Membrane anchoring and spontaneous release of CD16 (FcR III) by natural killer cells and granulocytes

CD16 is an IgG Fc receptor that is predominantly expressed on human natural killer (NK) cells and granulocytes. The CD16 antigen expressed on neutrophils is a 50 to 70-kDa glycoprotein attached to the plasma membrane by a phosphatidylinositol-glycan linkage that is susceptible to cleavage by phosphatidylinositol-specific phospholipase C (PIPLC). By contrast, treatment of NK cells with PIPLC did not cleave CD16 from the cell surface. Biochemical analysis of the deglycosylated CD16 revealed a substantial difference in the core polypeptides expressed by NK cells and granulocytes. Culture of radiolabeled NK cells resulted in the spontaneous release of a CD16 molecule, smaller than the membrane form of CD16. These findings demonstrate that structural differences exist in the CD16 antigens expressed on NK cells and granulocytes that may potentially influence their functional activities.     

Short communication: the number of HIV major NRTI mutations correlates directly with other antiretroviral-associated mutations and indirectly with replicative capacity and reduced drug susceptibility

While it is known that selection for specific HIV-1 drug resistance-associated mutations (DRM) occurs following ART failure, the patterns of resistance mutations, reduced susceptibility (RS), and replicative capacity (RC) that appear as the number of major NRTI mutations increases have been less well-studied. These changes were examined as a function of the number of major NRTI mutations using patient-derived HIV samples submitted for resistance testing between 2003-2005 (n = 35,222) that were grouped by number of NRTI-DRMs present. In the absence of NRTI-DRMs, few (3.4%) samples had RS to one or more NRTI, 33.6% to one or more NNRTI, and 12.6% to one or more PI. With one NRTI-DRM, 94% had RS to one or more NRTI, 50% to one or more NNRTI, and 33% to one or more PI. Increases in NRTI-DRMs were accompanied by increased prevalence of NNRTI and PI DRMs and RS. With one NRTI-DRM, the mean number of NRTIs with RS was 1.7, while when five NRTI-DRMs were present, RS to > or =5 NRTIs was observed. PI-DRM and RS increased at a slower rate than NNRTI-DRM and RS. RC declined from a mean of 97.8% for samples without NRTI-DRMs to 68.9% with one NRTI-DRM, possibly due to reduced fitness conferred by K65R or M184I/V, to an RC of 43.9% for samples with seven to eight NRTI-DRMs. The relatively high percent of samples with NNRTI-DRM but without NRTI-DRMs may result from selection following virologic failure, and/or transmission of virus uniquely resistant to NNRTI.     

Rate of Clinically Significant Postoperative Pancreatic Fistula in Pancreatic Neuroendocrine Tumors

Background

In 2005, the International Study Group of Pancreatic Fistula (ISGPF) developed a definition and grading system for postoperative pancreatic fistula (POPF). The authors sought to determine the rate of POPF after enucleation and/or resection of pancreatic neuroendocrine tumors (PNET) and to identify clinical, surgical, or pathologic factors associated with POPF.

Methods

A retrospective analysis of pancreatic enucleations and resections performed from March 1998 to April 2010. We defined a clinically significant POPF as a grade B that required nonoperative intervention and grade C.

Results

One hundred twenty-two patients were identified; 62 patients had enucleations and 60 patients had resections of PNET. The rate of clinically significant POPF was 23.7?% (29/122). For pancreatic enucleation, the POPF rate was 27.4?% (17/62, 14 grade B, 3 grade C). The pancreatic resection group had a POPF rate of 20?% (12/60, 10 grade B, 2 grade C). This difference was not significant (p?=?0.4). In univariate analyses, patients in the enucleation group with hereditary syndromes (p?=?0.02) and non-insulinoma tumors (p?=?0.02) had a higher POPF rate. Patients in the resection group with body mass index (BMI)?>?25 (p?p?p?=?0.02) had a higher POPF rate. Multivariate analyses revealed that hereditary syndromes were able to predict POPF in the enucleation group, while having BMI?>?25 and increasing lesion size were also associated with POPF in the group undergoing resection.

Conclusions

We found a clinically significant POPF rate after surgery in PNET to be 23.7?% with no difference by the type of operation. Our POPF rate is comparable to that reported in the literature for pancreatic resection for other types of tumors. Certain inherited genetic diseases—von Hippel–Lindau disease (VHL) and MEN-1—were associated with higher POPF rates.     

Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans

That NK cell receptors engage fast-evolving MHC class I ligands suggests that they, too, evolve rapidly. To test this hypothesis, the structure and class I specificity of chimpanzee KIR and CD94:NKG2 receptors were determined and compared to their human counterparts. The KIR families are divergent, with only three KIR conserved between chimpanzees and humans. By contrast, CD94:NKG2 receptors are conserved. Whereas receptors for polymorphic class I are divergent, those for nonpolymorphic class I are conserved. Although chimpanzee and human NK cells exhibit identical receptor specificities for MHC-C, they are mediated by nonorthologous KIR. These results demonstrate the rapid evolution of NK cell receptor systems and imply that "catching up" with class I is not the only force driving this evolution.     

Dual modulation of calcium channel current via recombinant α2-adrenoceptors in pheochromocytoma (PC-12) cells

 The ability of recombinant rat α_2D-and α_2B-adrenoceptors expressed in nerve-growth-factor-differentiated pheochromocytoma PC-12 cells to modulate Ca²⁺ currents, recorded by the whole-cell patch-clamp technique, has been studied. Ca²⁺ currents in different cells were either reversibly reduced or increased by dexmedetomidine, an α₂-adrenergic agonist, in a concentration-dependent manner. Pertussis toxin pretreatment reduced the number of cells that showed an inhibitory response and reduced the magnitude of inhibition. In cells expressing the α_2B-adrenoceptor, pertussis toxin increased the proportion of cells from which a stimulatory effect on Ca²⁺ currents could be recorded. The magnitude of the inhibitory responses was unaffected but the stimulatory responses were considerably reduced by the dihydropyridine Ca²⁺ channel blocker nifedipine (5 μM). All effects of dexmedetomidine were reversible upon wash-out and inhibited by the antagonist rauwolscine. The results support the idea that modulation of voltage-dependent Ca²⁺ channels in transfected PC-12 cells is mediated by activation of recombinant α_2D- and α_2B-adrenoceptors. This receptor activation predominantly causes inhibition of dihydropyridine-insensitive Ca²⁺ channels via pertussis-toxin-sensitive G proteins. Additionally receptor activation can also lead to stimulation of dihydropyridine-sensitive Ca²⁺ channels via pertussis-toxin-insensitive mechanisms. Received: 25 March 1997 / Received after revision: 27 August 1997 / Accepted: 12 September 1997