Synaptic vesicle protein 2A: basic facts and role in synaptic function

In recent years, there has been considerable interest in determining the function of synaptic vesicle protein 2A and its role as a target for antiepileptic drugs. Although it is known that synaptic vesicle protein 2A is involved in normal synaptic vesicle function, its participation in synaptic vesicle cycling and neurotransmitter release in normal and pathological conditions is unclear. However, the experimental evidence suggests that synaptic vesicle protein 2A could be a vesicular transporter, regulate synaptic exocytosis as a gel matrix, or modulate synaptotagmin‐1 activity. This review describes and discusses the participation of synaptic vesicle protein 2A in synaptic modulation in normal and pathological conditions.     

Effect of Hydrogen Peroxide at 35% on the Morphology of Enamel and Interference in the De-remineralization Process: An In Situ Study

SUMMARY This study evaluated the microhardness and histomorphology of bovine enamel when 35% hydrogen peroxide is used. A total of 44 specimens were adapted to removable devices used by 11 individuals subjected to dental caries challenge. A decrease in microhardness was observed for all groups after the cariogenic challenge. Microscopic analysis revealed that fragments subjected to cariogenic challenge associated with bleaching had more intense superficial histologic changes, but the depth of the lesions remained unchanged. It was concluded that 35% hydrogen peroxide enhanced the reduction in hardness and histomorphologic changes in the enamel surface exposed to cariogenic challenge.     

Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease

Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.     

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

Monocytes have a crucial role in both proinflammatory and anti-inflammatory phenomena occurring during sepsis. Monocyte recruitment and activation are orchestrated by the chemokine receptors CX3CR1 and CCR2 and their cognate ligands. However, little is known about the roles of these cells and chemokines during the acute phase of inflammation in sepsis. Using intravital microscopy in a murine model of polymicrobial sepsis, we showed that inflammatory Ly6C^high monocytes infiltrated kidneys, exhibited altered motility, and adhered strongly to the renal vascular wall in a chemokine receptor CX3CR1-dependent manner. Adoptive transfer of Cx3cr1-proficient monocyte-enriched bone marrow cells into septic Cx3cr1-depleted mice prevented kidney damage and promoted mouse survival. Modulation of CX3CR1 activation in septic mice controlled monocyte adhesion, regulated proinflammatory and anti-inflammatory cytokine expression, and was associated with the extent of kidney lesions such that the number of lesions decreased when CX3CR1 activity increased. Consistent with these results, the pro-adhesive I249 CX3CR1 allele in humans was associated with a lower incidence of AKI in patients with sepsis. These data show that inflammatory monocytes have a protective effect during sepsis via a CX3CR1-dependent adhesion mechanism. This receptor might be a new therapeutic target for kidney injury during sepsis.     

Low vs Standard Pressures in Gynecologic Laparoscopy: a Systematic Review

Background:

The optimal intraperitoneal pressure during laparoscopy is not known. Recent literature found benefits of using lower pressures, but the safety of doing abdominal surgery with low peritoneal pressures needs to be assessed. This systematic review compares low with standard pneumoperitoneum during gynecologic laparoscopy.

Database:

We searched Medline, Embase, and the Cochrane Library for randomized controlled trials comparing intraperitoneal pressures during gynecologic laparoscopy. Two authors reviewed references and extracted data from included trials. Risk ratios, mean differences, and standard mean differences were calculated and pooled using RevMan5. Of 2251 studies identified, three were included in the systematic review, for a total of 238 patients. We found a statistically significant but modest diminution in postoperative pain of 0.38 standardized unit based on an original 10-point scale (95% confidence interval [CI], –0.67 to –0.08) during the immediate postoperative period when using low intraperitoneal pressure of 8 mm Hg compared with ≥12 mm Hg and of 0.50 (95% CI, –0.80 to –0.21) 24 hours after the surgery. Lower pressures were associated with worse visualization of the surgical field (risk ratio, 10.31; 95% CI, 1.29–82.38). We found no difference between groups over blood loss, duration of surgery, hospital length of stay, or the need for increased pressure.

Conclusion:

Low intraperitoneal pressures during gynecologic laparoscopy cannot be recommended on the behalf of this review because improvement in pain scores is minimal and visualization of the surgical field is affected. The safety of this intervention as well as cost-effectiveness considerations need to be further studied.     

Human epidermal growth factor receptor 3 in head and neck squamous cell carcinomas

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs. HER3 is a significant factor in HNSCC treatment resistance. Indeed, HER3 is a major mechanism described for cetuximab resistance because of modification of epidermal growth factor receptor (EGFR) internalization and by phosphotidylinositol‐3‐kinase (PI3K)/AKT signaling pathway activation. HER3 also affects resistance to tyrosine kinase inhibitors (TKIs) and thereby promotes treatment escape and radiotherapy resistance by activation of the survival signaling pathway. To counteract this, pharmacologic inhibitors of HER3 are currently in development and could significantly improve HNSCC treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E2412–E2418, 2016     

Use of short-acting beta2-agonists during pregnancy and the risk of pregnancy-induced hypertension

BACKGROUND: The effect of inhaled short-acting beta(2)-agonists (SABAs) on pregnancy outcome, especially hypertensive complications, is not well documented. After the finding of a possible protective association of inhaled SABAs with pregnancy-induced hypertension (PIH) in a previous study, we decided to further investigate their effect on this condition. OBJECTIVE: We sought to determine the effect of inhaled SABA use during pregnancy on the risk of PIH (gestational hypertension, preeclampsia, or eclampsia) in asthmatic women. METHODS: Three of Quebec's administrative databases were linked to constitute a cohort of asthmatic women who had at least 1 delivery between 1990 and 2000. A nested case-control study was performed using up to 10 control subjects matched to each case patient for the year of conception and gestational age. Statistical analyses considered 22 confounders. RESULTS: The cohort was composed of 3505 asthmatic women who had a total of 4593 pregnancies. Three hundred two patients with PIH and 3013 control subjects were identified. Compared with nonuse, inhaled SABA use during pregnancy was significantly associated with a reduced risk of PIH (adjusted rate ratios: >0-3 doses/week, 0.62 (95% CI, 0.44-0.87); > 3-10 doses/week, 0.51 (95% CI, 0.34-0.79); and >10 doses/week, 0.48 (95% CI, 0.30-0.75)). CONCLUSIONS: To our knowledge, this is the first study reporting that inhaled SABA use during pregnancy is associated with a reduced risk of PIH. Potential explanations include pharmacologic and physiological effects or residual confounding. CLINICAL IMPLICATIONS: These results increase the evidence about the safety of inhaled SABAs in this population, although they should not undervalue the importance of maintaining good control of asthma symptoms.