Sodium-glucose cotransporter 2 inhibitors: A comprehensive review from cells to bedside

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) are oral medications approved for type 2 diabetes mellitus. Interestingly, during recent years, they have been promisingly considered as new medications for cardiovascular and kidney diseases. However, the mechanisms underlying these new benefits are not fully understood. Thanks to the discovery of multiple modes of action, the simple picture about mechanisms of action of SGLT2is has become more and more complex. Besides their effects in diabetes, there is increasing evidence for their beneficial effects in heart failure and chronic kidney diseases. In addition, many studies have provided evidence for the fruitful effects of SGLT2is in atherosclerotic cardiovascular disease. In this study, we present mounting evidence for the complex action modes of SGLT2is and their current applications in clinical practice.     

The evaluation of cognitive functions with P300 test for chronic obstructive pulmonary disease patients in attack and stable period

OBJECTIVES: Hypoxia, in chronic obstructive pulmonary disease (COPD), leads to a decrease in cerebral perfusion and an impairment of some cognitive abilities. We aimed to investigate the relation between arterial blood gas analysis (ABA) and pulmonary function test (PFT) parameters with cognitive function of COPD patients during attack and stable period. PATIENTS AND METHODS: ABA, PFT, P300 tests of 30 patients in stabilized period and 30 patients in attack, and 17 healthy controls were evaluated. RESULTS: When both COPD groups and controls were compared, it was seen that latency of P300 was shorter in the control group (p<0.001), but there was no difference between COPD groups (p>0.05). P300 amplitude measures were lower in both COPD groups than control group, but it was not statistically significant (p>0.05). When we compared the measures of attack group, we saw that arterial oxygen tension (PaO(2)), arterial oxygen saturation (SaO(2)), forced expiratory volume in 1s (FEV(1)), FEV(1)/forced vital capacity (FVC) values increased (p<0.001), and P300 latency shortened (p<0.05) in attack group during stable period. P300 latency correlated significantly with PaO(2) (r=-0.557, p<0.001), SaO(2) (r=-0.424, p<0.001), FEV(1) (r=-0.441, p<0.001), FEV(1)/FVC (r=-0.477, p<0.001) values, and age (r=0.329, p<0.05). P300 amplitude is only correlated with PaO(2) (r=0.236, p<0.05). CONCLUSION: Longer latency of P300 appears to be an expected sequel of COPD. P300 test can be considered as a potential objective marker of cognitive impairment.     

CCM2 expression during prenatal development and adult human neocortex

Cerebral cavernous malformation (CCM) is one of the most common types of vascular malformations of the central nervous system, affecting nearly one in 200 people. CCM lesions are characterized by grossly dilated vascular channels lined by a single layer of endothelium. Genetic linkage analyses have mapped three CCM loci to CCM1, CCM2 and CCM3. All three causative genes have now been identified allowing new insights into CCM pathophysiology. We focused on the CCM2 protein that might take place in blood vessel formation; we report here the expression patterns of CCM2 in prenatal development and adult human neocortex by means of immunohistochemistry and Western blot analysis. CCM2 was obviously detected in vascular endothelium and neuroglial precursor cells during development and also observed in arterial endothelium, neurons, some of the glial cells in adult neocortex. The expression patterns suggest that it could be one of the arterial markers whether this is a cause or a consequence of an altered vascular identity. CCM2 might play a role during vasculogenesis and angiogenesis during human brain development. Furthermore, with this study, CCM2 have been described for the first time in developing human neocortex.     

Letter to the Editor: Increased Risk of Revision,Reoperation, and Implant Constraint in TKA After Multiligament Knee Surgery

Clinical Orthopaedics and Related Research® -     

Spindle cell melanoma coexisting with chronic lymphocytic leukemia/small lymphocytic lymphoma: a rare collision tumor in multiple sites

A strong association has been reported between chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and malignant melanoma (MM). In rare cases of MM, lymphoid malignancies may be detected incidentally during sentinel lymph node biopsies. In this case, we found a unique collision of MM and CLL infiltration in the skin. An 88-year-old male patient presented with a mass on the nasal root. Histopathological examination of the skin biopsy specimen revealed a deeply infiltrative, atypical spindle cell proliferation in the background of a collagenous stroma. Accompanying this lesion, there were foci of monotonous lymphoid cell populations involving skin appendages. In the immunohistochemical studies, the spindle cells were diffusely positive for S100, and focally positive for Melan-A and HMB45; the lymphoid cells were positive for CD20, CD5, and Bcl-2 and negative for CD3, Bcl-6, CD10, and Cyclin D1. Histopathological and immunohistochemical findings were consistent with diagnoses of spindle cell melanoma and CLL. Interestingly, these two tumors together in their same morphological appearance were confirmed in a subsequent liver biopsy. Active skin surveillance of patients with CLL may be important to detect MM at an early stage that correlates with a better prognosis.     

A prospective cohort study on the prediction of the diagnosis-to-delivery time in preeclamptic pregnancies: should the sFlt-1/PlGF ratio be added to routine evaluations?

Purpose

To analyze the clinical and laboratory factors that potentially affect the diagnosis-to-delivery time in preeclamptic pregnancies.

Methods

In this cross-sectional study, we followed 24 early onset preeclampsia (E-PE) and 26 late-onset preeclampsia (L-PE) cases. Maternal serum samples were obtained at the time of diagnosis and stored at ??80 °C until ELISA analysis for soluble fms-like tyrosine kinase-1 (SFlt-1) and placental growth factor (PlGF) levels.

Results

The median follow-up duration was 68 (1–339) h in the E-PE group and 330 (7–1344) h in the L-PE group. Maternal mean arterial pressure (MAP) at hospitalization was the strongest variable, and the sFlt-1/PlGF ratio added significantly to the Cox regression model. In the E-PE cases, the median sFlt-1/PlGF ratio was significantly higher in the subgroup with a follow-up duration?>?48 h than in the subgroup of cases with a follow-up duration?≤?48 h (5109 vs. 2080; p?=?0.038), and none of the seven cases with an sFlt-1/PlGF ratio?≥?75th percentile delivered during the first 48 h. Neither the 24-h proteinuria nor the gestational age at diagnosis added to the predictive power of the MAP at hospitalization.

Conclusion

Incorporation of the sFlt-1/PlGF ratio to the routine evaluation of preeclamptic pregnancies may help in the prediction of progression and management planning.

     

AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer

Recent gene profiling studies have identified a new breast cancer subtype, the basal-like group, which expresses genes characteristic of basal epithelial cells and is associated with poor clinical outcomes. However, the genes responsible for the aggressive behavior observed in this group are largely unknown. Here we report that the small heat shock protein alpha-basic-crystallin (alphaB-crystallin) was commonly expressed in basal-like tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. We also demonstrate that overexpression of alphaB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, alphaB-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing alphaB-crystallin by RNA interference inhibited these abnormalities. alphaB-Crystallin overexpression also induced EGF- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the MAPK kinase/ERK (MEK/ERK) pathway. Moreover, the transformed phenotype conferred by alphaB-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing alphaB-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that alphaB-crystallin is a novel oncoprotein expressed in basal-like breast carcinomas that independently predicts shorter survival. Our data also implicate the MEK/ERK pathway as a potential therapeutic target for these tumors.