Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens

The "Adipo-Cerebral" Dialogue in Childhood Obesity: Focus on Growth and Puberty. Physiopathological and Nutritional Aspects

Overweight and obesity in children and adolescents are overwhelming problems in western countries. Adipocytes, far from being only fat deposits, are capable of endocrine functions, and the endocrine activity of adipose tissue, resumable in adipokines production, seems to be a key modulator of central nervous system function, suggesting the existence of an “adipo-cerebral axis.” This connection exerts a key role in children growth and puberty development, and it is exemplified by the leptin–kisspeptin interaction. The aim of this review was to describe recent advances in the knowledge of adipose tissue endocrine functions and their relations with nutrition and growth. The peculiarities of major adipokines are briefly summarized in the first paragraph; leptin and its interaction with kisspeptin are focused on in the second paragraph; the third paragraph deals with the regulation of the GH-IGF axis, with a special focus on the model represented by growth hormone deficiency (GHD); finally, old and new nutritional aspects are described in the last paragraph

Structural Characterization of the Highly Restricted Down Syndrome Critical Region on 21q22.13: New KCNJ6 and DSCR4 Transcript Isoforms

Down syndrome (DS) is caused by trisomy of chromosome 21 and it is the most common genetic cause of intellectual disability (ID) in humans. Subjects with DS show a typical phenotype marked by facial dysmorphisms and ID. Partial trisomy 21 (PT21) is a rare genotype characterized by the duplication of a delimited chromosome 21 (Hsa21) portion and it may or may not be associated with DS diagnosis. The highly restricted Down syndrome critical region (HR-DSCR) is a region of Hsa21 present in three copies in all individuals with PT21 and a diagnosis of DS. This region, located on distal 21q22.13, is 34 kbp long and does not include characterized genes. The HR-DSCR is annotated as an intergenic region between KCNJ6-201 transcript encoding for potassium inwardly rectifying channel subfamily J member 6 and DSCR4-201 transcript encoding Down syndrome critical region 4. Two transcripts recently identified by massive RNA-sequencing (RNA-Seq) and automatically annotated on Ensembl database reveal that the HR-DSCR seems to be partially crossed by KCNJ6-202 and DSCR4-202 isoforms. KCNJ6-202 shares the coding sequence with KCNJ6-201 which is involved in many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells. DSCR4-202 transcript has the first two exons in common with DSCR4-201, the only experimentally verified gene uniquely present in Hominidae. In this study, we performed in silico and in vitro analyses of the HR-DSCR. Bioinformatic data, obtained using Sequence Read Archive (SRA) and SRA-BLAST software, were confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Sanger sequencing on a panel of human tissues. Our data demonstrate that the HR-DSCR cannot be defined as an intergenic region. Further studies are needed to investigate the functional role of the new transcripts, likely involved in DS phenotypes

Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens

Arthrodesis in the Charcot foot: a systematic review

The Charcot foot is a condition characterized by a progressive derangement of the foot. The type of deformity and patient clinical conditions will lead to the proper surgical approach among exostectomy, arthrodesis (through external and/or internal fixation) and amputation. Many authors report good clinical outcomes performing the arthrodesis in Charcot foot; however, the choice of the most appropriate hardware is still an issue. The aim of this study is to analyze the outcomes of different hardware in midfoot and hindfoot Charcot arthrodesis

A Novel GCK Large Genomic Rearrangement in a Patient with MODY-2 Detected by Clinical Exome Sequencing

Maturity-onset diabetes of the young (MODY) is a rare form of non-autoimmune diabetes with an autosomal dominant inheritance. To date, 14 genes have been reported as genetic basis of MODY. GCK gene, encoding the glucokinase enzyme, was the first MODY gene to be identified. GCK heterozygous inactivating variants cause the GCK-MODY or MODY2 subtype. However, partial or whole gene deletions have been rarely identified, showing it to be a rare cause of GCK-MODY. We reported the molecular evaluation of a Ukrainian patient with clinical diagnosis of MODY2. We performed the Next generation sequencing of the clinical exome using the Clinical Exome Solution® kit (SOPHiA Genetics), followed by the design of a 14 genes virtual panel related to the suggestive diagnosis of MODY. Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). The SALSA MLPA kit for MODY (MRC-Holland) was used for relative quantification of GCK exons. From the molecular evaluation, no pathogenic sequence variants were detected in the investigated genes. Copy Number Variation analysis was able to identify a large deletion involving the last three exons of the GCK gene. This result was confirmed by MLPA. To the best of our knowledge, the identified rearrangement has never been reported in the literature

Clinical use of a 180-day implantable glucose sensor improves glycated haemoglobin and time in range in patients with type 1 diabetes

Aims: This real-world study evaluated the changes in glycated haemoglobin (HbA1c) and continuous glucose monitoring (CGM) metrics associated with use of the implantable 180-day Eversense CGM System (Eversense) in patients with type 1 diabetes. Materials and methods: This was a prospective, multicentre, observational study among adult participants aged ≥18 years with type 1 diabetes across seven diabetes-care centres in Italy who had Eversense inserted for the first time. HbA1c was measured at baseline and at 180 days. Changes in time in range [TIR (glucose 70–180 mg/dL)], time above range [TAR (glucose >180 mg/dL)], time below range [TBR (glucose <70 mg/dL)] and glycaemic variability were also assessed. Data were also analysed by previous CGM use and by mode of insulin delivery. Results: One-hundred patients were enrolled (mean age 36 ± 12 years, mean baseline HbA1c 7.4 ± 0.92% [57 ± 10 mmol/mol]). Fifty-six per cent of patients were users of the continuous subcutaneous insulin infusion pump and 45% were previous users of CGM. HbA1c significantly decreased in patients after 180 days of sensor wear (−0.43% ± 0.69%, 5 ± 8 mmol/mol, P < 0.0001). As expected, CGM-naïve patients achieved the greatest reduction in HbA1c (−0.74% ± 0.48%, 8 ± 5 mmol/mol). TIR significantly increased and TAR and mean daily sensor glucose significantly decreased while TBR did not change after 180 days of sensor wear. Conclusions: Real-world clinical use of the Eversense CGM System for 180 days was associated with significant improvements in HbA1c and CGM metrics among adults with type 1 diabetes. The study is registered on clinicaltrials.gov (NCT04160156)

Microvascular complications identify a specific coronary atherosclerotic phenotype in patients with type 2 diabetes mellitus

Background: Patients with type 2 diabetes mellitus (T2DM) are considered as a homogeneous cohort of patients. However, the specific role of diabetic microvascular complications (DMC), in determining the features of coronary plaques is poorly known. We investigated whether the presence of DMC may identify a different phenotype of patients associated to specific clinical, angiographic, optical coherence tomography (OCT) features and different prognosis. Methods: We prospectively enrolled consecutive T2DM patients with obstructive coronary artery disease (CAD) at their first coronary event. Patients were stratified according to the presence or absence of DMC, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. OCT assessment of the culprit vessel was performed in a subgroup of patients. The incidence of major adverse cardiac events (MACEs) was assessed at follow-up. Results: We enrolled 320 T2DM patients (mean age 70.3 ± 8.8 years; 234 [73.1%] men, 40% acute coronary syndrome, 60% chronic coronary syndrome). Patients with DMC (172 [53.75%]) presented a different clinical and biochemical profile and, of importance, a higher prevalence of multivessel CAD (109 [63.4%] vs. 68 [45.9%], p = 0.002). At OCT analysis, DMC was associated to a higher prevalence of large calcifications and healed plaques and to a lower prevalence of lipid plaques. Finally, MACEs rate was significantly higher (25 [14.5%] vs. 12 [8.1%], p = 0.007) in DMC patients, mainly driven by a higher rate of planned revascularizations, and DMC predicted the occurrence of MACEs (mean follow-up 33.4 ± 15.6 months). Conclusions: The presence of DMC identifies a distinct diabetic population with more severe CAD but with a more stable pattern of coronary atherosclerosis

Spatial Reorganization of Liquid Crystalline Domains of Red Blood Cells in Type 2 Diabetic Patients with Peripheral Artery Disease

In this work, we will investigate if red blood cell (RBC) membrane fluidity, influenced by several hyperglycemia-induced pathways, could provide a complementary index of HbA1c to monitor the development of type 2 diabetes mellitus (T2DM)-related macroangiopathic complications such as Peripheral Artery Disease (PAD). The contextual liquid crystalline (LC) domain spatial organization in the membrane was analysed to investigate the phase dynamics of the transition. Twenty-seven patients with long-duration T2DM were recruited and classified in DM, including 12 non-PAD patients, and DM + PAD, including 15 patients in any stage of PAD. Mean values of RBC generalized polarization (GP), representative of membrane fluidity, together with spatial organization of LC domains were compared between the two groups; p-values < 0.05 were considered statistically significant. Although comparable for anthropometric characteristics, duration of diabetes, and HbA1c, RBC membranes of PAD patients were found to be significantly more fluid (GP: 0.501 +/- 0.026) than non-PAD patients (GP: 0.519 +/- 0.007). These alterations were shown to be triggered by changes in both LC microdomain composition and distribution. We found a decrease in Feret diameter from 0.245 +/- 0.281 mu m in DM to 0.183 +/- 0.124 mu m in DM + PAD, and an increase in circularity. Altered RBC membrane fluidity is correlated to a spatial reconfiguration of LC domains, which, by possibly altering metabolic function, are associated with the development of T2DM-related macroangiopathic complications