A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

OBJECTIVE: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK. DESIGN: Cross-sectional nationwide survey of gynaecological oncologists and women with LS. SETTING: United Kingdom. METHODS: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK. MAIN OUTCOME MEASURES: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care. RESULTS: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care. CONCLUSIONS: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services. TWEETABLE ABSTRACT: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK.

Accurate determinations of alpha(s) from realistic lattice QCD.

We obtain a new value for the QCD coupling constant by combining lattice QCD simulations with experimental data for hadron masses. Our lattice analysis is the first to (1) include vacuum polarization effects from all three light-quark flavors (using MILC configurations), (2) include third-order terms in perturbation theory, (3) systematically estimate fourth and higher-order terms, (4) use an unambiguous lattice spacing, and (5) use an [symbol: see text](a2)-accurate QCD action. We use 28 different (but related) short-distance quantities to obtain alpha((5)/(MS))(M(Z)) = 0.1170(12).

Semileptonic decays of d mesons in three-flavor lattice QCD.

We present the first three-flavor lattice QCD calculations for D-->pilnu and D-->Klnu semileptonic decays. Simulations are carried out using ensembles of unquenched gauge fields generated by the MILC Collaboration. With an improved staggered action for light quarks, we are able to simulate at light quark masses down to 1/8 of the strange mass. Consequently, the systematic error from the chiral extrapolation is much smaller than in previous calculations with Wilson-type light quarks. Our results for the form factors at q(2)=0 are f(D-->pi)(+)(0)=0.64(3)(6) and f(D-->K)(+)(0)=0.73(3)(7), where the first error is statistical and the second is systematic, added in quadrature. Combining our results with experimental branching ratios, we obtain the Cabibbo-Kobayashi-Maskawa matrix elements |V(cd)|=0.239(10)(24)(20) and |V(cs)|=0.969(39)(94)(24), where the last errors are from experimental uncertainties.

Charmed-meson decay constants in three-flavor lattice QCD.

We present the first lattice QCD calculation with realistic sea quark content of the D+-meson decay constant f(D+). We use the MILC Collaboration's publicly available ensembles of lattice gauge fields, which have a quark sea with two flavors (up and down) much lighter than a third (strange). We obtain f(D+)=201+/-3+/-17 MeV, where the errors are statistical and a combination of systematic errors. We also obtain f(Ds)=249+/-3+/-16 MeV for the Ds meson.

Effects of angiotensin on renal cortical and papillary blood flows measured by laser-Doppler flowmetry.

The effects of angiotensin II (ANG II) or angiotensin III (ANG III) on renal cortical blood flow (CBF) or papillary blood flow (PBF) were investigated in Inactin-anesthetized young rats with the use of laser-Doppler flowmetry. Infusion of equimolar pressor doses of ANG II (300 ng.kg-1.min-1 iv) or ANG III (267 ng.kg-1.min-1) decreased CBF by 31 +/- 2.6% (P less than 0.001) and 20.3 +/- 3.2% (P less than 0.01), respectively but increased PBF by 19 +/- 6.1% (P less than 0.05) and 14.6 +/- 4.4% (P less than 0.05). The ANG II-induced increase in PBF was not prevented by aortic clamping to maintain constant renal perfusion pressure or pretreatment with the prostaglandin synthase inhibitor, indomethacin. The nonpeptide ANG II receptor antagonist, DuP 753 completely abolished the systemic and intrarenal effects of ANG II. After pretreatment with a kallikrein inhibitor, aprotinin, ANG II infusion increased mean arterial pressure but did not affect PBF, suggesting that kinins, but not prostaglandins, modulate the action of systemic ANG II on PBF. We conclude that circulating ANG II induces vasoconstriction in the cortex and also promotes the intrarenal production of kinins, which act to enhance papillary blood flow.

Amylin as a growth factor during fetal and postnatal development of the rat kidney.

We have previously reported that amylin has mitogenic actions on tubular epithelial cells isolated from mature rat kidney and cultured in vitro. In experiments using in situ hybridization, we have demonstrated that amylin mRNA can be detected transiently in rat metanephros from embryo day 17 (E17) to postnatal day 3 (PN3). These transcripts are localized in the sub-nephrogenic zone. RT-PCR was performed using oligonucleotide primers for rat amylin and mRNA extracted from fetal body (E19), PN1 and PN5 metanephroi, and adult rat kidney. These results corroborate the finding, using in situ hybridization, that there is a window of expression of rat amylin in the developing kidney in the perinatal period. During this period tubular elongation is evident and amylin peptide, detected by immunohistochemical staining, is found associated with developing tubules. Some of these tubules also express a brush border glycoprotein, detected by immunohistochemical staining. Amylin acts as a mitogen with primary cultures of proximal tubular epithelial cells from PN4 renal cortex. An amylin antagonist inhibited this mitogenic action suggesting that this was mediated by amylin receptors as previously described. We suggest that amylin peptide is biosynthesized in the developing proximal tubules, acts in an autocrine fashion to promote the proliferation and differentiation of brush border epithelial cells and hence plays an important role as a growth factor in the development of the kidney.

Transferable circulating factors and epithelial sodium transport after unilateral nephrectomy in the rat.

1. In order to investigate the role of circulating serum factors in the altered renal haemodynamics and enhanced renal tubular transport observed in renal growth, micropuncture experiments were performed on normal animals infused with 20% plasma derived from animals in whom unilateral nephrectomy had been performed 3 days previously. 2. When animals infused with plasma from uninephrectomized animals (NxP) were compared with those infused with control plasma, the former had a higher tubular fluid flow rate measured at both the late proximal (LP; 26.7 +/- 1.6 vs. 18.4 +/- 1.4 nl min-1; P < 0.001) and early distal (ED; 14.9 +/- 1.0 vs. 7.8 +/- 1.0 nl min-1; P < 0.0001) sites, which was reflected in the final urine flow rate (16.1 +/- 3.4 vs. 5.1 +/- 0.8 microliter min-1; P < 0.005). 3. The single nephron glomerular filtration rate (SNGFR) was higher in animals infused with NxP as determined from samples taken at the LP (45.8 +/- 2.8 vs. 35.7 +/- 2.3 nl min-1; P < 0.01) and at the ED (34.5 +/- 2.5 vs. 28.1 +/- 1.8 nl min-1; P = 0.05) sites. However, this increase was not reflected in the whole kidney GFR (1.04 +/- 0.06 vs. 0.89 +/- 0.06; P = 0.07), suggestive of a preferential increase in filtration in the outer cortical nephrons. 4. Tubular Na+ transport was higher in the animals infused with NxP as evidenced by a decrease in the fractional delivery of Na+ at the ED site (4.5 +/- 0.4 vs. 6.5 +/- 0.6% of the filtered load; P < 0.05). However, in the final urine there was a significant increase in the urinary sodium excretion in animals infused with NxP (0.67 +/- 0.14 vs. 0.29 +/- 0.09%; P < 0.05) indicating that natriuresis and probably diuresis was a result of inhibition of Na+ and water transport in the late distal tubule and collecting duct. 5. In conclusion, these experiments demonstrate that circulating factors induced by a reduction in renal mass significantly alter glomerular filtration and tubular Na+ transport.

Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney.

In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.

High-precision lattice QCD confronts experiment.

The recently developed Symanzik-improved staggered-quark discretization allows unquenched lattice-QCD simulations with much smaller (and more realistic) quark masses than previously possible. To test this formalism, we compare experiment with a variety of nonperturbative calculations in QCD drawn from a restricted set of "gold-plated" quantities. We find agreement to within statistical and systematic errors of 3% or less. We discuss the implications for phenomenology and, in particular, for heavy-quark physics.