An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Increasing influenza immunization rates among healthcare providers in an ambulatory-based, University Healthcare Setting☆.

OBJECTIVE: Despite its 'best practice' status as an intervention to combat healthcare-related influenza, many healthcare personnel (HCP) do not seek vaccinations themselves. The objective of this study was to achieve the Healthy People [HP] 2020's influenza vaccination goal of 90% among our HCP. DESIGN: The study utilized the model for improvement, consisting of Plan-Do-Study-Act (PDSA) cycles. Each influenza season served as a PDSA cycle until the HP 2020 vaccination goal was achieved. The quality improvement (QI) study was conducted over four influenza seasons (i.e. 2014-15; 2015-16; 2016-17 and 2017-18). SETTING: The study's setting was an ambulatory-based, university health center within a suburban university located in central New Jersey. PARTICIPANTS: Adapting the National Vaccine Advisory Committee's definition of HCP, clinical and non-clinical staff members (n = 110) participated in the QI-study. INTERVENTIONS: QI-interventions were centered on staff education/outreach, improved accessibility to influenza vaccines and frequent communication to staff over several PDSA cycles. MAIN OUTCOME & RESULTS: The QI-interventions significantly increased our overall vaccination coverage on our influenza vaccination status survey from 70.2% (2011-14 influenza seasons; n = 102) to 84.9% (2014-15 influenza season; n = 93) in PDSA 1, and 91.1% (2015-16 influenza season; n = 90) in PDSA cycle 2 (χ2 = 309.53, P < 0.001). Vaccination rates remained above the 90% performance goal during our quality control/assurance measuring periods (i.e. the 2016-18 influenza seasons). CONCLUSIONS: This study demonstrates that influenza vaccination coverage can significantly improve among HCP through the application of concurrent and multifaceted QI-interventions.

Factors influencing liver fibrosis and necroinflammation in HIV/HCV coinfection and HCV monoinfection.

OBJECTIVES: To define differences in liver histology between HIV/HCV coinfection and HCV monoinfection, and to investigate possible causative factors. METHODS: Liver biopsies (LBs) from 440 consecutive HIV/HCV-coinfected patients (Group HIV/HCV) and 374 consecutive HCV-monoinfected patients (Group HCV) were evaluated for necroinflammation and fibrosis (Ishak) by a pathologist unaware of the clinical and laboratory data. All patients were HBsAg-negative, with no history of alcohol abuse and naïve to anti-HCV treatment. At LB, 78.4% of patients in Group HIV/HCV were on an antiretroviral regimen. RESULTS: HIV/HCV-coinfected patients compared to the HCV-monoinfected patients were younger (p < 0.0001), more frequently males (p < 0.0001), and had HCV genotype 3 (p < 0.0001); they showed a good immunological condition (CD4+ cell count: 518 ± 166 cells/mm(3)). Patients in Group HIV/HCV more frequently showed a fibrosis score ≥4 (27.5 vs. 20.6%, p < 0.05) and a necroinflammation score ≥9 (25.9 vs. 13.4%; p < 0.0001). The prevalence of patients with fibrosis score ≥4 was significantly higher in older age classes in both Group HIV/HCV (p < 0.005) and Group HCV (p < 0.05). A necroinflammation score ≥9 was significantly higher in older age classes only in Group HIV/HCV (p < 0.05). A multivariate analysis for Group HIV/HCV revealed that the patient age and nadir of CD4+ cell count were independently associated to higher degrees of fibrosis, the patient age and antiretroviral treatment were associated to higher degrees of necroinflammation, and HCV genotype 3 was associated to higher degrees of steatosis. CONCLUSION: The data suggest a need for early anti-HCV treatment in both HCV-monoinfected and HIV/HCV-coinfected patients.

Left-sided brain injury associated with more hospital-acquired infections during inpatient rehabilitation.

OBJECTIVE: To test the hypothesis that a left-dominant brain immune network (LD-BIN) might affect the occurrence of infection during inpatient rehabilitation of stroke and traumatic brain injury (TBI). DESIGN: A retrospective analysis was performed on electronic medical records between January 2009 and December 2010. All patients with left- or right-sided stroke or TBI were included into the study. The LD-BIN hypothesis was tested by comparing HAI rates depending on whether patients had left- or right-sided brain lesions. SETTING: A large inpatient rehabilitation hospital. PARTICIPANTS: Among the patients (N=2236) with stroke or TBI who had either a left- or right-sided brain lesion, 163 patients were identified with HAIs. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Frequency of HAIs. RESULTS: In the 163 patients identified with HAIs with a diagnosis of stroke or TBI, chi-square analysis revealed a significantly higher proportion of HAIs among patients with left-sided (n=98; 60.1%) relative to right-sided (n=65; 39.9%) brain injuries (χ(2)=6.68, P<.01). These effects could not be attributed to either clinical or demographic factors. CONCLUSIONS: Our findings are consistent with the hypothesis that an LD-BIN may mediate vulnerability to infection during rehabilitation of patients with stroke or TBI. Further translational research investigating novel means of managing patients based on brain lesion location, and modulating the LD-BIN via behavioral and physiologic interventions, may result in neuroscience-based methods to improve infection resistance in brain-injured patients.

Bovine AAV transcytosis inhibition by tannic acid results in functional expression of CFTR in vitro and altered biodistribution in vivo.

Bovine adeno-associated virus (BAAV) can enter a cell either through a transcytosis or transduction pathway. We previously demonstrated that particles entering via the transcytosis pathway can be redirected to transduce the cell by blocking particle exocytosis with tannic acid (TA). To investigate whether this approach is useful in lung gene therapy applications, we tested the effect of TA on BAAV transduction in cystic fibrosis airway epithelia in vitro, and in mouse lung in vivo. Our findings suggest that BAAV transcytosis can occur in vivo and that treatment with TA reduces transcytosis and increases lung transduction. TA treatment did not impair the sorting and the activity of the BAAV expressed cystic fibrosis transmembrane regulator membrane protein.

Tolerability and efficacy of anti-HBV nucleos(t)ide analogues in HBV-DNA-positive cirrhotic patients with HBV/HCV dual infection.

We evaluated tolerability and virological and clinical impact of anti-Hepatitis B Virus (HBV) nucleos(t)ide analogues in cirrhotic patients with HBV/Hepatitis C Virus (HCV) coinfection. The virological and clinical course of 24 consecutive HBsAg/HBV-DNA/anti-HCV-positive patients with cirrhosis was compared with that of 24 HBsAg/HBV-DNA-positive, anti-HCV-negative cirrhotic patients, pair-matched for age (±5 years), sex, HBeAg/anti-HBe status and Child-Pugh class. Patients in both groups were previously untreated with oral antiviral agents at enrollment and were treated for at least 24 months (range 24-54). At the 12th and 18th month of treatment, HBV-DNA was negative in 21 (87.5%) and 23 (95.8%) patients with hepatitis B and C and in 20 (83.3%) and 22 (91.6%) in patients with isolated HBV; all patients in both groups were HBV-DNA-negative at month 24 and at subsequent observations. Treatment was well tolerated by all patients in both groups. At the last observation (for co-infected patients, median 44 months and range 24-54; for mono-infected patients, median 40 months and range 24-54), a deterioration in Child class was observed in eight (47%) of 17 patients in patients with both HBV and HCV who were HCV-RNA-positive at baseline, but in none of seven HCV-RNA-negative patients in the same group, and in one patient (4.2%) in the mono-infected patients. Reactivation of HCV infection was relatively infrequent (12.5% of cases) and never associated with a clinical deterioration. Treatment with nucleotides in HBsAg/HBV-DNA/anti-HCV-positive patients with cirrhosis showed a favourable virological effect in all cases, but a favourable clinical result only in the HCV-RNA-negative at baseline.

Pandemic Meets Endemic: The Role of Social Inequalities and Failing Public Health Policies as Drivers of Disparities in COVID-19 Mortality among White, Black, and Hispanic Communities in the United States of America.

The COVID-19 pandemic placed the United States of America (U.S.) under enormous strain, leaving it with higher deaths during the first wave of the outbreak compared to all other advanced economies. Blacks and Hispanics were among those hardest hit by the virus-a fact attributed to enduring problems related to the social determinants of health adversely affecting Communities of Color (CoC). In this study, we ask which distinct factors relating to policy stringency and community vulnerability influenced COVID-19 mortality among Whites, Blacks, and Hispanics during the first year of the pandemic. To address this question, we utilized a mix of correlational and regression analyses. Findings point to the highly divergent impact of public policy and vulnerability on COVID-19 mortality. Specifically, we observed that state-led measures aimed at controlling the spread of the virus only improved mortality for Whites. However, pre-existing social determinants of health (i.e., population density, epidemiological and healthcare system factors) played a significant role in determining COVID-19 outcomes for CoC, even in the face of stringent containment measures by states. This suggests that state-led policy to address present and/or future public health crises need to account for the particular nature of vulnerability affecting Blacks and Hispanics in the U.S.

Falls From Height, Facial Injuries and Fatalities: An Institutional Review.

Study Design: Retrospective cohort review. Objective: To investigate the relationship between falls from height and facial injuries. Methods: This is a retrospective cohort study, conducted over a 7-year period, of the medical records of all patients who presented to hospital for a maxillofacial injury following a fall from height. Fall heights were classified as low falls (1-3 m), high falls (3-10 m) and very high falls (≥10 m). Results: A total of 111 patients with 218 facial bone fractures were identified (78 men, 33 women and mean age 50.3 years). High falls were the most common (n = 58, 52.3%). Multiple fractures were identified in 51 (46.0%) patients. Orbital and middle third fractures were the most prevalent. Nasal, mandible, bilateral and fractures involving more than one facial third, increased as fall height increased, as did the requirement for operative fixation. The majority of patients had an associated injury (n = 100, 90.1%) and overall mortality was 6.3%. Conclusions: Falls from height are prevalent and there is a trend towards increased severity of facial injury, surgical intervention and associated morbidity as fall height increases. Falls from height are a significant public health concern and an important facet of maxillofacial trauma to recognise, as is the requirement for an interdisciplinary approach as they present to hospital.

Analysis of end-user satisfaction with electronic health records in college/university healthcare.

ObjectiveTo determine levels of Electronic Health Record (EHR) satisfaction in order to add to the body of knowledge and assist professionals in the college/university health field with system/vendor selection. Methods: Nine health centers, all within highly selective colleges and universities, participated in this benchmarking study. Multidisciplinary staff (n = 316) received an anonymous 32-item survey to assess levels of agreement/satisfaction on statements pertaining to their EHR's functionality. Results: The EHRs most commonly used were Point and Click, Medicat, Allscripts, and EPIC. There was considerable variation on levels of user satisfaction/agreement within features among the EHR systems, but differences were not statistically significant. Conclusion: No systems emerged as clear "winners" in terms of user satisfaction. Features were identified within systems that can be leveraged to meet specific care delivery and quality reporting needs among college/university health professionals, and could be considered in the use of EHRs by health services.

Differential role of dopamine in emotional attention and memory: evidence from Parkinson's disease.

Consistent with the hypothesis that dopamine is implicated in the processing of salient stimuli relevant to the modification of various behavioral responses, Parkinson's disease is associated with emotional blunting. To address the hypothesis that emotional attention and memory are modulated by dopaminergic neurotransmission in Parkinson's disease, we assessed 15 nondemented patients with Parkinson's disease while on and off dopaminergic medication and 15 age-matched healthy controls. Visual stimuli were presented, and recognition was used to assess emotional memory. Response latency was used as a measure of emotional attention modulation. Stimuli were varied based on valence (pleasant, neutral, and unpleasant) and arousal (high and low) dimensions. Controls had significantly better memory for positive than negative stimuli, whereas patients with Parkinson's disease tested off medication had significantly better memory for negative than positive items. This negativity bias was lost when they were tested while on dopaminergic medication. Reaction times in patients with Parkinson's disease off medication were longer than in healthy controls and, paradoxically, were even longer when on medication. Further, although both healthy controls and patients with Parkinson's disease in the "off" state had arousal-induced prolongation of reaction time, this effect was not seen in patients with Parkinson's disease on medication. These data indicate that dopaminergic neurotransmission is implicated in emotional memory and attention and suggest that dopamine mediates emotional memory via the valence dimension and emotional attention via arousal. Furthermore, our findings suggest that emotional changes in Parkinson's disease result from the effects of both the disease process and dopaminergic treatment.

Emotional processing affects movement speed.

Emotions can affect various aspects of human behavior. The impact of emotions on behavior is traditionally thought to occur at central, cognitive and motor preparation stages. Using EMG to measure the effects of emotion on movement, we found that emotional stimuli differing in valence and arousal elicited highly specific effects on peripheral movement time. This result has conceptual implications for the emotion-motion link and potentially practical implications for neurorehabilitation and professional environments where fast motor reactions are critical.

Convenient and reproducible in vivo gene transfer to mouse parotid glands.

OBJECTIVES: Published studies of gene transfer to mouse salivary glands have not employed the parotid glands. Parotid glands are the likely target tissue for most clinical applications of salivary gene transfer. The purpose of the present study was to develop a convenient and reproducible method of retroductal gene transfer to mouse parotid glands. METHODS: The volume for vector delivery was assessed by infusion of Toluidine Blue into Stensen's ducts of Balb/c mice after direct intraoral cannulation. Recombinant, serotype 5 adenoviral vectors, encoding either firefly luciferase or human erythropoietin (hEpo), were constructed and then administered to parotid glands (10(7) vector particles/gland). Transgene expression in vivo was measured by enzyme activity (luciferase) or an enzyme-linked immunosorbent assay (hEpo). Vector biodistribution was measured by real-time quantitative (Q) PCR. RESULTS: The chosen volume for mouse parotid vector delivery was 20µL. Little vector was detected outside of the targeted glands, with both QPCR and luciferase assays. Transgene expression was readily detected in glands (luciferase, hEpo), and serum and saliva (hEpo). Most secreted hEpo was detected in saliva. CONCLUSION: These studies show that mouse parotid glands can be conveniently and reproducibly targeted for gene transfer, and should be useful for pre-clinical studies with many murine disease models.

Coronary stenting for ST-elevation myocardial infarction vs. other indications in patients on oral anticoagulation: any difference in in-hospital management and outcome?

AIM: The aim of this paper was to compare the in-hospital management and outcome of patients on oral anticoagulation (OAC) undergoing coronary artery stenting (PCI-S) for ST-elevation myocardial infarction (STEMI) vs. other indications. METHODS: One hundred and sixteen patients on OAC at the time of PCI-S who were prospectively enrolled in a multi-center, observational registry, were evaluated. Patients were segregated according to whether PCI-S was performed for STEMI (group 1) or other indications, such as non ST-elevation acute coronary syndromes, stable angina, silent ischemia, etc. (group 2), and the pharmacological and procedural management, as well as the in-hospital outcome, were compared. RESULTS: No significant differences were observed in vascular access site, sheath size and type of stent implanted, nor was significantly different the use of glycoprotein IIb/IIIa inhibitors, and the use and dose of intravenous unfractionated heparin. Although not statistically different, the in-hospital occurrence of death (3.7% vs. 1.1%; OR 3.3; 95% confidence intervals [CI] 0.2-56.0), stent thrombosis (3.7% vs. 1.1%; OR 3.3; 95% CI 0.2-56.0) and major bleeding (7.4% vs. 2.2%; OR 3.4; 95% CI 0.4-25.9) was consistently about 3-fold higher in group 1. CONCLUSION: The in-hospital pharmacological and procedural management of OAC patients undergoing PCI-S for STEMI vs. other indications appears not different. Although not significantly different however, the in-hospital occurrence of major bleeding, as well as of death and stent thrombosis, appears substantially higher in patients treated for STEMI, warranting therefore further larger, prospective studies.

Challenging Rhinoplasty for the Cleft Lip and Palate Patient.

Cleft lip and palate patients represent one of the most challenging groups of patients for septorhinoplasty, presenting as a complex surgical obstacle for even the most seasoned surgeons. These individuals have undergone several surgeries throughout their lives, resulting in a considerable amount of scar tissue, significant asymmetries and structural deficits. Key factors in successfully treating cleft lip and palate patients are the reconstruction of the absent/asymmetric cartilages and the replacement of bony structures. The use of autogenous rib cartilage allows the surgeon to create various grafts as well as fortify the soft tissue to resist persistent soft tissue deformities.

A time series analysis of falls and injury in the inpatient rehabilitation setting.

The purpose of this study is to assess whether falls and injuries are influenced by a temporal pattern (defined as a pattern based on the time of day) in the inpatient acute rehabilitation unit/hospital (IRU/H) setting. A retrospective chart review and analysis of falls and injuries among inpatients admitted to our facility during a 9-month period was performed. The sample consisted of 367 patients who had fallen at least once; 71 had repeated falls, bringing the total number of falls to 438. Significant variation in the prevalence of falls (chi2 = 24.1, p <. 01) and injuries (chi2 = 12.90, p < .01) based on time of day and shift was observed. In addition, a temporal pattern of fall-related injuries with patients who had sustained stroke and brain injury (chi2 = 12.74, p = .045) was also observed. The findings from this study allow for the development of interventions that are appropriate when falls and injury are most prevalent for different clinical populations in the IRU/H setting.

Gene transfer using bovine adeno-associated virus in the guinea pig cochlea.

Gene transfer into the cells of the cochlea is useful for both research and therapy. Bovine adeno-associated virus (BAAV) is a new viral vector with potential for long-term gene expression with little or no side effects. In this study, we assessed transgene expression using BAAV with beta-actin-GFP as a reporter gene, in the cochleae of normal and deafened guinea pigs. We used two different routes to inoculate the cochlea: scala media (SM) or scala tympani (ST). Auditory brainstem response assessments were carried out before inoculation, 7 days after inoculation and immediately before killing, to assess the functional consequences of the treatment. We observed threshold shifts because of the surgical invasion, but no apparent pathology associated with the virus. Fourteen days after the injection, animals were killed and cochleae assessed histologically. Epi-fluorescence showed that BAAV transduced the supporting cells of both normal and deafened animals through SM and ST inoculations. Transgene expression in cells of the membranous labyrinth after ST inoculation is an important outcome because of the greater feasibility of this route for future clinical application. BAAV facilitates efficient transduction of the membranous labyrinth epithelium with minimum pathogenicity and may become clinically applicable for inner ear gene therapy.

The neuropathological basis for depression in Parkinson's disease.

Depression is found in 30-40% of all patients with Parkinson's disease (PD), but its etiology is unclear. Using neuropathology as a signpost for neurotransmitter function, we investigated the prevalence of pathological features found at postmortem and sought to uncover differences between depressed (n=11) and non-depressed (n=9) elderly PD patients. The results indicate a higher prevalence of pathological features in depressed compared to non-depressed PD patients, particularly in catecholamine areas of the brain; the locus coeruleus (neuronal loss: odds ratio=7.2, p=08; gliosis: odds ratio=18.0, p=008); dorsal vagus nerve (gliosis: odds ratio=7.63, p<0.05), and substantia nigra pars compacta (gliosis: odds ratio=2.85, ns). However, neuropathological differences were absent in the dorsal raphe nuclei, amygdala, and cortical regions. Our evidence suggests that depression in PD is related more to catecholaminergic than serotonergic system dysfunction.

Clinical Characteristics And Health Care Resources In Patients Treated With Oral Anticoagulants: Evidences From Italian Administrative Databases.

OBJECTIVES: 1) To evaluate anticoagulation treatment patterns and health care resource use in adult patients with a discharge diagnosis of non-valvular atrial fibrillation (NVAF) in an Italian real-world setting and 2) to describe the characteristics of NVAF patients in relation to treatment. DESIGN: A retrospective cohort study in a "real-world" setting. SETTING: Data were analysed by integrating administrative databases that included approximately 2,000,000 individuals assisted by the National Health System from two Italian Local Health Units. PARTICIPANTS: All adult patients with at least one hospital discharge or ≥2 outpatient visits with a diagnosis code for NVAF from 1/01/2011 to 31/12/2015 were included. MAIN OUTCOME MEASURES: Anticoagulation treatment patterns, health care resource use and major bleeding events that occurred during the follow-up period were evaluated. RESULTS: 32,863 NVAF patients were included, of whom 7,831 had at least one prescription of oral anticoagulants. Among them, 6,876 patients were vitamin K antagonists (VKA) users and 955 were non-vitamin K antagonist oral anticoagulant (NOAC) users at index date (ID). During the follow-up period, the use of antiplatelet drugs was higher among VKA-naïve users than the NOAC-naïve users. Among NOAC users, 76.1% showed an adherence level ≥80% during follow-up. The rate of bleeding events resulted higher for VKA patients compared to NOAC patients. The unadjusted incidence rate was 10.46 per 1000 person-year for VKA patients and 4.55 per 1,000 person-years for NOAC patients. The overall annual cost (in term of drugs, hospitalisations and outpatient specialist services) was € 5,156.13 for VKA and € 4,630.57 for NOAC. CONCLUSION: This unselected cohort study, on NVAF patients being prescribed oral anticoagulants, highlights that VKA was largely prescribed and the great majority of patients on NOACs were adherent to treatment. Most of the OAC patients still received antiplatelet agents in combination, and in NOAC patients, we registered a lower number of bleeding events compared with VKA.

Temporomandibular Disorders: "Occlusion" Matters!

By analogy with the journal's title Pain Research and Management, this review describes TMD Research and Management. More specific are the (1) research aspects of "occlusion," still one of the most controversial topics in TMD, and (2) as much as possible evidence-based management aspects of "TMD" for the dental practitioner. Research. The disorders temporomandibular dysfunction and the synonymous craniomandibular dysfunction are still being discussed intensely in the literature. Traditionally, attention is mostly devoted to occlusion and its relationship with these disorders. The conclusions reached are often contradictory. Considering the definitions of temporomandibular and craniomandibular dysfunctions/disorders and "occlusion," a possible explanation for this controversy can be found in the subsequent methodological problems of the studies. Based on a Medline search of these terms over the past 40 years related to contemporary terms such as "Evidence Based Dentistry" and "Pyramid of Evidence," these methodological aspects are examined, resulting in recommendations for future research and TMD-occlusal therapy. Management. To assist the dental practitioner in his/her daily routine to meet the modern standards of best practice, 7 guidelines are formulated that are explained and accompanied with clinical examples for an evidence-based treatment of patients with this disorder in general dental practices.

TTF-2/FOXE1 gene polymorphisms in Sicilian patients with permanent primary congenital hypothyroidism.

Thyroid transcription factor-2 (TTF-2/FOXE1) is a polyalanine domain protein that regulates thyroid embryogenesis, but very few patients with permanent primary congenital hypothyroidism (pCH) harbor germline mutations of this or other transcription factors that are involved in thyroid development that might explain the etiology of pCH. Variations within the polyalanine tract are found in a variety of genes and are often reported in association with malformation syndromes; pCH is frequently associated with thyroid malformations and extra-thyroidal malformations. Therefore, in this study we investigated whether alanine (Ala) length polymorphisms and non-polymorphic mutations of the TTF-2 gene in pCH patients might be involved in the pathogenesis of pCH. The entire coding region of the TTF-2 gene was analyzed in 57 Sicilian patients and 142 healthy controls. We found that the homozygous Ala14 polymorphism (Ala14/14) was less frequent in the pCH group than in the controls. In contrast, significantly more pCH patients than controls harbored the Ala16 polymorphism (Ala16/16 and Ala14/16). However, neither the Ala14/14 nor the Ala16 polymorphism was related to extra-thyroidal malformations. Two of the 57 patients carried Ala11/14 and Ala12/14, and one Ala14/14 patient also had the silent polymorphism 387 C/T (Leu129Leu). Other than known polymorphic variants we found no mutation in the TTF-2 gene. Therefore, this study demonstrates that mutations in the TTF-2 gene are rare in pCH patients and suggests that variations in the length of the Ala-tract could at least partially explain the etiology of pCH but not that of extra-thyroidal malformations.