G-SCC). Matching was based on gender, age and socio-economic rank. MAIN OUTCOME MEASURES: Variables studies as risk factors included the following: smoking, alcohol consumption, history of IVDA and infectious diseases. The variables were tested for association with the 2 groups and with each other. RESULTS: Forty-eight patients with SG-SCC were matched with 48 patients with G-SCC. IVDA rates significantly increased among patients with SG-SCC. Of the SG-SCC group, 18.8% had a positive history for IVDA compared with 2.1% of the G-SCC (P = .008). A history of IVDA was found to be a risk factor for SG-SCC, independent of smoking, excessive alcohol and socio-economic status. The odds ratio for patients with an IVDA history to have SG-SCC relatively to G-SCC was 10.846 (95% CI: 1.3-89.4). CONCLUSIONS: Intravenous opioid drug abuse represents an independent risk factor for SG-SCC. The pathogenesis should be investigated not just as a risk factor, as opioids are commonly used for pain management in oncologic patients.

Surgeon-performed thyroid ultrasound-proving utility and credibility in selecting patients for fine needle aspiration according to the American thyroid association guidelines. A retrospective study of 500 patients.

DESIGN: Case series with chart review. SETTING: Single academic centre. PARTICIPANTS: The data of all patients who underwent surgeon-performed ultrasound (SUS) between 7/2009 and 9/2012 were retrospectively reviewed. MAIN OUTCOME MEASURES: A correlation between sonographic features and a non-benign cytology\malignant pathology. RESULTS: Four hundred ninety-eight nodules were included. Solid texture, irregular margins, hypo-echogenicity and intranodular vascularity were significantly associated with malignancy when benign to non-benign cytology was compared, and when compared to malignant pathology. Lack of suspicious features was significantly associated with benign lesions, with a negative predictive value of 94%. Except for taller than wider shape, malignancy odds ratio was significantly higher for known suspicious features, reaching 4.81 for irregular borders (CI 2.42-9.55, P < .001). CONCLUSIONS: SUS has proven to be a reliable and consistent tool to assess the thyroid nodule risk stratification. Surgeons should recognise the potential of this tool and its implementation.

Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors.

BACKGROUND: Incidence of locoregional neuroendocrine tumors (NETs) is rising. However, after curative resection, the patterns and risk factors associated with recurrence remain unknown. Consensus guidelines recommend surveillance every 6-12 months for up to 10 years after surgery for resected, well-differentiated NETs irrespective of patient demographics, site, grade or stage of tumor with few exceptions. PATIENTS AND METHODS: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified localized and regional stage NET patients who underwent surgical resection between January 2002 and December 2011. Development of recurrence was identified by capturing at least two claims indicative of metastatic disease until 31 December 2013. RESULTS: Of the 2366 identified patients (median age 73 years), 369 (16%) developed metastatic disease within 5 years and only an additional 1% developed metastases between years 5 and 10 with the majority dying due to unrelated causes. The 5-year risk of developing metastases (hazard ratio, HR) varied significantly (log-rank P < 0.001) by grade: 9.9% versus 25.9% (2.2) versus 48.1% (4.4) for grades 1, 2, and ≥ 3, respectively; stage: 10.3% versus 31.1% (2.8) for localized versus regional; primary tumor size: 7.6% versus 15% (1.3) versus 26.6% (1.5) for <1, 1-2, and > 2 cm, respectively; and site: ranging from 11.3% for colon to 23.9% for pancreas. CONCLUSIONS: Contrary to current guidelines, our study suggests that surveillance recommendations should be tailored according to patient and tumor characteristics. Surveillance past 5 years may be avoided in elderly patients with competing morbidities or low risk of recurrence. Pancreatic, lung, higher grade, and regional NETs have a higher risk of recurrence and may be considered for future adjuvant trials.

The effect of Ramadan fast on the incidence of renal colic emergency department visits.

BACKGROUND: Renal colic (RC) is one of the most common reasons for emergency department (ED) visits. Although RC is associated with high ambient temperature and with physiological changes that occur during fast, the literature on between Ramadan and RC incidence is scarce. AIM: To investigate the association of ED visits with RC during Ramadan fast. METHODS: We obtained health data of patients visited the ED of a large tertiary centre during the years 2004-15, with a primary diagnosis of RC. To estimate the association of RC and Ramadan, we utilized bi-weekly RC incidence Poisson models adjusted for ambient temperature and seasonality in two ethnic groups residing in the region: Muslims and Jews. RESULTS: We identified 10 435 unique patients with 18 163 ED visits with primary diagnosis of RC. Although Muslims represent 18.5% of the population in the region, approximately 25% of the ED visits with RC attributed to this group. There was a positive and significant association of temperature and ED visits within all subgroups after adjusting for seasons. Positive association with Ramadan was observed during the first 2 weeks of fast within Muslims (R.R 1.27, 95% C.I 1.03-1.50) but not within Jewish community (R.R 1.061, 95% C.I 0.855-1.238). CONCLUSION: Our study demonstrates a significant and positive association between RC and Ramadan, while controlling to ambient temperature. In view of these findings, different prevention strategies should be investigated.

X-ray fluorescence-based differentiation of neck tissues in a bovine model: implications for potential intraoperative use.

This study explores the possibility of using X-ray fluorescence (XRF)-based trace-element analysis for differentiation of various bovine neck tissues. It is motivated by the requirement for an intra-operative in-vivo method for identifying parathyroid glands, particularly beneficial in surgery in the central neck-compartment. Using a dedicated X-ray spectral analysis, we examined ex-vivo XRF spectra from various histologically verified fresh neck tissues from cow, which was chosen as the animal model; these tissues included fat, muscle, thyroid, parathyroid, lymph nodes, thymus and salivary gland. The data for six trace elements K, Fe, Zn, Br, Rb and I, provided the basis for tissue identification by using multi-parameter analysis of the recorded XRF spectra. It is shown that the combination of XRF signals from these elements is sufficient for a reliable tissue differentiation. The average total abundance of these trace elements was evaluated in each tissue type, including parathyroid and salivary gland for the first time. It is shown that some tissues can unequivocally be identified on the basis of the abundance of a single element, for example, iodine and zinc for the identification of thyroid gland and muscle, respectively.

Expose of Fallacious Claims that Male Circumcision Will Increase HIV Infections in Africa

Despite over two decades of extensive research showing that male circumcision protects against heterosexual acquisition of HIV in men; and that includes findings from large randomized controlled trials leading to acceptance by the WHO/UNAIDS and the Cochrane Committee; opponents of circumcision continue to generate specious arguments to the contrary. In a recent issue of the Journal of Public Health in Africa; Van Howe and Storms claim that male circumcision will increase HIV infections in Africa. Here we review the statements they use in support of their thesis and show that there is no scientific basis to such an assertion. We also evaluate the statistics used and show that when these data are properly analyzed the results lead to a contrary conclusion affirming the major role of male circumcision in protecting against HIV infection in Africa. Researchers; policy makers and the wider community should rely on balanced scholarship when assessing scientific evidence. We trust that our assessment may help refute the claims by Van Howe and Storms; and provide reassurance on the importance of circumcision for HIV prevention

Increased number of offspring in first degree relatives of psychotic individuals: a partial explanation for the persistence of psychotic illnesses.

OBJECTIVE: As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls. METHOD: Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained. RESULTS: Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 +/- 2.7 vs. 3.4 +/- 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P < 0.001). CONCLUSION: These findings might imply that genes which increase susceptibility for schizophrenia may be associated with increased number of offspring, perhaps supplying a partial explanation for the persistence of psychosis.

Self-report of family functioning and risk for psychotic disorders in male adolescents with behavioural disturbances.

OBJECTIVE: Previous studies indicate that a poor family environment might affect vulnerability for the later manifestation of psychotic illness. The current study aims to examine family functioning prior to the onset of psychosis. METHOD: Subjects were 42,948, 17-year old males with behavioural disturbances who were asked about the functioning of their family by the Israeli Draft Board. Data on later psychiatric hospitalizations were obtained from a National Psychiatric Hospitalization Registry. RESULTS: Poorer self-reported family functioning was associated with greater risk for later hospitalization for psychosis [adjusted hazard ratio (HR) = 1.16, 95% CI = 1.05-1.27], with a trend in the same direction for schizophrenia (adjusted HR = 1.1, 95% CI = 0.98-1.24). CONCLUSION: In male adolescents with behavioural disturbances, perceived poorer family functioning is associated with increased risk for non-affective psychotic disorders and schizophrenia. These data do not enable us to determine if perceived familial dysfunction increases vulnerability for psychosis, if premorbid behavioural abnormalities disrupt family life, or neither.

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells.

Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8- and 2.6-fold decrease in cell proliferation, respectively) (P<0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8- and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (P<0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 microg ml(-1) VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 microg ml(-1) VP-16 (P<0.001). VP-16 enhanced the release of IL-1beta and TNF-alpha from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (P<0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.

Immunomodulatory effects of moxifloxacin in comparison to ciprofloxacin and G-CSF in a murine model of cyclophosphamide-induced leukopenia.

We analyzed the effect of the two quinolones moxifloxacin and ciprofloxacin on the repopulation of hematopoietic organs and on the production of cytokines by various organs of cyclophosphamide (CP)-induced leukopenic mice. The effect was compared to that of G-CSF. Cyclophosphamide injection induced a severe leukopenia, with nadir at day 4 post-injection. All the quinolone and G-CSF-treated animals showed WBC>500/microL at the nadir, compared to 50% of saline-treated mice. Cyclophosphamide induced a marked decrease in the number of myeloid progenitors (CFU-C) in bone marrow (BM) and spleen. Quinolone or G-CSF treatment resulted in a 1.4-4.3-fold increase in CFU-C numbers in the BM; no enhancement was observed in the spleen. Treatment with CP resulted in enhanced colony-stimulating activity (CSA) in bone shaft and spleen and decreased activity in bladder and lung. Treatment of CP-injected mice with quinolones significantly enhanced CSA in the bone shaft, spleen, lung and bladder on different days. In normal mice the highest levels of GM-CSF and IL-6 were observed in lung-conditioned medium (compared to bone shaft, spleen and bladder). Injection of CP resulted in a 22.5- and 93-fold decrease in GM-CSF and IL-6 levels, respectively, in lung-conditioned medium, while treatment with quinolones resulted in 2-4-fold increase in GM-CSF with no effect on IL-6 production. G-CSF treatment had no enhancing effect on GM-CSF nor on IL-6 production. We conclude that moxifloxacin and ciprofloxacin administered to CP-injected mice revert some of the immune suppressive effects of cyclophosphamide.