Niemann-Pick disease type C symptomatology: an expert-based clinical description

Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months–6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca®), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.

Natural antibody response to Plasmodium falciparum merozoite antigens MSP5, MSP9 and EBA175 is associated to clinical protection in the Brazilian Amazon

BACKGROUND: Antibodies have an essential role in the acquired immune response against blood stage P. falciparum infection. Although several antigens have been identified as important antibody targets, it is still elusive which antigens have to be recognized for clinical protection. Herein, we analyzed antibodies from plasmas from symptomatic or asymptomatic individuals living in the same geographic area in the Western Amazon, measuring their recognition of multiple merozoite antigens. METHODS: Specific fragments of genes encoding merozoite proteins AMA1 and members of MSP and EBL families from circulating P. falciparum field isolates present in asymptomatic and symptomatic patients were amplified by PCR. After cloning and expression of different versions of the antigens as recombinant GST-fusion peptides, we tested the reactivity of patients' plasmas by ELISA and the presence of IgG subclasses in the most reactive plasmas. RESULTS: 11 out of 24 recombinant antigens were recognized by plasmas from either symptomatic or asymptomatic infections. Antibodies to MSP9 (X2(DF=1) = 9.26/p = 0.0047) and MSP5 (X2(DF=1) = 8.29/p = 0.0069) were more prevalent in asymptomatic individuals whereas the opposite was observed for MSP1 block 2-MAD20 (X2(DF=1) = 6.41/p = 0.0206, Fisher's exact test). Plasmas from asymptomatic individuals reacted more intensely against MSP4 (U = 210.5, p < 0.03), MSP5 (U = 212, p < 0.004), MSP9 (U = 189.5, p < 0.002) and EBA175 (U = 197, p < 0.014, Mann-Whitney's U test). IgG1 and IgG3 were predominant for all antigens, but some patients also presented with IgG2 and IgG4. The recognition of MSP5 (OR = 0.112, IC95% = 0.021-0.585) and MSP9 (OR = 0.125, IC95% = 0.030-0.529, cross tab analysis) predicted 8.9 and 8 times less chances, respectively, to present symptoms. Higher antibody levels against MSP5 and EBA175 were associated by odds ratios of 9.4 (IC95% = 1.29-69.25) and 5.7 (IC95% = 1.12-29.62, logistic regression), respectively, with an asymptomatic status. CONCLUSIONS: Merozoite antigens were targets of cytophilic antibodies and antibodies against MSP5, MSP9 and EBA175 were independently associated with decreased symptoms.

Usefulness of clinical findings, nerve conduction studies and ultrasonography to predict response to surgical release in idiopathic carpal tunnel syndrome.

[EN] OBJECTIVES: To assess the usefulness of clinical findings, nerve conduction studies and ultrasonography performed by a rheumatologist to predict success in patients with idiopathic carpal tunnel syndrome (CTS) undergoing median nerve release. METHODS: Ninety consecutive patients with CTS (112 wrists) completed a specific CTS questionnaire and underwent physical examination and nerve conduction studies. Ultrasound examination was performed by a rheumatologist who was blind to any patient's data. Outcome variables were improvement >25% in symptoms of the CTS questionnaire and patient's overall satisfaction (5-point Likert scale) at 3 months postoperatively. Success was defined as improvement in both outcome variables. Receiver operating characteristics (ROC) curves and logistic regression analyses were used to assess the best predictive combination of preoperative findings. RESULTS: Success was achieved in 63% of the operated wrists. Utility parameters and area under the ROC curve (AUC) for individual findings was poor, ranging from 0.481 of the nerve conduction study to 0.634 of the cross-sectional area at tunnel outlet. Logistic regression identified the preoperative US parameters as the best predictive variables for success after 3 months. The best predictive combination (AUC=0.708) included a negative Phalen maneuver, plus absence of thenar atrophy, plus less than moderately abnormalities on nerve conduction studies plus a large maximal cross-sectional area along the tunnel by ultrasonography. CONCLUSION: Although cross-sectional area of the median nerve was the only predictor of success after three months of surgical release, isolated preoperative findings are not reliable predictors of success in patients with idiopathic CTS. A combination of findings that include ultrasound improves prediction.

Biomarkers in chronic obstructive pulmonary diseases. Clinical and functional correlations.

Asthma and chronic obstructive pulmonary disease (COPD) are two distinct lung diseases with distinctive clinical and inflammatory features. A proportion of asthmatic patients experience a fixed airflow obstruction that persists despite optimal pharmacologic treatment for reasons that are still largely unknown. We found that patients with asthma and COPD sharing a similar fixed airflow obstruction have an increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function is associated with specific features of the underlying inflammation. Airway inflammation increases during asthma exacerbation and disease severity. Less is known about the correlations between symptoms and airway inflammation in COPD patients. We found that there is no correlation between symptoms and lung function in COPD patients. Nevertheless symptoms changes are associated with specific inflammatory changes: cough is associated with an increase of sputum neutrophils in COPD, dyspnoea is associated with an increase of eosinophils. The mechanisms of this correlation remain unknown. Neutrophils inflammation is associated with bacterial colonization in stable COPD. Is not known whether inhaled corticosteroids might facilitate bacterial colonization in COPD patients. We found that the use of inhaled corticosteroids in COPD patients is associated with an increase of airway bacterial load and with an increase of airway pathogen detection. Bacterial and viral infections are the main causes of COPD and asthma exacerbations. Impaired innate immune responses to rhinovirus infections have been described in adult patients with atopic asthma. Whether this impaired immune condition is present early in life and whether is modulated by a concomitant atopic condition is currently unknown. We found that deficient innate immune responses to rhinovirus infection are already present early in life in atopic patients without asthma and in asthmatic subjects. These findings generalize the scenario of increased susceptibility to viral infections to other Th2 oriented conditions.

Data Mining in Clinical Practice for the Quantification of Motor Impairment in Parkinson's Disease

Advances in biomedical signal acquisition systems for motion analysis have led to lowcost and ubiquitous wearable sensors which can be used to record movement data in different settings. This implies the potential availability of large amounts of quantitative data. It is then crucial to identify and to extract the information of clinical relevance from the large amount of available data. This quantitative and objective information can be an important aid for clinical decision making. Data mining is the process of discovering such information in databases through data processing, selection of informative data, and identification of relevant patterns. The databases considered in this thesis store motion data from wearable sensors (specifically accelerometers) and clinical information (clinical data, scores, tests). The main goal of this thesis is to develop data mining tools which can provide quantitative information to the clinician in the field of movement disorders. This thesis will focus on motor impairment in Parkinson's disease (PD). Different databases related to Parkinson subjects in different stages of the disease were considered for this thesis. Each database is characterized by the data recorded during a specific motor task performed by different groups of subjects. The data mining techniques that were used in this thesis are feature selection (a technique which was used to find relevant information and to discard useless or redundant data), classification, clustering, and regression. The aims were to identify high risk subjects for PD, characterize the differences between early PD subjects and healthy ones, characterize PD subtypes and automatically assess the severity of symptoms in the home setting.

Role of new molecular approaches for the early diagnosis of bladder cancer in clinical practice

There is an urgent need to improve the performance of urine cytology for the diagnosis of bladder cancer. In preliminary studies, telomerase activity evaluated by telomeric repeat amplification protocol (TRAP) assay and chromosomal aneuploidy detected by fluorescence in situ hybridization (FISH) in the diagnosis of bladder cancer have produced important results. Urine cell-free (UCF) DNA has also been proposed as a potential marker for early bladder cancer diagnosis. In the first study the diagnostic performance of TRAP assay and FISH analysis was assessed, while the second study evaluated the potential role of UCF DNA integrity in early bladder cancer diagnosis. In the first cross-sectional study, 289 consecutive patients who presented with urinary symptoms underwent cystoscopy and cytology evaluation. In the second study, UCF DNA was isolated from 51 bladder cancer patients, 46 symptomatic patients, and 32 healthy volunteers. c-Myc, BCAS1 and HER2 gene sequences longer than 250 bp were quantified by real time PCR to verify UCF DNA integrity. In the first study, sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the cytology and TRAP combination; 0.78 and 0.78 for the cytology, TRAP and FISH combination; and 0.65 and 0.93 for the TRAP and FISH combination. In the second study, at the best cutoff of 0.1 ng/µl, UCF DNA integrity analysis showed a sensitivity of 0.73 and a specificity of 0.84 in healthy individuals and 0.83 in symptomatic patients. The preliminary results suggest that these biomarkers could potentially be used for the early diagnosis of bladder cancer, especially in high-risk populations (e.g, symptomatic individuals exposed to occupational risk) who may benefit from the use of noninvasive diagnostic tests in terms of cost-benefit.

Sellar collision tumor involving pituitary gonadotroph adenoma and chondroma: a potential clinical diagnosis

We report on a 74-year-old male patient who presented with progressive neuroophthalmologic symptoms soon after the administration of a long-acting gonadotropin-releasing hormone agonist for treatment of a prostate cancer. Imaging revealed a destructively growing and extensively calcified sellar mass inconsistent with a pituitary adenoma. A transseptal transsphenoidal tumor mass reduction yielded a histological diagnosis of a collision tumor comprised of a gonadotroph adenoma intermingled with osteochondroma. We discuss a potential causal relationship between the administration of the long-acting gonadotropin-releasing hormone agonist and the sudden appearance of the previously unsuspected sellar lesion. Although the association of these two tumors is very likely coincidental, the possibility of causal relationship is addressed.

Older Breast Cancer Survivors: Factors Associated with Self-reported Symptoms of Persistent Lymphedema Over 7 years of Follow-up

Lymphedema of the arm is a common complication of breast cancer with symptoms that can persist over long periods of time. For older women (over 50% of breast cancer cases) it means living with the potential for long-term complications of persistent lymphedema in conjunction with the common diseases and disabilities of aging over survivorship. We identified women > or =65 years diagnosed with primary stage I-IIIA breast cancer. Data were collected over 7 years of follow-up from consenting patients' medical records and telephone interviews. Data collected included self-reported symptoms of persistent lymphedema, breast cancer characteristics, and selected sociodemographic and health-related characteristics. The overall prevalence of symptoms of persistent lymphedema was 36% over 7 years of follow-up. Having stage II or III (OR = 1.77, 95% CI: 1.07-2.93) breast cancer and having a BMI >30 (OR = 3.04, 95% CI: 1.69-5.45) were statistically significantly predictive of symptoms of persistent lymphedema. Women > or =80 years were less likely to report symptoms of persistent lymphedema when compared to younger women (OR = 0.44, 95% CI: 0.18-0.95). Women with symptoms of persistent lymphedema consistently reported worse general mental health and physical function. Symptoms of persistent lymphedema were common in this population of older breast cancer survivors and had a noticeable effect on both physical function and general mental health. Our findings provide evidence of the impact of symptoms of persistent lymphedema on the quality of survivorship of older women. Clinical and research efforts focused on risk factors for symptoms of persistent lymphedema in older breast cancer survivors may lead to preventative and therapeutic measures that help maintain their health and well-being over increasing periods of survivorship.

Left atrial myxoma attached to the anterior mitral leaflet with symptoms suggestive of infective endocarditis

The case of a 55-year-old woman is presented, whose clinical signs were initially suggestive of infective endocarditis. Transthoracic echocardiography (TTE) provided the diagnosis of a large left atrial myxoma attached to the anterior mitral leaflet. Perioperative transesophageal echocardiography (TEE) confirmed preoperative findings and assisted the surgical team in the assessment of tumour size, area of attachment, and mobility. Following tumour resection, TEE demonstrated residual moderate mitral valve regurgitation, which resulted in a change of surgical strategy. This report reinforces the importance of intraoperative TEE to facilitate and optimize surgical and anaesthesiological management of patients presenting with non-specific cardiorespiratory symptoms.

Inherited cavernous malformations of the central nervous system: clinical and genetic features in 19 Swiss families

Cavernous malformations (CCMs) are benign, well-circumscribed, and mulberry-like vascular malformations that may be found in the central nervous system in up to 0.5% of the population. Cavernous malformations can be sporadic or inherited. The common symptoms are epilepsy, hemorrhages, focal neurological deficits, and headaches. However, CCMs are often asymptomatic. The familiar form is associated with three gene loci, namely 7q21-q22 (CCM1), 7p13-p15 (CCM2), and 3q25.2-q27 (CCM3) and is inherited as an autosomal dominant trait with incomplete penetrance. The CCM genes are identified as Krit 1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). Here, we present the clinical and genetic features of CCMs in 19 Swiss families. Furthermore, surgical aspects in such families are also discussed.

Clinical results with two different methods of root-end preparation and filling in apical surgery: mineral trioxide aggregate and adhesive resin composite

INTRODUCTION: The aim of apical surgery is to hermetically seal the root canal system after root-end resection, thereby enabling periradicular healing. The objective of this nonrandomized prospective clinical study was to report results of 2 different root-end preparation and filling methods, ie, mineral trioxide aggregate (MTA) and an adhesive resin composite (Retroplast). METHODS: The study included 353 consecutive cases with endodontic lesions limited to the periapical area. Root-end cavities were prepared with sonic microtips and filled with MTA (n = 178), or alternatively, a shallow concavity was prepared in the cut root face, with subsequent placement of an adhesive resin composite (Retroplast) (n = 175). Patients were recalled after 1 year. Cases were defined as healed when no clinical signs or symptoms were present and radiographs demonstrated complete or incomplete (scar tissue) healing of previous radiolucencies. RESULTS: The overall rate of healed cases was 85.5%. MTA-treated teeth demonstrated a significantly (P = .003) higher rate of healed cases (91.3%) compared with Retroplast-treated teeth (79.5%). Within the MTA group, 89.5%-100% of cases were classified as healed, depending on the type of treated tooth. In contrast, more variable rates ranging from 66.7%-100% were found in the Retroplast group. In particular, mandibular premolars and molars demonstrated considerably lower rates of healed cases when treated with Retroplast. CONCLUSIONS: MTA can be recommended for root-end filling in apical surgery, irrespective of the type of treated tooth. Retroplast should be used with caution for root-end sealing in apical surgery of mandibular premolars and molars.

Apical surgery of a maxillary molar creating a maxillary sinus window using ultrasonics: a clinical case

AIM: To describe a method of carrying out apical surgery of a maxillary molar using ultrasonics to create a lateral sinus window into the maxillary sinus and an endoscope to enhance visibility during surgery. SUMMARY: A 37-year-old female patient presented with tenderness to percussion of the maxillary second right molar. Root canal treatment had been undertaken, and the tooth restored with a metal-ceramic crown. Radiological examination revealed an apical radiolucency in close proximity to the maxillary sinus. Apical surgery of the molar was performed through the maxillary sinus, using ultrasonics for the osteotomy, creating a window in the lateral wall of the maxillary sinus. During surgery, the lining of the sinus was exposed and elevated without perforation. The root-end was resected using a round tungsten carbide drill, and the root-end cavity was prepared with ultrasonic retrotips. Root-end filling was accomplished with MTA(®) . An endoscope was used to examine the cut root face, the prepared cavity and the root-end filling. No intraoperative or postoperative complications were observed. At the 12-month follow-up, the tooth had no clinical signs or symptoms, and the radiograph demonstrated progressing resolution of the radiolucency. KEY LEARNING POINTS: When conventional root canal retreatment cannot be performed or has failed, apical surgery may be considered, even in maxillary molars with roots in close proximity to the maxillary sinus. Ultrasonic sinus window preparation allows more control and can minimize perforation of the sinus membrane when compared with conventional rotary drilling techniques. The endoscope enhances visibility during endodontic surgery, thus improving the quality of the case.

The association between extra-curricular sport participation and social anxiety symptoms in children

Social anxiety is a common psychological complaint that can have a significant and long-term negative impact on a child’s social and cognitive development. In the current study, the relationship between sport participation and social anxiety symptoms was investigated. Swiss primary school children (N = 201), parents, and teachers provided information about the children’s social anxiety symptoms, classroom behavior, and sport involvement. Gender differences were observed on social anxiety scores, where girls tended to report higher social anxiety symptoms, as well as on sport activity, where boys engaged in more sport involvement. MANCOVAs with gender as covariant showed no differences in social anxiety symptoms between children involved in an extracurricular sport and those not engaged in sport participation. Nevertheless, children engaged in team sports displayed fewer physical social anxiety symptoms than children involved in individual sports.

Basic symptoms and ultrahigh risk criteria: symptom development in the initial prodromal state

Symptom development during the prodromal phase of psychosis was explored retrospectively in first-episode psychosis patients with special emphasis on the assumed time-related syndromic sequence of "unspecific symptoms (UN)-predictive basic symptoms (BS)-attenuated psychotic symptoms (APS)-(transient) psychotic symptoms (PS)." Onset of syndromes was defined by first occurrence of any of their respective symptoms. Group means were inspected for time differences between syndromes and influence of sociodemographic and clinical characteristics on the recalled sequence. The sequence of "UN-BS/APS-PS" was clearly supported, and both BS and, though slightly less, APS were highly sensitive. However, onset of BS and APS did not show significant time difference in the whole sample (N = 126; 90% schizophrenia), although when each symptom is considered independently, APS tended to occur later than first predictive BS. On descriptive level, about one-third each recalled an earlier, equal and later onset of BS compared with APS. Level of education showed the greatest impact on the recall of the hypothesized sequence. Thereby, those with a higher school-leaving certificate supported the assumed sequence, whereas those of low educational background retrospectively dated APS before BS. These findings rather point out recognition and recall bias inherent to the retrospective design than true group characteristics. Future long-term prospective studies will have to explore this conclusively. However, as regards the criteria, the results support the notion of BS as at least a complementary approach to the ultrahigh risk criteria, which may also allow for an earlier detection of psychosis.

The Bern psychopathology scale for the assessment of system-specific psychotic symptoms

The translation from psychiatric core symptoms to brain functions and vice versa is a largely unresolved issue. In particular, the search for disorders of single brain regions explaining classical symptoms has not yielded the expected results. Based on the assumption that the psychopathology of psychosis is related to a functional imbalance of higher-order brain systems, the authors focused on three specific candidate brain circuitries, namely the language, and limbic and motor systems. These domains are of particular interest for understanding the disastrous communication breakdown during psychotic disorders. Core symptoms of psychosis were mapped on these domains by shaping their definitions in order to match the related brain functions. The resulting psychopathological assessment scale was tested for interrater reliability and internal consistency in a group of 168 psychotic patients. The items of the scale were reliable and a principal component analysis (PCA) was best explained by a solution resembling the three candidate systems. Based on the results, the scale was optimized as an instrument to identify patient subgroups characterized by a prevailing dysfunction of one or more of these systems. In conclusion, the scale is apt to distinguish symptom domains related to the activity of defined brain systems. PCA showed a certain degree of independence of the system-specific symptom clusters within the patient group, indicating relative subgroups of psychosis. The scale is understood as a research instrument to investigate psychoses based on a system-oriented approach. Possible immediate advantages in the clinical application of the understanding of psychoses related to system-specific symptom domains are also discussed.