Unique Clinical Manifestations Research Articles

Male patients with primary Sjögren's syndrome have unique clinical manifestations and circulating lymphocyte profiles.

We aimed to explore the relationship between clinical characteristics and circulating lymphocyte profiles in Chinese male patients with primary Sjögren's syndrome (pSS). Data from 397 patients with pSS were analyzed retrospectively. 37 were male, which is a prevalence of 9.3%. The clinical, laboratory, and immunophenotypic profiles of peripheral blood lymphocyte subsets were compared between male and female pSS patients. Male patients with primary Sjögren's syndrome have unique clinical manifestations and circulating lymphocyte profiles. Male patients complained more about xerophthalmia and presented with more extra-glandular manifestations as compared with female patients. The CD4+/CD8+ ratio (P = 0.030), the prevalence of CD4-CD8- T cells in lymphocytes (P = 0.020), the absolute number of CD4-CD8- T cells (P = 0.035), the prevalence of CD4+ T cells in lymphocytes (P < 0.001), and the absolute number of CD4+ T cells (P = 0.023) were significantly lower in male patients compared to female patients. On the other hand, the prevalence of CD8+CD28+ T cells (P = 0.030) and CD4+CD25high T cells (P = 0.040) in lymphocytes was significantly higher in male patients than in female patients. Moreover, compared to females with pSS, an elevated serum IgG level, low C3 and C4 levels, anti-SSB positivity, and ANA titers of ≥ 1:160 positivity were more frequent in male with pSS. Male patients with pSS have distinctive peripheral blood lymphocyte subpopulations, present with more severe clinical symptoms and immunological features, and have an unfavorable prognosis. Key Points • Male patients with pSS have more severe clinical symptoms and specific characteristics of peripheral blood lymphocyte subsets. • Male pSS patients exhibit a higher intensity of the disease (as evaluated by ESSDAI). • Male patients with pSS require individualized treatment regimens and closer follow-up.

Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

Oral Chagas Disease in Colombia-Confirmed and Suspected Routes of Transmission.

Chagas disease (CD) remains endemic throughout many regions of Colombia despite implementing decades of vector control strategies in several departments. Some regions have had a significant decrease in vectorial transmission, but the oral ingestion of Trypanosoma cruzi through consumption of contaminated food and drink products is increasingly described. This form of transmission has important public health relevance in Colombia due to an increase in reported acute CD cases and clinical manifestations that often lead to significant morbidity and mortality. Oral CD in Colombia has been associated with the consumption of contaminated fruit juices, such as palm wine, sugar cane, or tangerine juice and water for consumption, or contaminated surfaces where food has been prepared. Another interesting route of oral transmission includes ingestion of unbeknownst infected armadillos' blood, which is related to a traditional medicine practice in Colombia. Some earlier reports have also implemented consumption of infected bush meat as a source, but this is still being debated. Within the Amazon Basin, oral transmission is now considered the principal cause of acute CD in these regions. Furthermore, new cases of acute CD are now being seen in departments where CD has not been documented, and triatomine vectors are not naturally found, thus raising suspicion for oral transmission. The oral CD could also be considered a food-borne zoonosis, and odoriferous didelphid secretions have been implemented in contaminating the human dwelling environment, increasing the risk of consumption of infectious metacyclic trypomastigotes. In this article, we will discuss the complex transmission dynamics of oral CD in Colombia and further examine the unique clinical manifestations of this route of infection. New insights into the oral transmission of Trypanosoma cruzi are being discovered in Colombia, which can help bring increased awareness and a better understanding of this neglected tropical disease to reduce the burden of CD throughout Latin America.

Surgery for Central Nervous System Tuberculosis in Children.

Tuberculosis (TB) is the second most common cause of death due to a single infectious agent worldwide after COVID-19. Central nervous system tuberculosis is widely prevalent in the world, especially in the developing countries and continues to be a socioeconomic problem. It is highly devastating form of tuberculosis leading to unacceptable levels of morbidity and mortality despite appropriate antitubercular therapy. The clinical symptoms are varied and nonspecific. They can be easily overlooked. Tuberculous meningitis is the most common presentation and its sequelae viz. vasculitis, infarction and hydrocephalus can be devastating. The ensuing cognitive, intellectual, and endocrinological outcome can be a significant source of morbidity and mortality, especially in resource constrained countries. Early diagnosis and treatment of tuberculous meningitis and institution of treatment is helpful in limiting the course of disease process. The diagnosis of CNS tuberculosis remains a formidable diagnostic challenge. The microbiological methods alone cannot be relied upon. CSF diversion procedures need to be performed at the appropriate time in order to achieve good outcomes. Tuberculous pachymeningitis and arachnoiditis are morbid sequelae of tuberculous meningitis. Tuberculomas present as mass lesions in the craniospinal axis. Tuberculous abscess can mimic pyogenic abscess and requires high index of suspicion. Calvarial tuberculosis is seen in children and responds well to antituberculous chemotherapy. Tuberculosis of the spinal cord is seen similar to intracranial tuberculosis in pathogenesis but with its own unique clinical manifestations and management. Multidrug-resistant tuberculosis is a formidable problem, and alternate chemotherapy should be promptly instituted. The pathogenesis, clinical features, diagnosis, and management of central nervous system tuberculosis in children are summarized. Heightened clinical suspicion is paramount to ensure prompt investigation. Early diagnosis and treatment are essential to a gratifying outcome and prevent complications.

B-Lymphoblastic Leukemia Presenting with Eosinophilia: A Case Report and Review

B-lymphoblastic leukemia (B-ALL) presenting with eosinophilia represents a rare entity. In particular, the unique clinical manifestations as well as the genetic and molecular pathogenesis of the associated eosinophilia have been topics of debate and investigation. Herein, we present a case of B-ALL presenting with concomitant eosinophilia and a review of the published cases, including 120 additional cases. The patient, at presentation, was a 20-year-old female who presented with cardiac, neurologic, and cutaneous signs of eosinophilia and with leukocytosis (WBC 51, 40% eosinophils, 0% blasts), anemia, and thrombocytopenia. Imaging revealed multi-focal brain infarcts, pulmonary infiltrates, and myocarditis. Empiric steroids, colchicine, and intravenous immunoglobulin were initiated. One week after presentation, bone marrow biopsy revealed a hypercellular (&amp;gt;95%) marrow with 50% blasts and marked eosinophilia, which on later review revealed an immunophenotype most consistent with B-ALL (positive for Pax5, CD10, CD19, CD20, cCD22, CD34, CD45, CD79a, HLA-DR, and TdT and negative for MPO and CD117). Conventional cytogenetic analysis of the bone marrow was unable to be performed. Fluorescence in situ hybridization (FISH) revealed an IGH rearrangement in 10.5% of nuclei analyzed. After three weeks of treatment with steroids and resolution of symptomatic organ involvement, a repeat bone marrow biopsy did not show any evidence of malignancy or genetic abnormalities. The patient was continued on a steroid taper, did not initiate further antileukemic therapy, and was lost to follow up. Ten weeks after initial presentation and after completing a steroid taper, the patient presented with diffuse bone pain. Repeat bone marrow biopsy showed B-ALL with 64% blasts and increased eosinophils, normal conventional cytogenetics and hematologic malignancy sequencing panel, and FISH with gain of Xp in 20.5% of nuclei analyzed; a lumbar puncture did not detect blasts in the cerebrospinal fluid. The patient began induction therapy with aBFM, rituximab, PEG-asparaginase, and intrathecal cytarabine. A bone marrow biopsy performed four months after her initial presentation revealed a mildly hypocellular marrow with 3% B-lymphoblasts and no eosinophilia, suggesting residual disease, with no evidence of cytogenetic or molecular genetic abnormalities. As a result, therapy with blinatumomab was initiated. A follow up bone marrow biopsy performed six months after her initial presentation revealed a hypocellular marrow with multilineage maturation and no excess blasts with normal cytogenetic and molecular genetic studies. A literature review identified 120 additional cases of ALL with eosinophilia. In summary, it tends to present in adolescent males, often with mild anemia and thrombocytopenia and no peripheral blasts, which can lead to a delay in diagnosis of ALL. The eosinophilia is often symptomatic, with cardiopulmonary involvement being the most common, and can lead to rapid mortality in a substantial number of cases. A significant proportion of cases of ALL with eosinophilia involve t(5;14)(q31;q32), leading to overexpression of IL-3, which was not definitively found in this patient; however, there are numerous other recurrent abnormalities that may be contributing to the pathogenesis, both concurrently with and in the absence of this translocation, including other rearrangements of IGH as well as IKZF1 and CDKN2A abnormalities. Prompt diagnosis, now commonly using sensitive molecular diagnostic assays, and initiation of glucocorticoids for symptom control and subsequent antileukemic therapy, are essential to avoiding complications of eosinophilia in such patients.

Normal intellectual ability and hyperprolactinemia as unique clinical manifestations of congenital hypothyroidism: A case report and review of hypotheses.

Congenital hypothyroidism is the deficiency of thyroid hormone in infants and hyperprolactinemia is frequently observed. Previously reported cases typically involve intellectual disability, highlighting this particular unique case report to the first reported patient demonstrating normal intellectual ability despite experiencing growth and gonad dysfunction. This study aims to present a case and review medical hypotheses related to the patient's condition. A 19-year-old female presented with a chief complaint of irregular menstruation for up to 40 days or not occurring at all. The patient experienced the first menstruation at the age of 16 years old. The patient's height was 133 cm, body weight 40 kg, and body mass index 22.61 kg/m2; other family members were normal. Physical examination showed no abnormalities, and laboratory examination showed suppressed serum free T4 (FT4) level (6.41 pmol/L), elevated thyroid stimulating hormone (TSH) level (333.700 µIU/mL), and elevated prolactin hormone level (32.03 ng/mL). Ultrasound of the thyroid gland found hypoplasia of the left and right thyroid glands. The patient was a college student enrolled in a public national university and had never complained about academic performance throughout the patient's education. The patient was diagnosed with congenital hypothyroidism and hyperprolactinemia. The patient was administered up to 100 µg daily of oral levothyroxine, which improved the patient's menstrual cycles. The patient's delayed diagnosis may be attributed to central congenital hypothyroidism being underdiagnosed. We hypothesized that thyroid-releasing hormone receptor (TRHR) gene mutation might contribute to the underlying cause of hyperprolactinemia and normal intellectual ability of the patient. Further study on the significance of TRHR gene mutations in congenital hypothyroidism is required to improve diagnosis and treatment.

Morquio A Syndrome Case Report and Literature Review

Morquio A syndrome is an autosomal recessive disorder, one of 50 lysosomal storage diseases (LSDs), and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme causes specific glycosaminoglycan (GAG) accumulation: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced in the cartilage, therefore, the undegraded substrates accumulate mainly in cartilage and in its extracelluar matrix (ECM), causing direct leads to direct impact on cartilage and bone development and leading to the resultant systemic skeletal spondyloepiphyseal dysplasia. Chondrogenesis, the earliest phase of skeletal formation that leads to cartilage and bone formation is controlled by cellular interactions with the ECM, growth and differentiation factors and other molecules that affect signaling pathways and transcription factors in a temporal-spatial manner. In Morquio A patients, in early childhood or even at birth, the cartilage is disrupted presumably as a result of abnormal chondrogenesis and/or endochondral ossification. The unique clinical features are characterized by a marked short stature, odontoid hypoplasia, protrusion of the chest, kyphoscoliosis, platyspondyly, coxa valga, abnormal gait, and laxity of joints.In spite of many descriptions of the unique clinical manifestations, diagnosis delay still occurs. The pathogenesis of systemic skeletal dysplasia in Morquio A syndrome remains an enigmatic challenge. In this review article, screening, diagnosis, pathogenesis and current and future therapies of Morquio A are discussed.

Overstrain on the longitudinal band of the cruciform ligament during flexion in the setting of sandwich deformity at the craniovertebral junction: a finite element analysis

BACKGROUND CONTEXTIn the setting of “sandwich deformity” (concomitant C1 occipitalization and C2–3 nonsegmentation), the C1–2 joint becomes the only mobile joint in the craniovertebral junction. Atlantoaxial dislocation develops earlier with severer symptoms in sandwich deformity, which has been hypothesized to be due to the repetitive excessive tension in the ligaments between C1 and C2. PURPOSETo elucidate whether and how the major ligaments of the C1–2 joint are affected in sandwich deformity, and to find out the ligament most responsible for the earlier development and severer symptoms of atlantoaxial dislocation in sandwich deformity. STUDY DESIGNA finite element (FE) analysis study. METHODSA three-dimensional FE model from occiput to C5 was established using anatomical data from a thin-slice CT scan of a healthy volunteer. Sandwich deformity was simulated by eliminating any C0–1 and C2–3 segmental motion respectively. Flexion torque was applied, and the range of motion of each segment and the tension sustained by the major ligaments of C1–2 (including the transverse and longitudinal bands of the cruciform ligament, the alar ligaments, and the apical ligament) were analyzed. RESULTSTension sustained by the longitudinal band of the cruciform ligament and the apical ligament during flexion is significantly larger in the FE model of sandwich deformity. In contrast, tension in the other ligaments is not significantly changed in the sandwich deformity model compared with the normal model. CONCLUSIONSConsidering the importance of the longitudinal band of the cruciform ligament to the stability of the C1–2 joint, our findings implicate that the early onset, severe dislocation, and unique clinical manifestations of atlantoaxial dislocation in patients with sandwich deformity are mainly due to the enlarged force loaded on the longitudinal band of the cruciform ligament. CLINICAL SIGNIFICANCEThe enlarged force loaded on the longitudinal band of the cruciform ligament can add to its laxity and thus reducing its ability to restrict the cranial migration of the odontoid process. This is in accordance with our clinical experience that dislocation of the atlantoaxial joint in patients with sandwich deformity is mainly craniocaudal, which means severer cranial neuropathy, Chiari deformity, and syringomyelia, and more difficult surgical treatment.

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum.

Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.

Simultaneous Expression of Chicken Granulocyte Monocyte Colony-Stimulating Factor and the Hemagglutinin-Neuraminidase Epitope of the Virulent Newcastle Disease Virus Genotype VII C22 Strain in a Functional Synthetic Recombinant Adenovirus as a Genotype-Matched Vaccine with Potential Antiviral Activity.

When it comes to the prevention of clinical signs and mortality associated with infection of the Newcastle disease virus (NDV), vaccination has been very effective. However, recent evidence has proven that more highly virulent strains are emerging that bypass existing immune protection and pose a serious threat to the global poultry industry. Here, a novel rescued adenovirus 5-coexpressed chicken granulocyte monocyte colony-stimulating factor (ChGM-CSF) bio-adjuvant and C22-hemagglutinin-neuraminidase (HN) boosted chickens' immunological genetic resistance and thus improved the immunological effectiveness of the critical new-generation vaccine in vitro and in vivo. Accordingly, the hemagglutination inhibition (HI) titers (log2) of the recombinant adenovirus (rAdv)-ChGM-CSF-HN-immunized chickens had greater, more persistent, and longer-lasting NDV-specific antibodies than the La Sota and rAdv-HN-inoculated birds. Moreover, humoral and adaptive immunological conditions were shown to be in harmony after rAdv-ChGM-CSF-HN inoculation and uniformly enhanced the expression of alpha interferon (IFN-α), IFN-β, IFN-γ, interleukin-1β (IL-1β), IL-2, IL-16, IL-18, and IL-22. Postchallenge, the control challenge (CC), wild-type adenovirus (wtAdv), and rAdv-ChGM-CSF groups developed unique NDV clinical manifestations, significant viral shedding, high tissue viral loads, gross and microscopic lesions, and 100% mortality within 7 days. The La Sota, rAdv-HN, and rAdv-ChGM-CSF-HN groups were healthy and had 100% survival rates. The rAdv-ChGM-CSF-HN group swiftly regulated and stopped viral shedding and had lower tissue viral loads than all groups at 5 days postchallenge (dpc). Thus, the antiviral activity of ChGM-CSF offered robust immune protection in the face of challenge and reduced viral replication convincingly. Our advance innovation concepts, combining ChGM-CSF with a field-circulating strain epitope, could lead to the development of a safe, genotype-matched, universal transgenic vaccine that could eradicate the disease globally, reducing poverty and food insecurity. IMPORTANCE We studied the biological characterization of the developed functional synthetic recombinant adenoviruses, which showed a high degree of safety, thermostability, and genetic stability for up to 20 passages. It was demonstrated through both in vitro and in vivo testing that the immunogenicity of the proposed vaccine, which uses the T2A peptide from the Thosea asigna virus capsid protein supported by glycine and serine, helps with efficiency to generate a multicistronic vector, enables expression of two functional proteins in rAdv-ChGM-CSF-HN, and is superior to that of comparable vaccines. Additionally, adenovirus can be used to produce vaccines matching the virulent field-circulating strain epitope. Because there is no preexisting human adenoviral immunity detected in animals, the potency of adenoviral vaccines looks promising. Also, it ensures that the living vector does not carry the resistance gene that codes for the kanamycin antibiotic. Accordingly, a human recombinant adenoviral vaccine that has undergone biological improvements is beneficial and important.

A Case of Mediastinal Carcinosarcoma With Beta-HCG Production and KRAS Mutation.

Carcinosarcomas of mediastinum are rare and only few well-documented cases are available in the literature. We report a detailed description of mediastinal carcinosarcoma with unique clinical manifestations and immunohistochemical and molecular profiles. A 44-year-old female with an enlarging anterior mediastinal mass was found to have a positive pregnancy test. Thoracoscopic biopsy revealed that the mass represented a carcinosarcoma with adenocarcinoma and chondrosarcoma components. The tumor focally expressed beta-HCG by immunohistochemistry and had KRAS G12A missense mutation by next generation sequencing. The case documents a rare presentation of carcinosarcoma within the mediastinum with uncommon paraneoplastic syndrome and genetic profile. Awareness of these unusual clinical and pathological manifestations of the tumor will help in reaching correct diagnosis and proper management of such patients.

Association of Plasma Biomarkers with Sleep Outcomes and Treatment Response After Mild Traumatic Brain Injury.

Sleep disturbances occur in up to 70% of patients with mild traumatic brain injury (mTBI). Modern mTBI management recommends targeted treatment for the patient's unique clinical manifestations (i.e., obstructive sleep apnea, insomnia). The purpose of this study was to evaluate the association of plasma biomarkers with symptom reports, overnight sleep evaluations, and response to treatment for sleep disturbances secondary to mTBI. This study is a secondary analysis of a prospective multiple interventional trial of patients with chronic issues related to mTBI. Pre- and post-intervention assessments were conducted, including overnight sleep apnea evaluation, the Pittsburgh Sleep Quality Index (PSQI), and blinded analysis of blood biomarkers. Bivariate Spearman correlations were conducted for pre-intervention plasma biomarker concentrations and 1) PSQI change scores and 2) pre-intervention sleep apnea outcomes (i.e., oxygen saturation measures). A backward logistic regression model was built to evaluate the association of pre-intervention plasma biomarkers with improvement in PSQI over the treatment period (p < 0.05). Participants were 36.3 ± 8.6 years old and 6.1 ± 3.8 years from their index mTBI. Participants reported subjective improvements (PSQI = -3.7 ± 3.8), whereas 39.3% (n = 11) had improved PSQI scores beyond the minimum clinically important difference (MCID). PSQI change scores correlated with von Willebrand factor (vWF; ρ = -0.50; p = 0.02) and tau (ρ = -0.53; p = 0.01). Hyperphosphorylated tau correlated with average saturation (ρ = -0.29; p = 0.03), lowest desaturation (ρ = -0.27; p = 0.048), and baseline saturation (ρ = -0.31; p = 0.02). The multi-variate model (R 2 = 0.33; p = 0.001) retained only pre-intervention vWF as a predictor (odds ratio = 3.41; 95% confidence interval, 1.44-8.08; p = 0.005) of improving PSQI scores beyond the MCID. vWF had good discrimination (area under the curve = 0.83; p = 0.01), with an overall accuracy of 77%, sensitivity of 46.2%, and specificity of 90.0%. Validation of vWF as a potential predictive biomarker of sleep improvement post-mTBI could optimize personalized management and healthcare utilization.

A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment

Enamel knots and Hertwig epithelial root sheath (HERS) regulate the growth and folding of the dental epithelium, which subsequently determines the final form of tooth crown and roots. We would like to investigate the genetic etiology of seven patients affected with unique clinical manifestations, including multiple supernumerary cusps, single prominent premolars, and single-rooted molars. Oral and radiographic examination and whole-exome or Sanger sequencing were performed in seven patients. Immunohistochemical study during early tooth development in mice was performed. A heterozygous variant (c. 865A>G; p.Ile289Val) in CACNA1S was identified in all the patients, but not in an unaffected family member and control. Immunohistochemical study showed high expression of Cacna1s in the secondary enamel knot. This CACNA1S variant seemed to cause impaired dental epithelial folding; too much folding in the molars and less folding in the premolars; and delayed folding (invagination) of HERS, which resulted in single-rooted molars or taurodontism. Our observation suggests that the mutation in CACNA1S might disrupt calcium influx, resulting in impaired dental epithelium folding, and subsequent abnormal crown and root morphology.

Nomogram for predicting the distal adding-on phenomenon in severe and rigid scoliosis.

The distal adding-on phenomenon has attracted extensive discussion in the field of spine surgery due to the continual occurrence after scoliosis correction. Previous work has mainly focused on adolescent idiopathic scoliosis (AIS), and a relatively high number of theories for the mechanism of the distal adding-on phenomenon has been proposed for these kinds of patients. Severe and rigid scoliosis, as a special disease form, has a unique etiology, clinical manifestations and internal mechanisms distinct from those of AIS. Given the uniqueness of this disease, the mechanism and causes of the distal adding-on phenomenon have been infrequently studied in depth. To define clinical and radiological factors associated with distal adding-on in patients with severe and rigid scoliosis. Radiographic parameters and demographic data of patients with severe and rigid scoliosis were evaluated preoperatively, after posterior instrumentation and fusion surgery, and at the final follow-up via radiographs. According to the appearance of distal adding-on at the final follow-up, the patients were grouped into the Adding-on and the Non-adding-on groups. Various radiological parameters were analyzed in stepwise multivariate logistic regression to identify the variables associated with distal adding-on, which were then incorporated into a nomogram. The predictive performance and calibration of the nomograms for distal adding-on were assessed using C statistics and calibration plots. 93 patients (21 in the Adding-on and 72 in the Non-adding-on group) were included. The incidence of distal adding-on was 22.6%. The variables associated with distal adding-on were the anterior release, posterior internal distraction, and later posterior spinal fusion (IP) procedure, the posterior vertebral column resection and posterior spinal fusion (PVCR) procedure, postoperative apical vertebral translation (Post-AVT) and preoperative slope of the line linking the pedicles on the concave side of the upper- and lower-end vertebrae (Tan α). Combining these factors, the nomogram achieved a concordance index of 0.92 in predicting distal adding-on and had well-fitted calibration curves. For patient with a negative Tanα in severe and rigid scoliosis, the risk of distal adding-on tended to increase, and it is recommended to give priority to IP or PVCR. In the final correction, a smaller Post-AVT should not be pursued excessively.

Serum metabolomics identified metabolite biomarkers and distinguished maturity-onset diabetes of the young from type 1 diabetes in the Chinese population

BackgroundMaturity-onset diabetes of the young (MODY) patients have unique clinical manifestations and need individualized treatments. We identified novel serum metabolic biomarkers to distinguish MODY and explore the possible mechanism of the clinical manifestation and complications of MODY. MethodsFasting serum samples were collected from MODY3 (n = 17), MODY2 (n = 33), type 1 diabetes (T1DM) (n = 34) and healthy individuals (n = 30), and were analyzed using the ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) metabolomic platform. Results4 metabolites were found significantly fluctuated between groups, including glycerophosphocholine, LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine. Glycerophosphocholine was selected as a diagnostic biomarker. The the area under the ROC curve (AUC) for distinguishing MODYs from healthy controls and differentiating MODY3 from T1DM reached 1.0. The combination of metabolites also gained good diagnostic value. The AUC of the combination of LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine for discriminating MODY3 from T1DM was 0.983. Besides, the combination of clinical indices and metabolites helped to better differentiate the 2 MODY subtypes. ConclusionsWe identified the metabolic profiles of MODY2 and MODY3 and found promising biomarkers for distinguishing MODY from T1DM, which provides evidence for the pathogenesis and characteristic clinical manifestations of patients with MODY2 and MODY3.

Clinical Сharacteristics of Patients with Lumbar Disc Herniation: A Retrospective Comparative Study of 58 Females

INTRODUCTION. Low back pain (LBP) is a common discomfort in young women during pregnancy and after childbirth. These female patients with lumbar disc herniation (LDH) have unique clinical manifestations, but few studies have been reported. AIM. To investigate the clinical characteristics of female patients with LDH after childbirth and to provide basis for rehabilitation andtreatment. MATERIAL AND METHODS. We collected the clinical data of 58 female patients with LDH, analyzed the clinical characteristics. We usedCT scan to determine the location and type of LDH, observed the dural sac of lumbar intervertebral disc, serum 25 hydroxyvitaminD (25[OH] D) levels were measured and compared with healthy women and pregnant women. RESULTS. Our results showed that according to the age distribution of patients with low back pain was the most common among 30-34years old, accounting for 43.1% of all patients. Patients with LDH accounted for the highest proportion of patients with LBP, up to 55.2%.L4-L5 segment was the most common part of LDH, accounting for 46.9%, followed by L5-S1 segment, accounting for 31.3%. Protrusionwas the most common type of LDH, accounting for 84.4%. Among 34 patients with LDH, 15 patients (46.9%) had dural sac compression.The serum 25(OH) D level of patients with LDH was 11.36±5.16 ng/ml, lower than that of healthy women (first control group, 15.22±3.42ng/ml, p=0.022), and pregnant women (second control group, 18.95±6.94 ng/ml, p&lt;0.011). CONCLUSION. LDH is one of the main causes of LBP in female patients. Female patients with LDH have their specific features in terms ofage distribution, location and type of intervertebral disc herniation, especially the serum 25(OH)D level of female patients is significantlylow. To clarify the clinical characteristics of female patients with LDH is very important for the rehabilitation treatment.

Immunoglobulin M Monoclonal Gammopathies of Clinical Significance.

Immunoglobulin M monoclonal gammopathy of undetermined significance (MGUS) comprises 15-20% of all cases of MGUS. IgM MGUS is distinct from other forms of MGUS in that the typical primary progression events include Waldenstrom macroglobulinaemia and light chain amyloidosis. Owing to its large pentameric structure, IgM molecules have high intrinsic viscosity and precipitate more readily than other immunoglobulin subtypes. They are also more commonly associated with autoimmune phenomena, resulting in unique clinical manifestations. Organ damage attributable to the paraprotein, not fulfilling criteria for a lymphoid or plasma cell malignancy has recently been termed monoclonal gammopathy of clinical significance (MGCS) and encompasses an important family of disorders for which diagnostic and treatment algorithms are evolving. IgM related MGCS include unique entities such as cold haemagglutinin disease, IgM related neuropathies, renal manifestations and Schnitzler’s syndrome. The diagnostic approach to, and management of these disorders differs significantly from other categories of MGCS. We describe a practical approach to the evaluation of these patients and our approach to their treatment. We will also elaborate on the key unmet needs in IgM MGCS and highlight potential areas for future research.

Distinct Patterns of Amyloid Pathology in Autopsies of Transthyretin S77Y and A97S Amyloidosis: Significance of Symptomatology and Cell Biology.

Hereditary transthyretin (ATTRv) amyloidosis is a systemic disease with amyloid deposition in the peripheral and autonomic nervous systems caused by mutation of transthyretin (TTR) gene. The mutant TTR S77Y is the second prevalent mutation in many countries. In Taiwan, A97S mutant accounts for more than 90% of cases. Although distinct clinical manifestations such as dysphagia, carpal tunnel syndrome, and sudden cardiac death occur, the underlying pathology has not been elucidated. Here, we report the first autopsy cases of ATTRv S77Y and A97S and comprehensively compare the pathology underlying the unique clinical manifestations. This study demonstrated the following: (1) distinct spatial patterns of amyloid deposits in peripheral nerves, with a tendency toward more amyloid deposition in the large peripheral nerves, particularly the median nerves, and scarcely in the sural nerves, and different amyloid distribution in different genotypes; (2) amyloid deposits in the conduction system of the heart in addition to surrounding cardiomyocytes; (3) extensive amyloid deposits in the larynx and gastrointestinal tract, contributing to the unique clinical symptom of dysphagia; and (4) characteristic TTR intracytoplasmic inclusions in the hepatocytes of A97S. The pathology of the first autopsied cases of ATTRv S77Y and A97S provides pathology and mechanisms underlying unique clinical manifestations.

ROS and Endoplasmic Reticulum Stress in Pulmonary Disease.

Pulmonary diseases are main causes of morbidity and mortality worldwide. Current studies show that though specific pulmonary diseases and correlative lung-metabolic deviance own unique pathophysiology and clinical manifestations, they always tend to exhibit common characteristics including reactive oxygen species (ROS) signaling and disruptions of proteostasis bringing about accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER is generated by the unfolded protein response. When the adaptive unfolded protein response (UPR) fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis, which is called ER stress. The ER stress mainly includes the accumulation of misfolded and unfolded proteins in lumen and the disorder of Ca2+ balance. ROS mediates several critical aspects of the ER stress response. We summarize the latest advances in of the UPR and ER stress in the pathogenesis of pulmonary disease and discuss potential therapeutic strategies aimed at restoring ER proteostasis in pulmonary disease.

Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia.

Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype (p-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient.