Defective expression of apoptosis‐related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation

Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis‐related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)‐based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIM_EL, FAS, FASL, A1, BCL2, BCLX_L, CFLIP_L and CIAP2 genes were up‐regulated after AHSCT. With the exception of BIK, BIM_EL and A1, all genes reached levels similar to controls at day + 720 post‐transplantation. Furthermore, in these patients, we observed increased CD8⁺ Fas⁺ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIP_L and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post‐AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLX_L and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl‐2 expression before transplantation. At 1 year post‐AHSCT, expression of Bak, Bim, Bcl‐2, Bcl‐xL and cFlip‐L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis‐related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re‐establishment of immune tolerance during the first 2 years post‐transplantation.     

HLA‐A,HLA‐B,HLA‐DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China

Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA‐A, HLA‐B and HLA‐DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA‐A, 30 HLA‐B and 13 HLA‐DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A‐B‐DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02‐B*46‐DRB1*09, A*33‐B*58‐DRB1*03 and A*30‐B*13‐DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A‐B, 106 B‐DRB1, 54 A‐DRB1 haplotypes with positive LD, in which 51 A‐B, 60 B‐DRB1, 32 A‐DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA‐A, HLA‐B and HLA‐DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.     

CT‐measured bone attenuation in patients with chronic obstructive pulmonary disease: Relation to clinical features and outcomes

Osteoporosis is highly prevalent in chronic obstructive pulmonary disease (COPD) patients and has been related to several clinical features. However, most studies have been in relatively small COPD cohorts. Therefore, the objectives of this study were to compare bone attenuation measured on low‐dose chest computed tomography (CT) between COPD subjects and smoker and nonsmoker controls, and to relate bone attenuation to clinical parameters, inflammatory biomarkers, and outcomes in a large, well‐characterized COPD cohort. We studied 1634 COPD subjects, 259 smoker controls, and 186 nonsmoker controls who participated in a large longitudinal study (ECLIPSE). We measured bone attenuation, extent of emphysema, and coronary artery calcification (Agatston score) on baseline CT scans, and clinical parameters, inflammatory biomarkers, and outcomes. Bone attenuation was lower in COPD subjects compared with smoker and nonsmoker controls (164.9 ± 49.5 Hounsfield units [HU] versus 183.8 ± 46.1 HU versus 212.1 ± 54.4 HU, p < 0.001). Bone attenuation was not significantly different between COPD subjects and smoker controls after adjustment for age, sex, and pack‐years of smoking. In the COPD subjects, bone attenuation correlated positively with forced expiratory volume in 1 second (FEV₁, r = 0.062, p = 0.014), FEV₁/forced vital capacity (FVC) ratio (r = 0.102, p < 0.001), body mass index (r = 0.243, p < 0.001), fat‐free mass index (FFMI, r = 0.265, p < 0.001), and C‐reactive protein (r = 0.104, p < 0.001), and correlated negatively with extent of emphysema (r = ?0.090, p < 0.001), Agatston score (r = ?0.177, p < 0.001), and interleukin‐8 (r = ?0.054, p = 0.035). In a multiple regression model, older age, lower FFMI and higher Agatston score were associated with lower bone attenuation. Lower bone attenuation was associated with higher exacerbation (r = ?0.057, p = 0.022) and hospitalization (r = ?0.078, p = 0.002) rates but was not associated with all‐cause mortality. In conclusion, CT‐measured bone attenuation was lower in COPD subjects compared with nonsmoker controls but not compared with smoker controls, after adjustment for age, sex, and pack‐years of smoking. In the COPD subjects, bone attenuation was associated with age, body composition, and coronary artery calcification but was not associated with all‐cause mortality.     

Camel-related pancreatico-duodenal injuries: a report of three cases and review of literature

Background

Human pancreatico-duodenal injuries caused by camels are extremely rare.

Objective

We report three patients who sustained camel-related pancreatico-duodenal injuries and review the literature on this topic.

Results

A 32-year camel caregiver was kicked by a camel which then stepped on his abdomen trying to kill him. The patient''s abdomen was soft and lax. CT scan of the abdomen showed free retroperitoneal air. Laparotomy revealed a complete tear of the anterior wall of the second part of duodenum which was primarily repaired. A 40-year camel caregiver was directly kicked into his abdomen by a camel. He developed traumatic pancreatitis which was treated conservatively. A 31-year-old male fell down on his abdomen while riding a camel. Abdominal examination revealed tenderness and guarding. Abdominal CT Scan showed complete transection of the neck of the pancreas which was confirmed by laparotomy. The patient had distal pancreatectomy with preservation of the spleen. All patients were discharged home in good condition.

Conclusion

These cases demonstrate the misleading presentation of the camel-realted pancreatico-duodenal injuries and their unique mechanism of injury.     

Weight reduction improves markers of hepatic function and insulin resistance in type-2 diabetic patients with non-alcoholic fatty liver

Objective

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing dramatically affecting up to 30% of the population worldwide. At present, treatment options are limited and pharmacological management of NAFLD has had disappointing results. Some of the best available evidence to improve NAFLD concerns lifestyle modification.

Objective

To detect the degree of weight reduction needed to improve the markers of hepatic function and insulin resistance in type-2 diabetics with NAFLD.

Methods

One hundred type-2 diabetic male patients with NAFLD were included into this study and divided into two equal groups. Group (A) received aerobic exercise training in addition to diet regimen. Group (B) received no treatment intervention.

Results

There was a 26.99%, 40.8%, 33.81%, 32.73%, 37.8% and 15 % reduction in mean values of Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma - Glutamyltransferase (GGT) and Homeostasis Model Assessment-Insulin Resistance-index (HOMA-IR) and BMI respectively in group (A) at the end of the study. While there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment.

Conclusion

About 15 % reduction in BMI is effective to improve the liver condition and insulin resistance in type-2 diabetics with NAFLD.     

Proximal tubular cells contain a phenotypically distinct,scattered cell population involved in tubular regeneration

Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre‐existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24‐, CD133‐, and vimentin‐positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent ‘normal’ proximal tubular cells, these CD24‐positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co‐localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24‐positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24‐positive – indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24‐positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo – arguing against the notion that these cells represent a pre‐existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High Imminent Vertebral Fracture Risk in Subjects With COPD With a Prevalent or Incident Vertebral Fracture

Subjects with chronic obstructive pulmonary disease (COPD) have an increased risk of vertebral fractures (VFs); however, VF incidence is largely unknown. Therefore, the aim of our study was to determine the incidence of new and/or worsening VF in subjects with COPD. Smokers and subjects with COPD (GOLD II–IV) from the ECLIPSE study with complete set of chest CT scans (baseline and 1‐ and 3‐year follow‐up) to evaluate vertebrae T₁ down to L₁ were included. If a VF was diagnosed on the last scan, detailed VF assessment of the previous scans was performed. VFs were scored according to the method of Genant as mild, moderate, or severe. Main outcome measure was the cumulative incidence of new and/or worsening VF at subject level, within 1 and 3 years. Of 1239 subjects (mean age 61 years, 757 males [61%], 999 subjects with COPD), 253 (20.5%) had ≥1 prevalent VF. The cumulative incidence of VFs was 10.1% within 1 year and 24.0% within 3 years. After adjustment for age, sex, body mass index (BMI), pack‐years, and smoking status, prevalence and incidence were similar between smokers and COPD GOLD stages. Within 1 year, 29.2% of the subjects with a prevalent VF had an incident VF, compared with 5.1% in absence of prevalent VF (hazard ratio [HR] = 5.1; 95% confidence interval [CI] 3.6–7.4) and 58.5% versus 15.0% within 3 years (HR = 3.6; 95% CI 2.9–4.6). The incidence of VF was higher with increasing number and severity of prevalent VFs. Among subjects having an incident VF within the first year, 57.3% had a subsequent VF within the next 2 years. In this study, more than half of the smokers and subjects with COPD with a prevalent VF or an incident VF within the first year sustained a subsequent VF within 3 years. The 3‐year risk was even higher in the presence of multiple or severe prevalent VFs. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Role of prostaglandin/cAMP pathway in the diuretic and hypotensive effects of purified fraction of Maytenus ilicifolia Mart ex Reissek (Celastraceae)

Ethnopharmacological relevance

Although Maytenus ilicifolia is used in Brazilian folk medicine as a diuretic drug, no study has been conducted to this date in order to evaluate this ethnopharmacological statement. So, the aim of this study was to evaluate possible mechanisms involved in acute diuretic activity of the ethanolic supernatant of the infusion (SEI) obtained from Maytenus ilicifolia and to assess its relationship with a hypotensive activity by a bioassay-guided fractionation using normotensive Wistar rats.

Material and methods

The preparation obtained from the infusion (SEI) and their respective fractions (Fr·H₂O and Fr·EtOAc) were orally administered in a single dose to rats. The urine excretion rate, pH, density, conductivity and content of Na⁺, K⁺, Cl⁻ and HCO₃⁻ were measured in the urine of saline-loaded animals. Samples of the concentration of electrolytes, urea, creatinine, aldosterone, vasopressin and angiotensin converting enzyme (ACE) activity were evaluated in collected serum. The hypotensive activity and the involvement of nitric oxide, bradykinin and prostaglandin/cAMP pathway in the hypotensive and diuretic effects were also determined.

Results

Water and Na⁺ excretion rate were significantly increased by Fr·EtOAc and the arterial pressure was significantly reduced, while the urinary excretion of potassium and chloride were reduced. Pre-treatment with indomethacin or DDA (2′,5′-dideoxyadenosine) significantly reduced the hypotensive and diuretic activity observed. All other parameters evaluated were not affected by any treatment.

Conclusion

The present study reveals that Fr·EtOAc obtained from Maytenus ilicifolia may present compounds responsible for diuretic and hypotensive activities, and this effect, could involve the prostaglandin/cAMP pathway.     

The carcinogenicity of smegma: debunking a myth

BACKGROUND: Smegma is widely believed to cause penile, cervical and prostate cancer. This nearly ubiquitous myth continues to permeate the medical literature despite a lack of valid supportive evidence. METHODS: A historical perspective of medical ideas pertaining to smegma is provided, and the original studies in both animals and humans are reanalysed using the appropriate statistical methods. RESULTS: Evidence supporting the role of smegma as a carcinogen is found wanting. CONCLUSIONS: Assertions that smegma is carcinogenic cannot be justified on scientific grounds.