Paraneoplastic Cerebellar Degeneration Secondary to BRAF Mutant Melanoma Metastasis from an Occult Primary Cancer

Melanoma metastasis from an unknown primary cancer has an incidence of 3.2% among melanoma patients. Furthermore, paraneoplastic neurological syndromes (PNS) are rare, occurring in 1-3% of patients with malignancies. Paraneoplastic cerebellar degeneration (PCD) is one of the classic PNS and is characterized by acute or subacute onset of ataxia and/or presence of onconeural antibodies. A 61-year-old male with ataxia, vertigo, and headache later developed dysarthria, multidirectional nystagmus, hyperactive delirium, auditory hallucinations, psychomotor agitation, and myoclonus. Toxicological, metabolic, infectious, and autoimmune etiologies were assessed and reported negative. An osteolytic lesion was observed in the right iliac crest via computed tomography (CT). A positron emission tomography-CT reported increased fluorodeoxyglucose uptake of a right iliac and right inguinal ganglion. After biopsy of the right inguinal ganglion, a BRAF mutation-positive melanoma metastasis from an occult primary cancer was diagnosed. Dermatologic, ophthalmologic, and endoscopic gastrointestinal assessment did not reveal a primary malignant melanoma. The patient's movement disorders and neuropsychiatric symptoms improved with quetiapine, prednisone, azathioprine, and cyclophosphamide. Oncological management was conducted with MAPK pathway inhibitors (i.e., dabrafenib and trametinib). Movement disorders associated with neuropsychiatric symptoms are complex to diagnose. PNS are rare and often associated with antibodies against neural antigens expressed by the tumor. The case presented above describes a patient with a BRAF-positive malignant melanoma metastasis from an occult primary associated with PCD - to the best of our knowledge, the first reported in the literature.</p

Major trends in the development of ankle rehabilitation devices

In this paper we review the ankle rehabilitation devices, both those that are already commercially available and those which are in the stage of development in laboratories and research centers. Also, a rehabilitation device is proposed here including reporting results of clinical trials prior to its availability at a commercial level. At the end of the paper there is a mention about the possibility of developing a rehabilitation ankle machine with some particular features

Multi-technical approach for the characterization of polychrome decorative surfaces at Spanish Mission Churches in Nueva Vizcaya (Chihuahua, Mexico)

An interdisciplinary and multi-institutional group of science and art conservation specialists has provided new insight into the painting materials used in the polychrome walls and wooden ceilings in four seventeenth century Spanish colonial churches of Nueva Vizcaya (Chihuahua, Mexico). A multi-analytical study of the decorative surfaces was performed in situ using spectroscopic approaches (XRF, FORS), False Colour Infrared Reflectography–IRFC, as well as micro sampling (ATR-FTIR, LM, GC/MS). A survey of natural resources and study (ATR-FTIR, LM) was carried out to elucidate the natural occurrence of a select number of materials in the surrounding areas of the churches. The present paper presents a multi-analytical study and characterization of green, red-orange and black colour pigments and binders selected from the decorative surfaces. The aim of this study is to highlight relationships between local materials and those from the original polychrome ceilings, in order to understand the material and technological influences that converged in the Spanish colonial architecture of northern Mexico

Holter-determined arrhythmias in young elite athletes with suspected risk: Insights from a 20-year experience

PurposeWe assessed the occurrence of rhythm alterations in elite athletes with suspected risk using Holter monitoring, and the association of Holter-determined rhythm alterations with echocardiographic findings.MethodsA large cohort of Spanish elite athletes (N = 6,579, 34% female) underwent in-depth cardiological examination (including echocardiographic evaluation, and resting and exercise electrocardiogram [ECG]) between 01/02/1998 and 12/31/2018. Holter monitoring was performed in those reporting cardiovascular symptoms, with suspicion of cardiac structural abnormalities potentially associated with dangerous arrhythmias, or with resting/exercise ECG features prompting a closer examination. We assessed the occurrence of cardiac rhythm alterations, as well as the association between echocardiography-determined conditions and rhythm alterations.ResultsMost athletes (N = 5925) did not show any sign/symptom related to arrhythmia (including normal resting and exercise/post-exercise ECG results) whereas 9.9% (N = 654; 28% female; median age, 24 years [interquartile range 19–28]; competition experience [mean ± SD] 10±6 years) met the criteria to undergo Holter monitoring. Among the latter, sinus bradycardia was the most common finding (present in 96% of cases), yet with a relatively low proportion of severe (&lt;30 bpm) bradycardia (12% of endurance athletes during night-time). Premature atrial and ventricular beats were also common (61.9 and 39.4%, respectively) but sinus pauses ≥3 s, high-grade atrioventricular blocks, and atrial fibrillation/flutter were rare (&lt;1%). Polymorphic premature ventricular contractions (PVC, 1.4%) and idioventricular rhythm (0.005%) were also rare. PVC couplets were relatively prevalent (10.7%), but complex ventricular arrhythmias were not frequent (PVC triplets: 1.8%; sustained ventricular tachycardia: 0.0%; and nonsustained ventricular tachycardia: 1.5%). On the other hand, no associations were found between arrhythmias (including their different morphologies) and major cardiac structural alterations (including mitral prolapse). However, an association was found between mild mitral regurgitation and supraventricular (odds ratio 2.61; 95% confidence interval 1.08–6.32) and ventricular (2.80; 1.15–6.78; p = 0.02) arrhythmias, as well as between mild or moderate mitral regurgitation and ventricular arrhythmias (2.49; 1.03–6.01).ConclusionsIrrespective of the sports discipline, “dangerous” ventricular arrhythmias are overall infrequent even among young elite athletes who require Holter monitoring due to the presence of symptoms or abnormal echocardiographic/ECG findings, and do not seem to be associated with underlying serious cardiac structural pathologies

Prevalence of Human Papilloma Virus Infections and Cervical Cytological Abnormalities among Korean Women with Systemic Lupus Erythematosus

We performed a multicenter cross-sectional study of 134 sexually active systemic lupus erythematosus (SLE) patients to investigate the prevalence of and risk factors for high risk human papilloma virus (HPV) infection and cervical cytological abnormalities among Korean women with SLE. In this multicenter cross-sectional study, HPV testing and routine cervical cytologic examination was performed. HPV was typed using a hybrid method or the polymerase chain reaction. Data on 4,595 healthy women were used for comparison. SLE patients had greater prevalence of high-risk HPV infection (24.6% vs. 7.9%, P<0.001, odds ratio 3.8, 95% confidence interval 2.5-5.7) and of abnormal cervical cytology (16.4 vs. 2.8%, P<0.001, OR 4.4, 95% CI 2.5-7.8) compared with controls. SLE itself was identified as independent risk factors for high risk HPV infection among Korean women (OR 3.8, 95% CI 2.5-5.7) along with ≥2 sexual partners (OR 8.5, 95% CI 1.2-61.6), and Pap smear abnormalities (OR 97.3, 95% CI 6.5-1,456.7). High-risk HPV infection and cervical cytological abnormalities were more common among Korean women with SLE than controls. SLE itself may be a risk factor for HPV infection among Korean women, suggesting the importance of close monitoring of HPV infections and abnormal Pap smears in SLE patients

Native-state stability determines the extent of degradation relative to secretion of protein variants from Pichia pastoris.

We have investigated the relationship between the stability and secreted yield of a series of mutational variants of human lysozyme (HuL) in Pichia pastoris. We show that genes directly involved in the unfolded protein response (UPR), ER-associated degradation (ERAD) and ER-phagy are transcriptionally up-regulated more quickly and to higher levels in response to expression of more highly-destabilised HuL variants and those variants are secreted to lower yield. We also show that the less stable variants are retained within the cell and may also be targeted for degradation. To explore the relationship between stability and secretion further, two different single-chain-variable-fragment (scFv) antibodies were also expressed in P. pastoris, but only one of the scFvs gave rise to secreted protein. The non-secreted scFv was detected within the cell and the UPR indicators were pronounced, as they were for the poorly-secreted HuL variants. The non-secreted scFv was modified by changing either the framework regions or the linker to improve the predicted stability of the scFv and secretion was then achieved and the levels of UPR indicators were lowered Our data support the hypothesis that less stable proteins are targeted for degradation over secretion and that this accounts for the decrease in the yields observed. We discuss the secretion of proteins in relation to lysozyme amyloidosis, in particular, and optimised protein secretion, in general

High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma

In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2–3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-γ gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship