Molecular pathology of NEU1 gene in sialidosis

Lysosomal sialidase (EC 3.2.1.18) has a dual physiological function; it participates in intralysosomal catabolism of sialylated glycoconjugates and is involved in cellular immune response. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in autosomal recessive disorder, sialidosis, which is characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. Sialidosis type I is a milder, late-onset, normosomatic form of the disorder. Type I patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia, and seizures. The severe early-onset form, sialidosis type II, is also associated with dysostosis multiplex, Hurler-like phenotype, mental retardation, and hepatosplenomegaly. We summarize information on the 34 unique mutations determined so far in the sialidase gene, including four novel missense and one novel nonsense mutations found in two Czech and two French sialidosis patients. The analysis of sialidase mutations in sialidosis revealed considerable molecular heterogeneity, reflecting the diversity of clinical phenotypes that make molecular diagnosis difficult. The majority of sialidosis patients have had missense mutations, many of which have been expressed; their effects on activity, stability, intracellular localization, and supramolecular organization of sialidase were studied. A structural model of sialidase allowed us to localize mutations in the sialidase molecule and to predict their impact on the tertiary structure and biochemical properties of the enzyme.     

Squamous-lined cysts of the pancreas: lymphoepithelial cysts, dermoid cysts (teratomas), and accessory-splenic epidermoid cysts

In the pancreas, 3 types of morphologically similar lesions may present as "squamous cysts": Lymphoepithelial cysts, dermoid cysts (monodermal teratomas), and epidermoid cysts in intrapancreatic accessory spleen. Lymphoepithelial cysts (LECs) are seen predominantly in men (M/F: 4/1) and in adulthood (mean age, 56, and range, 35 to 74 years). They may occur at any site of the organ (head, body, or tail). LECs are well-delineated cysts that may be multilocular (60%) or unilocular (40%), and they are characterized microscopically by stratified squamous epithelium surrounded by a band of mature lymphoid tissue with intervening well-formed germinal centers. Solid lymphoepithelial clusters are seldom seen. The pathogenesis of LECs is unclear; clinical diseases that are known to be associated with their counterparts in the salivary glands such as Sjogren disease or human immunodeficiency virus have not been documented for the LECs of the pancreas. The second type of squamous-lined cyst in the pancreas is the epidermoid cyst arising in intrapancreatic accessory spleen. These are located almost exclusively in the tail of the pancreas, in the fourth decade of life (mean age = 38). Their mean size is 4.5 cm (range, 2.3 to 6.5). In some cases, the cyst lining may be partly mucinous. Dermoid cysts of the pancreas are also rare. The cases that appear to be true dermoid cysts occur in a younger age group (mean age, 23, range, 2 to 53 years), and in contrast with LEC, there is no gender predominance. Mucinous epithelium, respiratory-type mucosa and sebaceous units are more readily identifiable in dermoid cysts, and they may contain hair. Subepithelial lymphoid tissue is not a feature. They are sometimes complicated by suppurative infections. The importance of these lesions is in their distinction from other cystic neoplasms, especially mucinous cystic tumors.     

Chromosome 22q11.2 deletion and phenotypic features in 30 patients with conotruncal heart defects

This report describes the dysmorphic features and frequency of 22q11.2 deletion (del22q11) in 30 Turkish patients with conotruncal heart defects (CTHDs). Fluorescence in situ hybridization (FISH) analysis revealed deletions in the 22q11.2 region in nine (30%) individuals. The CTHDs in this group were tetralogy of Fallot (four cases), double-outlet right ventricle (DORV) (two cases), transposition of great arteries (two cases), and ventricular septal defect (VSD) associated with other CTHDs (one case). The frequency of del22q11 in the study group was relatively high because many of the patients with dysmorphic findings also had cardiac anomalies involving the pulmonary artery, ductus arteriosus, or the aortic arch and its main branches. Twenty of the 30 patients exhibited several dysmorphic findings. Two of the nine patients with del22q11 exhibited no apparent dysmorphic features other than sacral dimple. Interestingly, one of the patients with del22q11 had a phenotypic appearance similar to that seen in oculo-auriculo-vertebral spectrum (OAVS). This individual had left microtia, atresia of the external meatus, mandibular asymmetry, and peripheral facial nerve paralysis. His mental development was normal and there were no abnormalities on ophthalmological examination. The CTHDs in this patient were situs inversus dextrocardia, DORV, pulmonary stenosis, and VSD. Radiographs of this patient showed platybasia, complete fusion of C2-C3, and posterior fusion of the T1-T2 vertebrae. This particular case indicates that the phenotypic features of del22q11 and OAVS may overlap.     

Matrix Metalloproteinase and Cytokine Profiles in Monocytes over the Course of Stroke

Stroke is a common cause of death and disability in our society. Stroke is associated with changes in immune responses within the central nervous system as well as systemically. The cells contributing to such changes as well as the factors contributing to formation of the inflammatory infiltrate observed in stroke remain to be clarified. In this study, blood monocytes and corresponding mononuclear cells (MNC) were separated and examined in parallel within 4 days and 1–3 months after onset of ischemic stroke. Numbers of TNF--, IL-12-, IL-6-, and IL-10-secreting cells and of cells expressing mRNA for matrix metalloproteinase (MMP)-1, -2, -7, -9 and tissue inhibitor of MMP (TIMP)-1 were studied. The TNF--, IL-12-, and IL-6-secreting monocytes and MNC were elevated during the acute phase compared to healthy controls. Such differences were not observed when stroke patients were examined during convalescence. The IL-10-secreting monocytes did not change over the course of stroke. Levels of monocytes expressing MMP-1, MMP-7 and TIMP-1 mRNA were elevated in the acute phase of stroke patients compared to convalescence and healthy controls, as were levels of MMP-1, -2, -7, -9 and TIMP-1 mRNA expressing blood MNC. The MMP-2 and -9 activity as measured by zymography also was higher in MNC supernatants in the acute phase of stroke compared to convalescence. The high levels of proinflammatory cytokines and MMPs in blood monocytes and MNC further demonstrate the presence of systemic aberrations in the acute phase of stroke. Such changes may contribute to the influx of blood-borne cells into the ischemic lesions during the acute phase of stroke.     

Paraduodenal pancreatitis: a clinico-pathologically distinct entity unifying "cystic dystrophy of heterotopic pancreas", "para-duodenal wall cyst", and "groove pancreatitis"

A distinct form of chronic pancreatitis occurring predominantly in and around the duodenal wall (near the minor papilla) has been reported under various names, including cystic dystrophy of heterotopic pancreas, pancreatic hamartoma of duodenum, para-duodenal wall cyst, myoadenomatosis, and groove pancreatitis. Our experience with these lesions and the review of the literature show that these lesions have the following common characteristics: (1) The duodenal wall contains dilated ducts, some with inspissated secretions, and pseudocystic changes as well as adjacent stromal reactions including hypercellular granulation tissue, foreign-body type giant cell reaction engulfing mucoprotein material, and myofibroblastic proliferation. (2) Brunner's gland hyperplasia is typically present. (3) Dense myoid stromal proliferation, with intervening rounded lobules of pancreatic acinar tissue, creates a histologic picture reminiscent of "myoadenomatosis," "pancreatic hamartoma," or even leiomyoma in some cases. (4) Spillover of fibrosis into the adjacent pancreas and soft tissue occurs, especially in the "groove" area (between the pancreas, common bile duct and duodenum), including the region around the common bile duct. (5) Clinically, these lesions often mimic "pancreas cancer" or periampullary tumors, because of marked scarring as well as the ill-defined borders of the process. Patients with these findings are predominantly males, 40-50 years old, with a history of alcohol abuse. That the process is often centered in the region of minor papilla (and the adjacent pancreas) suggests that an anatomic variation of the ductal system may render this area particularly susceptible to the effects of alcoholic injury, and the myo-adenomatoid and cystic changes on the duodenal wall may in turn represent changes related to a localized recurrent pancreatitis. In conclusion, these clinicopathologic findings characterize a distinctive process that can be referred to as paraduodenal pancreatitis.     

Persistent extramural vascular invasion positivity on magnetic resonance imaging after neoadjuvant chemoradiotherapy predicts poor outcome in rectal cancer

BackgroundIn rectal cancer, extramural vascular invasion (EMVI) is the presence of tumour cells in blood vessels outside the muscular layer, which is associated with poor prognosis. Regression of EMVI on MRI following neoadjuvant chemoradiotherapy or its persistence may have prognostic implications.MethodsThis retrospective study included 52 patients with rectal cancer who underwent total mesorectal excision following long-course neoadjuvant chemoradiotherapy (CRT). EMVI assessments were done on previous pelvic MRIs obtained before neoadjuvant CRT and eight weeks after the completion of neoadjuvant chemoradiotherapy in initially EMVI positive cases.ResultsPersistently EMVI positive patients had worse overall survival and disease-free survival compared to initially EMVI negative patients and patients who returned to negative (p < 0.001 for both). Multivariate analysis identified persistent EMVI positivity after neoadjuvant treatment (HR, 102.9; p = 0.003) as significant independent predictor of worse overall survival; and persistent EMVI positivity (HR, 17.0; p = 0.002), mesorectal fascia involvement after neoadjuvant treatment (HR, 8.0; p = 0.017), and poor differentiation (HR, 10.3, p = 0.012) as significant independent predictors of worse disease-free survival.ConclusionPersistent EMVI positivity after neoadjuvant therapy appears to be an independent factor for poor overall survival; and persistent EMVI positivity as well as mesorectal fascia involvement on post neoadjuvant therapy MRI and poor differentiation appears to be important predictors of poor disease-free survival in rectal cancer patients.     

Ultrasonography and erythrocyte distribution width in patients with plantar fasciitis

BackgroundThe measurement of plantar fascia thickness with ultrasonography can be used for both for diagnosis and as a response-to-treatment parameter in plantar fasciitis. Furthermore, with the recent studies, red cell distribution width may be used as an inflammatory marker. Aim of this study is to investigate the association of red cell distribution width and ultrasonography on diagnosis and monitoring of treatment in patients with plantar fasciitis.MethodsClinically diagnosed 102 patients with plantar fasciitis between the dates January 2016 to July 2018 were analysed. Hemogram, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and plantar fascial ultrasonography were obtained on initial evaluation and in 1 month, 2 months and 3 months of the standard nonoperative treatment; American Orthopaedic Foot & Ankle Hindfoot Score (AOFAS) and Visual Analog Scale (VAS) scores were recorded. Posthoc and multivariate logistic regression analysis were used for statistical analysis on SPSS 21.0.ResultsRed cell distribution width was correlated with plantar fascia thickness by the end of the 1 month (r = 0.26, P = .013). Female sex, BMI over 30 kg/m², higher red cell distribution width and higher plantar fascia thickness were associated with plantar fasciitis on initial evaluation. Higher red cell distribution width together with higher plantar fascia thickness were also found to be a risk factor for both on initial evaluation and 1 month after treatment in plantar fasciitis.ConclusionThis study shows that association of red cell distribution width and plantar fascia thickness can be not only a diagnostic predictor but also an indicator of treatment response in plantar fasciitis.Level of clinical evidenceLevel IV     

MUC1 and MUC2 in pancreatic neoplasia

MUCs are glycoproteins with various roles in homeostasis and carcinogenesis. Among other actions, MUC1 may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, participating in cancer progression. In contrast, MUC2 is normally found only in goblet cells, where it contributes to the protective barrier function of these cells. Recently, a tumour suppressor role has been demonstrated for MUC2, and both MUC1 and MUC2 appear to have important roles in pancreatic neoplasia. MUC1 appears to be a marker of aggressive phenotype and may facilitate the vascular spread of carcinoma cells. In contrast, MUC2 is rarely detectable in aggressive pancreatic tumours, but is commonly expressed in intraductal papillary mucinous neoplasms (IPMNs), which are rare, indolent tumours, in intestinal IPMNs, and in indolent colloid carcinomas. MUC2 appears to be not only a marker of this indolent pathway, but also partly responsible for its less aggressive nature. Thus, in pancreatic neoplasia, MUC1 and MUC2 have potential diagnostic and prognostic value as markers of aggressive and indolent phenotypes, respectively, and have potential as therapeutic targets.     

The “vaccine” hubbub: Viral load comparisons of SARS-CoV-2 Delta and Omicron variants against different vaccine–booster vaccine combinations

There is a significant body of evidence showing that efficient vaccination schemes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is helping control the coronavirus disease 2019 (COVID-19) pandemic. However, this goal cannot be achieved without real world data highlighting the impact of vaccines against viral spread. In this study, we have aimed at differentially investigating the impact of COVID-19 vaccines (CoronaVac, Pfizer/BioNTech, Astra/Zeneca Oxford, Janssen) used in North Cyprus in limiting the viral load of Delta and Omicron variants of SARS-COV-2. We have utilized real-time quantitative polymerase chain reaction cycle threshold values (Ct values) as a proxy of viral load of the two SARS-CoV-2 variants. Our results indicate that the administration of at least two doses of the messenger RNA-based Pfizer/BioNTech vaccine leads to the lowest viral load (highest Ct values) obtained for both Omicron and Delta variants. Interestingly, regardless of the vaccine type used, our study revealed that Delta variant produced significantly higher viral loads (lower Ct values) compared with the Omicron variant, where the latter was more commonly associated with younger patients. Viral spread is a crucial factor that can help determine the future of the pandemic. Thus, prioritizing vaccines that will play a role in not only preventing severe disease but also in limiting viral load and spread may contribute to infection control strategies.     

Spindle cell tumors associated with mycobacteria in lymph nodes of HIV-positive patients: 'Kaposi sarcoma with mycobacteria' and 'mycobacterial pseudotumor'.

Patients infected with HIV often have unusual manifestations of common infections and neoplasms. One such example is "mycobacterial pseudotumor," an exuberant spindle cell lesion induced in lymph nodes by mycobacteria. Kaposi sarcoma also produces a spindle cell proliferation in lymph nodes of HIV-positive patients. These two entities must be differentiated from one another because of differences in treatment and prognosis. We report here, however, three cases of intranodal Kaposi sarcoma with simultaneous mycobacterial infection, the occurrence of which has not been clearly documented. For comparison, we also studied three cases of mycobacterial pseudotumor, of which 14 cases have been described to date. There was considerable histologic overlap between these two lesions. Acid-fast bacilli were present in all cases, predominantly in the more epithelioid histiocytes in the cases of Kaposi sarcoma, and in spindle and epithelioid cells in the cases of mycobacterial pseudotumor. The morphologic features that favored Kaposi sarcoma over mycobacterial pseudotumor were the prominent fascicular arrangement of spindle cells and slitlike spaces, the lack of granular, acidophilic cytoplasm, and the presence of mitoses. Immunohistochemistry was a reliable adjunct study in the differential diagnosis, as the spindle cells in mycobacterial pseudotumor were positive for S-100 protein and CD68 whereas those of Kaposi sarcoma were CD31- and CD34-positive but negative for S-100 protein and CD68. Awareness that Kaposi sarcoma may coexist with mycobacterial infection in the same biopsy specimen is important because these lesions may be misdiagnosed as mycobacterial pseudotumor. The clinical impact of distinguishing between Kaposi sarcoma with mycobacteria and mycobacterial pseudotumor is significant because the presence of Kaposi sarcoma alters treatment and prognosis.