bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus
Authors: Russ-Silsby James , Patel Kashyap A. , Laver Thomas W. , Hawkes Gareth , Johnson Matthew B. , Wakeling Matthew N. , Patil Prashant P. , Hattersley Andrew T. , Flanagan Sarah E. , Weedon Michael N. , De Franco Elisa
Published: August 2023

ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human β-cell function.

Article Highlights
Genome-Wide Association Study Identifies Pharmacogenomic Variants Associated With Metformin Glycemic Response in African American Patients With Type 2 Diabetes
Authors: Wu Baojun , Yee Sook Wah , Xiao Shujie , Xu Fei , Sridhar Sneha B. , Yang Mao , Hochstadt Samantha , Cabral Whitney , Lanfear David E. , Hedderson Monique M. , Giacomini Kathleen M. , Williams L. Keoki
Published: August 2023

OBJECTIVE

Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes.

RESEARCH DESIGN AND METHODS

Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND.

RESULTS

The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10−9). None of the significant discovery variants replicated in European Americans DIAMOND participants.

CONCLUSIONS

We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.
The Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depends on Haptoglobin Phenotype Among White and Black ACCORD Participants
Authors: Cahill Leah E. , Warren Rachel A. , Carew Allie S. , Levy Andrew P. , Ginsberg Henry N. , Sapp John , Lache Orit , Rimm Eric B.
Published: August 2023

OBJECTIVE

Intensive glycemic therapy reduced coronary artery disease (CAD) events among White participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the haptoglobin (Hp)2-2 phenotype, while participants without the Hp2-2 phenotype had no CAD benefit. The association between achieved glycated hemoglobin (HbA1c) and CAD for each Hp phenotype remains unknown.

RESEARCH DESIGN AND METHODS

Achieved HbA1c was similar in each phenotype throughout the study. Prospectively collected HbA1c data (categorized as <6.0%, 6.0–6.5%, 6.6–6.9%, or ≥8.0% compared with 7.0–7.9%) from the ACCORD study, updated every 4 months over a median of 4.7 years, were analyzed in relation to CAD in the Hp2-2 (n = 3,322) and non–Hp2-2 (n = 5,949) phenotypes separately overall, and within White (63%, 37% Hp2-2) and Black (19%, 26% Hp2-2) participants using Cox proportional hazards regression with time-varying covariables.

RESULTS

Compared with HbA1c of 7.0–7.9%, having HbA1c ≥8.0% was associated with CAD risk among White (adjusted HR [aHR] 1.43, 95% CI 1.03–1.98) and Black (2.86, 1.09–7.51) participants with the Hp2-2 phenotype, but not when all Hp2-2 participants were combined overall (1.30, 0.99–1.70), and not among participants without the Hp2-2 phenotype. HbA1c <7.0% was not associated with a lower risk of CAD for any Hp phenotype.

CONCLUSIONS

Achieving HbA1c >8.0% compared with 7.0–7.9% was consistently associated with incident CAD risk among White and Black ACCORD participants with the Hp2-2 phenotype, while no association was observed among participants without the Hp2-2 phenotype. We found no evidence that HbA1c concentration <7.0% prevents CAD in either Hp phenotype group.
Duration of Type 2 Diabetes and Incidence of Cancer: An Observational Study in England
Authors: Zaccardi Francesco , Ling Suping , Brown Karen , Davies Melanie , Khunti Kamlesh
Published: August 2023

OBJECTIVE

To investigate the association between duration of type 2 diabetes and cancer incidence.

RESEARCH DESIGN AND METHODS

In the Clinical Practice Research Datalink database, we identified 130,764 individuals with type 2 diabetes aged ≥35 years at diagnosis who were linked to hospital and mortality records. We used sex-stratified Royston–Parmar models with two timescales to estimate incidence rates of all cancers, the four commonest cancers in the U.K. (colorectal, lung, prostate, breast), and the obesity-related cancers (e.g., liver, ovary) between 1 January 1998 and 14 January 2019, by age and diabetes duration.

RESULTS

During 1,089,923 person-years, 18,977 incident cancers occurred. At the same age, rates of all cancers in men and women did not vary across durations ranging from diagnosis to 20 years; conversely, for any duration, there was a strong, positive association between age and cancer rates. In men, the rate ratio (95% CI) comparing 20 with 5 years of duration was 1.18 (0.82–1.69) at 60 years of age and 0.90 (0.75–1.08) at 80 years; corresponding ratios in women were 1.07 (0.71–1.63) and 0.84 (0.66–1.05). This pattern was observed also for the four commonest cancers. For obesity-related cancers, although rates were generally higher in individuals with a higher BMI, there was no association with duration at any level of BMI.

CONCLUSIONS

In this study, we did not find evidence of an association between duration of type 2 diabetes and risk of cancer, with the higher risk observed for longer durations related to ageing.
Treg-specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T Cell Stability
Authors: Thirawatananond Puchong , E. Brown Matthew , K. Sachs Lindsey , M. Arnoletti Juan , Yeh Wen-I , L. Posgai Amanda , R. Shapiro Melanie , Chen Yi-Guang , M. Brusko Todd
Published: August 2023

Co-stimulation serves as a critical checkpoint for T cell activation, and several genetic variants affecting co-stimulatory pathways confer risk for autoimmune diseases. A single nucleotide polymorphism (rs763361) in the CD226 gene encoding a co-stimulatory receptor increases susceptibility to multiple autoimmune diseases, including type 1 diabetes. We previously found that Cd226 knockout protected non-obese diabetic (NOD) mice from disease, but the impact of CD226 on individual immune subsets remained unclear. Our prior reports implicate regulatory T cells (Treg), as human CD226+ Tregs exhibit reduced suppressive function. Hence, we hypothesized that genomic Cd226 gene deletion would increase Treg stability, and Treg-specific Cd226 deletion would inhibit diabetes in NOD mice. Indeed, crossing NOD.Cd226-/- and a NOD Treg-lineage tracing strain resulted in decreased pancreatic Foxp3-deficient “ex-Tregs.” We generated a novel Treg-conditional knockout (Treg∆Cd226) strain that displayed decreased insulitis and diabetes incidence. CD226-deficient pancreatic Tregs had increased expression of the co-inhibitory counter-receptor TIGIT. Moreover, NOD splenocytes treated with a TIGIT-Fc fusion protein exhibited reduced T cell proliferation and IFN-γ production following anti-CD3/CD28 stimulation. This study demonstrates that a CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this co-stimulatory pathway to halt autoimmunity.

Keywords: CD226, NOD mouse, regulatory T cell, type 1 diabetes, conditional knockout, Treg stability

Highlights

· We previously found that Cd226 genomic knockout in NOD mice reduced insulitis severity and diabetes incidence, but the impact on individual immune subsets remained unclear.

· Human CD226+ Tregs exhibit reduced suppressive function suggesting Cd226 gKO would increase Treg stability, and Treg-specific Cd226 deletion would inhibit diabetes in NOD.

· Treg-conditional CD226 KO reduced insulitis and delayed diabetes onset in female NOD mice while CD226 gKO NODs displayed reduced ex-Tregs in pancreas and increased TIGIT expression on Tregs.

CD226/TIGIT imbalance contributes to Treg instability in NOD mice and highlights the potential for therapeutic targeting this co-stimulatory pathway in type 1 diabetes.
Establishment of Pancreatic Beta Cell-specific Gene Knockout System Based on CRISPR-Cas9 Technology with AAV8-mediated gRNA Delivery
Authors: Ueki Kyosei , Nishida Yuya , Aoyama Shuhei , Uzawa Hirotsugu , Kanai Akiko , Ito Minami , Ikeda Koki , Iida Hitoshi , Miyatsuka Takeshi , Watada Hirotaka
Published: August 2023

The Cre-loxP system provides valuable resources to analyze the importance of tissue-specific gene knockout, including pancreatic beta cells associated with the pathogenesis of diabetes mellitus. However, it is expensive and time-consuming to generate transgenic mice harboring floxed genes of interest and cross them with cell-specific Cre-expression mice. We establish a βCas9 system with mice expressing Cas9 in pancreatic beta cells and adeno-associated virus 8 (AAV8) -mediated gRNA delivery based on CRISPR-Cas9 technology to overcome those shortcomings. Interbreeding CAG-LoxP-Stop-LoxP (LSL)-Cas9 with Ins1-Cre mice generates normal glucose-tolerant βCas9 mice expressing Cas9 with fluorescent reporter EGFP specifically in beta cells. We also show significant beta cell-specific gene knockout efficiency with AAV8-mediated delivery of gRNA for EGFP reporter by intraperitoneal injection in the mice. As a proof of concept, we administer AAV8 to βCas9 mice for expressing gRNA for Pdx1, a culprit gene of maturity-onset diabetes of the young 4 (MODY4). As reported previously, we demonstrate that those mice show glucose intolerance with trans-differentiation of Pdx1 knockout beta cells into glucagon-expressing cells. We successfully generate a convenient beta cell-specific gene knockout system with βCas9 mice and AAV8-mediated gRNA delivery.

ARTICLE HIGHLIGHTS

・ Generating pancreatic beta cell-specific gene knockout mice without time- and money-consuming breeding could be beneficial.

・ We establish a convenient βCas9 system, which enables the beta cell-specific gene knockout with mice expressing Cas9 in pancreatic beta cells and adeno-associated virus 8-mediated gRNA delivery by simple intraperitoneal injection.

・ A fluorescent reporter-based estimation shows the high efficiency of gene knockout in the βCas9 system.

・ Beta cell-specific Pdx1 knockout in the βCas9 system validates the concept of our procedure by demonstrating glucose intolerance and trans-differentiation.
Element concentrations in serum, erythrocytes, hair and urine of alopecia patients
Authors: Mussalo-Rauhamaa H , Lakomaa EL , Kianto U , Lehto J.
Published: August 2023

The trace element concentrations of Se, Rb, Zn, Fe, Co, Cs, Mg, Ca, F, Cu, Cr and Ag in serum and of Se, Rb, Zn, Fe, Co and Cs in red cells of Finnish alopecia patients were determined. In addition the Cu and Zn content in 24 h urine and Cu, Zn, Cd, Cr and Se concentrations in the hair of these patients were studied. No differences in element concentrations of the samples mentioned above as compared to those of the normal population could be found. In addition, there was no tendency of excesses or deficiences of elements analysed in the samples. Statistically significant difference was found between the copper content of serum in alopecia areata and alopecia universalis patients and also between the copper content of serum in alopecia areata plus alopecia totalis and alopecia universalis patients. The selenium concentration in serum samples of a few patients was low, but this is in agreement with the fact that the selenium content in the Finnish population is low due to the scanty content of selenium in food.
Changes in laboratory variables induced by isotretinoin treatment of acne
Authors: Michaëlsson G , Vahlquist A , Mobacken H , Hersle K , Landegren J , Rönnerfält L , Nordin K , Franzén K , Pettersson
Published: August 2023

During a trial of isotretinoin (0.5 mg/kg body weight/day for 3 months) in 90 patients with severe acne, the leucocyte (WBC) count, and particularly the number of neutrophils, decreased significantly. In patients with a good response the mean WBC count fell by 24% and the neutrophils by 33%, whereas in those with a poor response these variables decreased by 8% and 14%, respectively. The serum ALAT, ASAT, cholesterol and triglyceride levels increased significantly. Patients with a poor response (n = 35) received a higher dosage (0.75 mg/kg) for an additional 3 months, and during this period there was a further decrease in the WBC and neutrophil counts and an increase in the triglyceride level. In the other patients, who initially responded well, the dosage was decreased to 0.1 or 0 mg/kg during the second 3-month period, which resulted in reversion of the laboratory variables to the pre-treatment levels. The observed changes were clearly both dose-dependent and reversible.
Dermal mast cells in mastocytosis: fixation, distribution and quantitation
Authors: Olafsson JH , Roupe G , Enerbäck L.
Published: August 2023

The mast cell distribution and number were studied in skin biopsies of 18 mastocytosis patients and 10 controls. The biopsies were stained for mast cells with toluidine blue at pH 0.5. The number in the upper dermis of lesional abdominal skin was at least twice as high as that of normal adjacent skin. Fixation in iso-osmotic 0.6% formaldehyde and 0.5% acetic acid, revealed more mast cells than conventional 4% formaldehyde fixation. Staining for 5 days, when compared to the normal for 30 min, increased the number of demonstrable mast cells just as did the change in fixation. Conventional formaldehyde fixation thus partially blocks the dye-binding of cutaneous mast cells, about 20% of the cells escaping detection. The degree of aldehyde blocking was similar in lesional and normal skin. A more pronounced blocking of dye-binding has been demonstrated previously in gut mucosal mast cells. Whether the blocking of dye-binding is an expression of heterogeneity in dermal mast cells remains to be determined.
Pustular psoriasis of v. Zumbusch type associated with recurring cholestatic jaundice
Authors: Aronsson A , Nilsson A.
Published: August 2023

A 46-year-old man with pustular psoriasis and recurring episodes of severe cholestatic liver disease is described. Six icteric periods have occurred parallelling high activity of the skin disease.
Nevoid hyperkeratosis of the nipple and areola mammae: ineffectiveness of etretinate therapy
Authors: Ortonne JP , El Baze P , Juhlin L.
Published: August 2023

A woman with nevoid hyperkeratosis of the nipple and areola appearing during puberty is described. It remained unchanged during two pregnancies and caused no problem when breast feeding her two children. Etretinate (1 mg/kg/day) was ineffective in the treatment of this dermatosis.
Antigen specific human T cell lines specific for cobalt chloride
Authors: Löfström A , Wigzell H.
Published: August 2023

T lymphocyte lines specific for cobalt (CoCl2) were established from one cobalt and nickel sensitive donor. The lines were generated by stimulating peripheral blood mononuclear cells (PBL) with CoCl2 for 7 days. The activated blasts were maintained in interleukin 2 containing media and every 7-10 day restimulated with antigen (CoCl2) and fresh irradiated PBL. The antigen specificity of the lines was attested by their capacity to proliferate and release of IL 2 under restimulation by CoCl2 and not by an antigen like NiSO4, towards which the donor was also sensitized. The cell lines were of the helper phenotype, T3/T4 positive subset, as determined by monoclonal antibodies. Analysis of the HLA class II restriction by using allogeneic PBL as antigen presenting cells and the capacity of anti HLA-D antibodies to effectively inhibit the specific response indicated that the antigen specific T cell response to contact allergens like cobalt chloride is restricted to HLA class II antigens.
Spontaneous remission of dermatitis herpetiformis: dietary and gastrointestinal studies
Authors: Mobacken H , Andersson H , Dahlberg E , Fransson K , Gillberg R , Kastrup W , Stockbrügger R.
Published: August 2023

Out of 98 patients with dermatitis herpetiformis (DH) living in Gothenburg, 14 were in spontaneous remission (29% of the patients without gluten free diet). Eight of these volunteered for dietary interviews and further studies. They do not seem to differ from symptomatic DH patients in the frequency of HLA-B8, achlorhydria or small-bowel enteropathy. Their estimated mean daily intake of gluten was below 12 g in six. The mean gluten intake of the eight patients in remission is significantly less than in a group of 34 patients with dapsone-requiring DH on non-restricted diet. Urinary iodine excretion was low in five, all previously instructed to restrict their iodine intake. Dietary factors could thus be suspected to be responsible for some spontaneous remissions in DH.
Association between HLA-B16 and psoriatic spondylitis
Authors: Crivellato E , Zacchi T.
Published: August 2023

The frequency distribution of HLA antigens was studied in a group of 40 patients with psoriatic arthritis from a region in North-eastern Italy. Our results indicate: 1) a strong association, in this population, between HLA-B16 and inflammatory spinal involvement; 2) a failure to confirm previous reports on HLA-B27 increased frequency in psoriatic spondylitis and/or sacroiliitis.
Erythema elevatum diutinum and pre-AIDS
Authors: Da Cunha Bang F , Weismann K , Ralfkiaer E , Pallesen G , Lange Wantzin G.
Published: August 2023

Erythema elevatum diutinum (EED) is a chronic disease with symmetrical persistent erythematous nodules and plaques primarily in an acral distribution. EED is often associated with infections, especially of streptococcals. An immunological reaction has been proposed as pathogenetic mechanism. We describe a patient, who developed EED secondary to a LAV/HTLV III positive lymphadenopathy syndrome. Immunological investigation of a skin lesion and a lymph node biopsy is described.
Local and systemic effect of ultraviolet irradiation (UVB and UVA) on human allergic contact dermatitis
Authors: Sjövall P , Christensen OB.
Published: August 2023

In subjects hypersensitive to nickel we have investigated local and systemic effect of whole body exposure of cumulative suberythema UVB doses as well as solarium-UVA exposure. UVB possesses both locally and systemically a suppressive effect on human allergic contact dermatitis, but UVA has no such effect. The systemic suppressive effect of UVB might be of therapeutic importance in patients with severe chronic dermatitis of the hands when adding this effect to a local suppressive effect. Also, patch testing should not be performed during UVB and/or overt sun exposure.
Skin tumors and reactive cellular infiltrate: further studies
Authors: Claudatus Jr JC , D'Ovidio R , Lospalluti M , Meneghini CL.
Published: August 2023

Twenty-two non-ulcerated basal cell carcinomas and 30 non-ulcerated squamous cell carcinomas were selected to study the reactive cellular infiltrate, utilizing histological, histoenzymatic and immunological methods. Substantial differences in cell behaviour were observed between the two tumors: advanced and metastatic squamous cell carcinoma showed prominent presence of T8+ lymphocytes, Leu 7+ cells, macrophages, mast cells and granulocytes, notably eosinophils. Degranulation of mast cells was seen both in the tumor itself and in the adjacent stroma. The basal cell carcinoma presented a low count of T4+, T8+ lymphocytes, whereas Leu 7+ cells and granulocytes were absent.
Acute febrile neutrophilic dermatosis (Sweet´s syndrome) following BCG vaccination
Authors: Radeff B , Harms M.
Published: August 2023

Several factors may trigger or be associated with acute febrile neutrophilic dermatosis (AFND). We report a case of AFND following BCG vaccination as an interesting association although no direct interrelation can be certified.
The effect of capsaicin on some experimental inflammations in human skin
Authors: Wallengren J , Möller H.
Published: August 2023

Topical application of capsaicin is thought to deplete substance P from local sensory nerve terminals. In experiments on human skin inflammation was induced by injection of substance P (SP) or histamine intradermally, UV irradiation, non-immunologic contact urticaria, tuberculin reaction, contact allergens and benzalkonium chloride with or without capsaicin pretreatment. The flare response to SP and histamine was suppressed by capsaicin pretreatment whereas the wheal was enlarged. Interestingly, capsaicin pretreatment enhanced the responses to all other inflammatory agents.
Heterogeneity of serum IgE levels in atopic dermatitis
Authors: Uehara M.
Published: August 2023

To determine whether serum IgE levels in patients with atopic dermatitis (AD) have a relationship to familial background of atopic respiratory disease (ARD), serum IgE levels were measured in 50 AD patients who had personal history of ARD, 37 AD patients who did not have personal history of ARD but had family history of ARD, and 52 "pure" AD patients who had neither personal nor family history of ARD. The "pure" AD patients showed significantly lower serum IgE levels than AD patients who had personal or family history of ARD. It is suggested that AD patients may be classified into at least two subgroups: those with ARD predisposition who have an enhanced IgE producing potential, and those without ARD predisposition who have a low or not-enhanced ability for IgE production.
Hyaluronate in suction blisters from patients with scleroderma and various skin disorders
Authors: Juhlin L , Tengblad A , Ortonne JP , Lacour JP.
Published: August 2023

With a specific radioassay hyaluronic acid (hyaluronate) concentrations have been determined in suction blister fluid from abdominal skin and serum. Healthy subjects, patients with acrosclerosis, CRST, mucinosis and urticaria had 0.8-5.6 micrograms/ml of hyaluronate in their suction blisters, which is about 100 times more than the serum level. Increased concentrations were noted in blister fluid from patients with active lesions of systemic and localized scleroderma as well as lichen sclerosus. Here the increase could be due to an increased production of hyaluronate in the dermis. High levels of hyaluronate were, however, also found in blister fluid from patients with other types of inflamed skin. An increased leakage into the blister of hyaluronate from the dermis, probably through the lymph vessels, therefore seems best to explain the high concentrations of hyaluronate.
Tissue distribution of aromatic retinoid (etretinate) in three autopsy cases: drug accumulation in adrenals and fat
Authors: Vahlquist A , Rollman O , Pihl-Lundin I.
Published: August 2023

The problematic storage of etretinate in fat during chronic etretinate therapy prompted us to search for other "high-affinity" tissues in 3 patients studied at autopsy. Specimens from eleven organs were analysed for etretinate and its main metabolite, etretin, by high-performance liquid chromatography. The results confirmed an accumulation of etretinate in fat and to a lesser degree in liver. High levels of etretinate were also found in the adrenals and, in one case, this value exceeded that of the fat tissue. Low levels were observed in several other organs, notably the kidneys, brain and testis. With the possible exception of liver and gut, the metabolite did not accumulate in any particular organ. Although the available data is still limited, the risk that the accumulation of etretinate in the adrenals may adversely affect adrenal function must be examined.
Extensive hemangiomatosis of the extremities with the same histopathological pattern as the early lesion of Kaposi´s sarcoma
Authors: Brehmer-Andersson E , Torssander J , Tengvar M.
Published: August 2023

For 13 years a 28-year-old man had on his hands and feet bluish red patches, which had slowly progressed in size. Biopsy specimens exhibited an abnormal vascular pattern similar to that seen in early lesions of Kaposi´s sarcoma. Skeletal radiographs of the hands and feet showed lesions indicating hemangiomatosis.
Trichochromuria in melanosis of melanoma
Authors: Rorsman H , Agrup P , Carlén B , Hansson C , Jonsson N , Rosengren E , Tegner E.
Published: August 2023

Two patients with metastasizing melanoma and diffuse melanosis have previously been reported to excrete large quantities of trichochromes in the urine. The present study describes 2 further melanoma patients with diffuse melanosis and trichochromuria. The hair of one of the patients which had been red in childhood and turned brown in adult age returned to red with the appearance of melanosis. Normal excretion of a methylated melanocytic metabolite, 6-hydroxy-5-methoxyindole-2-carboxylic acid, was observed in this patient, possibly indicating exhaustion of the methylating system. The other patients excreted large quantities of 6-hydroxy-5-methoxyindole-2-carboxylic acid. Both patients showed highly increased excretion of 5-S-cysteinyldopa. Both patients with melanosis exhibited fine electrone-dense granules in lysosomes of dermal histiocytes. The findings support the concept that trichochromes or similar pigments in dermal histiocytes are responsible for diffuse melanosis in melanoma patients.
Expansion of large granular lymphocytes in psoriatic erythroderma. A case report
Authors: Calvieri S , Fattorossi A.
Published: August 2023

A psoriasis patient developed erythroderma after the withdrawal of a self-administered chronic topical glucocorticoid therapy. A marked expansion of cells with the morphological and phenotypic features of large granular lymphocytes was noticed in peripheral blood. Functional investigations revealed that these cells responded poorly to polyclonal activators and exhibited antibody-dependent cellular cytotoxicity and natural killer activity. Blood abnormalities completely subsided in about two months in the absence of any cytostatic therapy and coincided with the recovery from the erythroderma and the spreading of classical psoriatic plaque lesions. This excluded an underlying malignant process. This patient represents the first report of a previously undescribed immunological disorder in psoriatic erythroderma.
Ultrastructural aspects of melanization of hamster Ab amelanotic melanoma in primary cell culture
Authors: Bomirski A , Słomiński A.
Published: August 2023

When the hamster Ab amelanotic melanoma has been grown as subcutaneous transplants in hamsters, melanin and identifiable melanosomes have never been observed by electron microscopy. When the cells were placed in primary cell culture, melanosomes of a granular type which contained small amounts of melanin appeared during the first 24 hours of cell culture. As the cultures grew older, the number and degree of melanization of the melanosomes increased, and eventually after 3-5 days they were found in all melanoma cells.
Demonstration of leukotriene B4 in the scale extracts of psoriasis and inflammatory pustular dermatoses. Correlation with leukocyte chemotactic activity and C5a anaphylatoxin
Authors: Takematsu H , Terui T , Tagami H.
Published: August 2023

We carried out quantification of the levels of leukotriene B4 (LTB4), a highly potent cell membrane-derived leukocyte chemotactic factor, in scale extracts of psoriasis and related inflammatory dermatoses characterized by sterile subcorneal pustule formation by using radioimmunoassay. A small amount of LTB4 was demonstrable even in extracts from non-inflammatory stratum corneum, but larger amounts were detected in the scale extract from pustular psoriasis and in those from psoriasis vulgaris. There was a significant correlation between the LTB4 and C5a levels in scale extracts, suggesting that complement activation and generation of LTB4 are a closely related event in psoriatic lesions. However, in contrast to highly significant correlation noted between the amount of C5a and chemotactic activity for polymorphonuclear leukocytes (PMN) detectable in scale extracts, LTB4 levels correlated only marginally with the chemotactic activity.
IgE-mediated anaphylaxis to mustard
Authors: Widström L , Johansson SG.
Published: August 2023

A young woman had recurrent urticaria and angioneurotic edema following ingestion of mustard and mayonnaise. IgE-mediated allergy to mustard seeds and seeds of botanically related plants was confirmed by RAST.
Systemic treatment of mollusca contagiosa with inosiplex
Authors: Gross G , Jogerst C , Schöpf E.
Published: August 2023

The ensuing regression of mollusca contagiosa in 7 of 9 children, 6 of whom were suffering from atopic dermatitis, was observed during systemic treatment with inosiplex. In our report the involutional process of mollusca contagiosa did not differ clinically from the inflammatory course observed in spontaneous healing. It is supposed that inosiplex enhances underlying defective immunological mechanisms which lead to a restoration of the host defence.
Effective Houses: Property Rights and Settlement in Iron Age Eastern Norway
Authors: Gjerpe Lars Erik
Published: August 2023

This book examines property rights, settlement structure and social organization in Norway’s Østlandet in the Iron age (500 BC–AD 1050). Inspired by ethnographical and anthropological studies, a model of a stateless, agrarian and hierarchical society with socially based rights to land is presented. In this model, where there are no territorially embedded rights, society is better represented as a heterarchy or anarchy than as a hierarchy. Power in society was shared between the honoured warrior, the powerless leader and perhaps also the productive farmer. This model differs from that presented by standard Norwegian research, where the retrogressive method is combined with a belief in the stability and continuity of the farm. A critical study of Norwegian research history is therefore an essential part of this book. This study has also been able to make use of new and extensive settlement evidence gained from machine-stripping of topsoil from large areas in the past thirty years; this has shed new light on the issues discussed in the book related to building practices and the settlement pattern.
Vaginal Transection Versus Vaginal Entry Cuff Closure Technique Following Elective Abdominal Hysterectomy for Benign Lesions - A Prospective Comparative Study
Authors: Singh Mamta
Published: August 2023

Background: Total abdominal hysterectomy is most common performed gynaecological operation. There is no standard recommendation or guidelines regarding management of vaginal cuff. This study aimed to determine the advantages and disadvantages of vaginal transection versus vaginal entry technique following elective abdominal hysterectomies for benign lesions.
Methodology: This is a comparative study involving 180 women undergoing elective hysterectomy in Sparsh hospital, from 10 Jan 2015 to 10 Jan 2020. Patient was randomized to either transactional vaginal or vagina entry technique of cuff closure. In this, we compare Operating time, length of hospital stays, estimated blood loss, post operative discharge. Vaginal length, vaginal cuff infection and granulation after 6 weeks follow up time. A prospective study on all hysterectomies performed by the single senior surgeon at Sparsh hospital in order to eliminate possible differences in surgical techniques and abilities.
Result: We found in this study that operating time, blood loss, post operative discharge from vault is less in transection technique of vaginal cuff closure in comparison to vaginal entry technique. Febrile complain is more in vaginal entry cuff group patients. Hospital stay is long in vaginal entry technique patients. There is no difference in post operative vaginal length in both the techniques. Transection technique is easy to perform. 
Conclusion: Transection cuff closure technique is better than vaginal entry technique.
STRUCTURAL FEATURES OF THE BONE TISSUE OF THE LOWER JAW
Authors: Pykalyuk Vasyl , Mostoviy Semyon , Lavrenyuk Volodymyr
Published: August 2023

The review considers the features of morphogenesis of the lower jaw, its diﬀ erences in comparison with tubular bones. Its embryogistogenesis, remodeling processes, osteogenic potential of mesenchymal stem cells are described. The features of the cytological structure of the cellular osteoblastic, osteocyte and osteoclast clusters are shown, their functional role is cleared. Its posttranslating modiﬁ cations are presented as a result of intermolecular stitching and that hydroxylation of lysine, which are the most important determinant of the knocking of cogagen, determining the strength and elasticity of the lower jaw.
Antibacterial, anti-adhesive and anti-biofilm-forming activity of plant complexes against periodontopathogenic bacteria in vitro
Authors: Nosova MA , Latif II , Kraeva LA , Khamdulaeva GN , Sharov AN , Kopetskiy IS , Eremin DA , Postnikova EV , Postnikov MA
Published: August 2023

Periodontitis is a problem urgent in Russia and throughout the world in general. Because of the dynamically changing flora causing this diseases, the treatment methods designed against it should be adapted on a regular basis. The classic approach to arresting development of the acute process relies on 0.2–0.12% chlorhexidine, a chemical antiseptic, but after 3 weeks of use, its efficacy drops drastically because pathogenic flora adjusts thereto. In the recent years, plantbased complexes with antiseptic properties have shown their capacity to challenge the classic approach. Obviously, efficacy of active ingredients depends on the form of the final product. The marker of periodontitis in the oral cavity is Staphylococcus aureus. Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii have virulence markers that are copathogens for periodontitis. This study aimed to find plant-based preparations capable of eliminating the said microbes and Streptococcus mitis, Streptococcus oralis, Streptococcus salivarius, Enterococcus faecalis. We compared antibacterial, adhesion and biofilm formation preventing properties of Phytodent plant-based products in various forms: water solution, water-alcohol solution, oil solution, gel. Long exposure form — gel — proved to be the most effective in terms of the properties tested. Products with synthetic and plant-based antiseptics, as well as those with plant-based antiseptics in maximum concentration (elixir), had comparable efficacy. Water and oil solutions are less effective because of the lower active ingredient concentration and relatively brief exposure. Our results support the results of clinical studies dedicated to the use of Phytodent products as oral care products in the context of periodontitis prevention and treatment. We recommend conducting further studies comparing compositions, cross- and comparative studies investigating the effect of frequency of application and time of exposure, such studies registering titers of active ingredient concentrations, and with subjects thereof including mixed biofilms.
Strategy The principal's Leadership Style in Implementing “Merdeka Belajar” in Schools
Authors: Mastur Mastur
Published: August 2023

Curriculum changes are part of improving the existing education system in Indonesia. Principal leadership has an important role and position in achieving educational goals. This study aims to discuss the principal's leadership style in implementing "merdeka belajar" in schools. This research uses the literature study method, which collects materials from books, journals, articles, and other sources related to the principal's leadership strategy in realizing Independent Learning in schools. The study results show that implementing the independent curriculum makes teachers more professional through various coaching and training. The principal carries out his role as a mediator and motivator for teacher participation in curriculum training. The principal also acts as a participant in regular meetings or discussions. The principal also supervises evaluators in implementing the independent curriculum. The factor faced by school principals is the lack of smoothness of the internet network as a means for teachers to use technology in learning. School principals consider the expected results of the theories in the research in making decisions to answer problems and improve the quality or quality of education by implementing an independent curriculum.
A IMPORTÂNCIA DO COMPLIANCE NO COMBATE À CORRUPÇÃO NA ADMINISTRAÇÃO PÚBLICA BRASILEIRA
Authors: Castro Ester Ariel Fonseca de , Santana Geovana Mendes de , Rodrigues Stephanie da Silva , Luiz Fernanda Gouvêa
Published: August 2023

O presente artigo tem por objetivo analisar a importância do Compliance no combate à corrupção na administração pública brasileira. Desta forma, a pesquisa desenvolvida descreve como o tema pode abrandar a corrupção no Brasil. Adota-se para a formulação e estruturação científica desta pesquisa, artigos científicos e monografias dos últimos 5 (cinco) anos, com abordagem qualitativa e dados bibliográficos, com o intuito de responder à pergunta-problema: “como o Compliance ajuda a diminuir a corrupção na administração pública no Brasil?”. Tais artigos e monografias foram selecionados e analisados de acordo com critérios estabelecidos pela equipe. Por mais, com a conclusão deste estudo, constatou-se que o Programa de Integridade e/ou Compliance, quando presente na Administração Pública, torna-se imprescindível para o combate à corrupção.
CONSEQUÊNCIAS DA AUSÊNCIA DE TERAPIA TROMBOLÍTICA EM PACIENTES BOA-VISTENSES PÓS ACIDENTE VASCULAR CEREBRAL AGUDO
Authors: Mello Higor de Andrade , Silva Esther Areia , Souza Iara Leão Luna de
Published: August 2023

O acidente vascular cerebral (AVC) consiste na interrupção do fluxo sanguíneo para áreas cerebrais. Possui diversos fatores de risco e representa motivo de incapacidade e óbito no mundo. Como tratamento, usam-se trombolíticos que reestabelecem o fluxo sanguíneo cerebral pela dissolução do coágulo. Infelizmente, muitos pacientes ainda não recebem o medicamento. Diante disso, esse trabalho visa compreender o prognóstico dos pacientes que fizeram uso da terapia trombolítica e dos que não fizeram, na cidade de Boa Vista, depois da pandemia por COVID-19. O trabalho tem aprovação do Comitê de Ética em Pesquisa (CEP) da Universidade Estadual de Roraima, sob o parecer de número 5.453.516. Realizou-se uma pesquisa qualitativa através de entrevista com neurologistas para verificar o andamento clínico dos pacientes durante a internação na fase aguda. Nesse contexto, verificou-se que até certo período era incomum o uso de trombolíticos devido sua indisponibilidade, isso dificultava a recuperação dos pacientes, corroborando mau prognóstico. Adicionalmente, torna-se oneroso à família um paciente dependente. Atualmente existem fármacos disponíveis, assim, o grande gargalo atual é conscientizar a população para identificar os sintomas para que ocorra tratamento imediato. Dessa forma, com base nos resultados obtidos, será possível traçar novas estratégias para que menos pessoas sejam prejudicadas terapeuticamente.
Energías alternas en Zacatecas: Una nueva metodología para evaluar la competitividad territorial
Authors:   Tecnológico Universitario de Aguascalientes, Esparza Santos Luisa Fernanda , Pedroza Ramírez Ángel David ,   Tecnológico Universitario de Aguascalientes
Published: August 2023

Se considera como energías alternas a todas aquellas que provienen de los recursos naturales. En el esfuerzo por su implementación surge un nuevo término llamado competitividad territorial. Este artículo presenta una implementación de una nueva metodología de análisis de competitividad territorial del estado de Zacatecas en la adopción de las siguientes energías alternas: eólica, solar, geotérmica e hidráulica. La metodología descrita se basa en tres perspectivas contables: ambiental, humana y económico-financiera. Para la perspectiva ambiental, se analizaron algunas variables relacionadas con las energías en mención y se propusieron los mejores municipios para cada energía. La perspectiva humana analizó la existencia de mano de obra calificada en México para la implementación de energías alternas. Finalmente, en la perspectiva económico-financiera, se analizó si es posible el destinar recurso para estos fines basados en el presupuesto para dicho estado. Esta investigación concluye con una lista de los municipios más aptos para las energías mencionadas que, bajo esta nueva metodología de análisis, propone a Zacatecas con competitividad territorial para la adopción de energías alternas.
Aprendizaje, identidad y convivio: significados construidos por estudiantes de una experiencia de teatro aplicado a la educación
Authors: Barrientos Lezcano Sebastián , Cadavid Valderrama César Augusto
Published: August 2023

Este artículo da cuenta de una investigación tendiente a comprender los significados construidos por estudiantes de Psicología de la experiencia de teatro aplicado a la educación en el curso de Teorías de la Personalidad de la Universidad Pontificia Bolivariana, en Medellín, Colombia. Como base teórica se tomó la psicología posracionalista y se empleó un enfoque cualitativo con una metodología narrativa. Se diseñó una técnica mixta que incluye la narración libre y el autoanálisis a partitr de elementos dramatúrgico-narrativos para reconocer la experiencia de teatro aplicado e identificar los elementos dramáticos de la experiencia de los estudiantes. La información fue sintetizada en matrices de análisis cualitativa, lo que permitió identificar tres categorías emergentes que dan cuenta de los hallazgos: el aprendizaje, la identidad y el convivio. Se halló que los significados se relacionan con la experiencia de aprendizaje, con los cuestionamientos y configuraciones sobre la propia identidad y con el encuentro que supone un ejercicio de creación teatral y su puesta en escena ante un público. Se concluye que la piscología postracionalista permite reflexionar sobre la experiencia humana y que el teatro aplicado se constituye como un lugar para la autoconstrucción del sujeto.
EDUCAÇÃO E SEXUALIDADE: PERCEPÇÃO DE ESCOLARES DO ENSINO MÉDIO SOBRE INFECÇÃO E PREVENÇÃO DO HIV
Authors: Oliveira Francisco Eliando Silva , Marques Regina Célia Pereira , Santos Pablo de Castro
Published: August 2023

A adolescência é a fase da vida caracterizada por profundas transformações que são próprias do processo de amadurecimento humano na construção de sua identidade intelectual e sexual, sendo esta, marcada, muitas vezes, pela atividade sexual desprotegida e gerando um problema de saúde pública com novos desafios éticos para a saúde e educação. A escola tem papel fundamental na prevenção de doenças, dentre as quais a AIDS, por orientar os/as adolescentes para o desenvolvimento de habilidades condicionantes ao exercício de uma vida saudável. Trata-se de um estudo exploratório descritivo com abordagem quanti-qualitativa que objetivou analisar a percepção de 75 alunos/as entre 14 e 19 anos de três escolas de ensino médio de um município do interior cearense, acerca dos desafios enfrentados pelos alunos/as na efetivação do conhecimento adquirido nesta etapa da educação básica sobre a transmissão e prevenção do vírus HIV. Os dados foram coletados em fevereiro de 2020, por meio de questionário estruturado com perguntas discursivas e fechadas de múltipla escolha, respeitando às considerações éticas propostas nas Resoluções 466/12 e 510/16 e aprovado no Comitê de Ética da UERN. Os dados revelaram que a escola é a principal fonte de transmissão de informações sobre prevenção ao HIV, tratando o assunto principalmente nas aulas da disciplina de biologia. Os/as alunos/as, em sua totalidade, reconheceram o preservativo como uma forma preventiva ao vírus, apesar que muitos consideraram o acesso limitado. No estudo, mais da metade dos escolares relataram que a exposição ao vírus HIV se dá por falta de consciência e atitude própria dos/as adolescentes, onde um considerável percentual se julga mal informado e possui dúvidas relacionadas ao tema. Concluiu-se que há a necessidade de campanhas preventivas específicas para a desconstrução da falsa percepção de informação efetiva desta população, sendo a escola o ambiente privilegiado para a construção de diálogos cooperativos sobre saúde sexual e a prevenção do vírus HIV.
Entendendo o transtorno bipolar
Authors: Moreno Ricardo Alberto , Del Porto Jose Alberto
Published: August 2023

O transtorno bipolar é uma doença que se caracteriza pela alteração no humor do padecente. Essas alterações se alternam por períodos de humor exaltado com períodos de depressão. Ainda é desconhecido o fator que desencadeia o transtorno bipolar, mas acredita-se que fatores externos, meio ambiente, hormônios, hereditariedade, peculiaridades biológicas, entre outros fatores que possam fazer com que a doença se desenvolva. O padecente de transtorno bipolar apresentam fácil distração, hiperatividade, aumento de energia, fala em excesso, autoestima muito alta, compulsão alimentar ou de bebidas alcoólicas, pouco controle de temperamento, entre outros.
A saúde mental do médico
Authors: Lippi José Raimundo da Silva , Baldassin Sergio Pedro , Alves Hamer Nastasy Palhares
Published: August 2023

Os médicos têm a missão de cuidar de seus pacientes, mas quem cuida também precisa de cuidados. Por conta de toda a pressão do dia-a-dia os médicos chegam a um nível de estresse muito alto que pode desencadear diversas doenças como depressão, dependência química e, consequentemente, o suicídio. Segundo estudos divulgados os médicos se suicidam cinco vezes mais do que o resto da população. O Conselho Regional de Medicina do Estado de São Paulo divulgou um estudo em que diz que em 2012 entre as causas externas de morte de médicos em São Paulo, o suicídio aparece em segundo lugar: 21% no caso das mulheres e 18% em homens.
Transtornos mentais e suicídio na adolescência
Authors: Moraes César de , Barbirato Fábio , Silva Júnior Estácio Amaro da
Published: August 2023

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