Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status.

BACKGROUND: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. METHODS: We have updated and extended our population-based analysis of breast cancer diagnosed at the age < or =30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan-Meier curves were generated to assess overall survival, contralateral breast cancer and other second primaries. RESULTS: Survival analysis of all 288 patients showed poor overall survival, although this improved from a 15-year survival of only 46% in those diagnosed between 1980 and 1989 to 58% in those diagnosed between 1990 and 1997 (P=0.05). Contralateral breast cancer rates were at a steady rate of 0.6 per 1000, although the rates in mutation carriers were approximately 2 per 1000. Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed. BRCAPRO accurately predicted the number of carriers for BRCA1 and BRCA2 and was sensitive and specific at the 10 and 20% threshold, respectively. However, BRCAPRO did not seem to give any weight to DCIS, which accounted for two BRCA1 carriers and three TP53 carriers and overpredicted mutations at the high end of the spectrum, with only 6 of 11 (54%) with a >90% probability having identifiable BRCA1/2 mutations. INTERPRETATION: Rates of new primaries are predicted to some extent by mutation status. BRCAPRO is useful at determining those patients aged < or =30 years to be tested.

Addition of pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 testing.

BACKGROUND: Selection for genetic testing of BRCA1/BRCA2 is an important area of healthcare. Although testing costs for mutational analysis are falling, costs in North America remain in excess of US$3000 (UK price can be 690 pounds). Guidelines in most countries use a 10-20% threshold of detecting a mutation in BRCA1/2 combined within a family before mutational analysis is considered. A number of computer-based models have been developed. However, use of these models can be time consuming and difficult. The Manchester scoring system was developed in 2003 to simplify the selection process without losing accuracy. METHODS: In order to increase accuracy of prediction, breast pathology of the index case was incorporated into the Manchester scoring system based on 2156 samples from unrelated non-Jewish patients fully tested for BRCA1/2, and the scores were adapted accordingly. Results/ DISCUSSION: Data from breast pathology allowed adjustment of BRCA1 and combined BRCA1/2 scores alone. There was a lack of pathological homogeneity for BRCA2, therefore specific pathological correlates could not be identified. Upward adjustments in BRCA1 mutation prediction scores were made for grade 3 ductal cancers, oestrogen receptor (ER) and triple-negative tumours. Downward adjustments in the score were made for grade 1 tumours, lobular cancer, ductal carcinoma in situ and ER/HER2 positivity. Application of the updated scoring system led to four and nine more mutations in BRCA1 being identified at the 10% and 20% threshold, respectively. Furthermore, 65 and 58 fewer cases met the 10% and 20% threshold, respectively, for testing. Moreover, the adjusted score significantly improved the trade-off between sensitivity and specificity for BRCA1/2 prediction.

Collecting duct sodium reabsorption in deoxycorticosterone-treated rats.

In vitro studies of isolated, perfused, cortical collecting tubules have demonstrated that prior chronic deoxycorticosterone acetate (DOCA) treatment increases sodium reabsorption in this nephron segment, yet sodium balance in vivo is maintained. To evaluate the effect of chronic DOCA treatment on collecting duct sodium reabsorption in vivo, we compared fractional sodium delivery (FD(Na)%) out of the superficial late distal tubule with the fraction of sodium remaining at the base and the tip of the papillary collecting duct during extracellular fluid volume expansion in untreated, salt-treated, and DOCA-salt-treated rats. In untreated rats, FD(Na)% to the distal tubule was 6.5+/-1.0%, and to the base was 8.7+/-1.6% (Delta2.2+/-0.9%, P < 0.05). FD(Na)% to the tip was 4.9+/-1.1%, significantly less than FD(Na)% to the base (Delta3.7+/-1.1%, P < 0.01). In salt-treated rats, FD(Na)% to the distal tubule was 8.3+/-0.8%, and to the base was 10.4+/-1.1%. FD(Na)% to the tip was 5.9+/-0.6%, significantly less than FD(Na)% to the base (Delta 4.6+/-1.0%, P < 0.005). In DOCA-salt-treated rats, FD(Na)% to the distal tubule was 16.1+/-2.6% and to the base was 9.5+/-1.9% (Delta 6.6+/-1.7%, P < 0.005). FD(Na)% to the tip was 5.9+/-1.2%, also significantly less than FD(Na)% to the base (Delta 3.6+/-1.1%, P < 0.01). We conclude that (a) in DOCA-salt-treated rats, sodium delivery to the end of the superficial distal tubule is greater than in untreated or salt-treated rats; (b) in DOCA-salt-treated rats, sodium delivery to the end of the superficial distal tubule is greater than to the base of the papillary collecting duct, suggesting stimulation of sodium reabsorption in the cortical and(or) outer medullary collecting duct; and (c) sodium reabsorption by the papillary collecting duct is unaffected by chronic DOCA-salt treatment in the volume-expanded rat.

Effect of increased peritubule protein concentration on proximal tubule reabsorption in the presence and absence of extracellular volume expansion.

The effect of increased peritubule capillary oncotic pressure on sodium reabsorption by the proximal tubule of the dog was investistigated after extracellular volume expansion (ECVE) with Ringer's solution or during continued hydropenia. Control measurements were made after ECVE or during hydropenia and again during renal arterial infusion with hyperoncotic albumin solution. Absolute reabsorption by the proximal tubule was calculated from fractional reabsorption and single nephron filtration rates as determined by micropuncture. Direct measurements of efferent arteriole protein were used to determine efferent arteriolar oncotic pressure. Albumin infused into the renal artery after ECVE significantly increased efferent oncotic pressure by 17.6 plus or minus 5.3 mm Hg. Fractional and absolute reabsorption by the proximal tubule increased from 20 plus or minus 6 to 37 plus or minus 5% and from 22 plus or minus 6 to 36 plus or minus 7 nl/min, respectively. During hydropenia, the albumin infusion significantly increased efferent oncotic pressure by 15.0 plus or minus 4.4 mm Hg. However, in contrast to the effect seen during ECVE, neither fractional nor absolute reabsorption was changed, delta equals 0.3 plus or minus 1.5% and 3 plus or minus 5 nl/min, respectively. Single nephron filtration rates were not significantly different between the groups and were unchanged by the albumin infusion. Peritubule capillary hydrostatic pressures, measured with a null-servo device, were not changed by the albumin infusion in either group. Renal interstitial hydrostatic pressure, measured from chronically implanted polyethylene capsules, was decreased significantly from 7.2 plus or minus 0.9 to 3.4 plus or minus 0.6 mm Hg in the hydropenic group and from 0.6 plus or minus 0.6 to 4.8 plus or minus 0.7 mm Hg in the Ringer's expanded group. In the hydropenic group, the increase in efferent oncotic pressure was nearly compensated for by changes in interstitial forces so that the calculated net force for capillary uptake was almost unchanged, 17.8 mm Hg before vs. 21.4 mm Hg during the albumin infusion. The increased efferent oncotic pressure in the Ringer's expanded group was not compensated, so that the calculated net force for uptake was increased, 11.9 mm Hg before to 22.2 mm Hg during the albumin infusion. Thus, while the increase in efferent oncotic pressure during albumin infusion was not significantly different between the groups, absolute and fractional reabsorptions were increased only in the animals in which the extracellular volume was expanded. The results suggest that ECVE alters the effect of increased peritubule oncotic pressure on sodium reabsorption by the proximal tubule.

Administration of atrial natriuretic factor inhibits sodium-coupled transport in proximal tubules.

The newly discovered peptides extracted from cardiac atria, atrial natriuretic factors (ANFs), when administered parenterally cause renal hemodynamic changes and natriuresis. The nephron sites and cellular mechanism accounting for profound increase in Na+ excretion in response to ANFs are not yet clarified. In the present study we investigated whether synthetic ANF peptide alters the reabsorption of Na+ and reabsorption of solutes cotransported with Na+ in the proximal tubules of rats. Synthetic ANF peptide consisting of 26 amino acids, 4 micrograms/kg body wt/h, or vehicle in controls, was infused to surgically thyroparathyroidectomized anesthetized rats. After determination of the fractional excretion (FE) of electrolytes (Na+, K+, Pi, Ca2+, Mg2+, HCO3), the kidneys were removed and luminal brush border membrane vesicles (BBMVs) were prepared from renal cortex. Solute transport was measured in BBMVs by rapid filtration techniques. Infusion of ANF peptide increased FENa, FEPi, and FEHCO3; but FECa, FEK, and FEMg were not changed. The increase in FENa was significantly correlated, on the one hand, with increase of FEPi (r = 0.9, n = 7; P less than 0.01) and with increase of FEHCO3 (r = 0.89, n = 7; P less than 0.01). On the other hand, FENa did not correlate with FEK, FECa, or with FEMg. The Na+ gradient-dependent uptake of Pi by BBMVs prepared from renal cortex of rats receiving ANF infusion was significantly (P less than 0.05) decreased (-25%), whereas the Na+ gradient-dependent uptake of L-[3H]proline and of D-[3H]glucose or the diffusional uptake of 22Na+ were not changed. ANF-elicited change in FEPi showed a close inverse correlation with decrease of Na+-dependent Pi uptake by BBMVs isolated from infused rats (r = 0.99, n = 7; P less than 0.001). Direct addition of ANF to BBMVs in vitro did not change the Na+ gradient-dependent Pi uptake. In rats infused with ANF, the rate of amiloride-sensitive Na+-H+ exchange across the brush border membrane (BBM) was significantly (P less than 0.05) decreased (-40%), whereas the diffusional 22Na+ uptake (0.5 min) and the equilibrium (120 min) uptake of 22Na+ were not changed. The inhibition of Na+-H+ exchange after ANF was likely due to alteration of the BBM antiporter itself, in that the H+ conductance of BBMVs was not increased. We conclude that synthetic ANF (a) decreases tubular Na+ reabsorption linked to reabsorption of HCO3 in proximal tubules, and (b) inhibits proximal tubular reabsorption of Pi coupled to Na+ reabsorption, independent of secretion and/or action of parathyroid hormone or calcitonin. These ANF effects are associated with inhibition of Na+-Pi synport and of Na+-H+ antiport in luminal BBMs. Our findings document that inhibition of Na+-coupled transport processes in proximal tubules is an integral part of the renal response to ANF.

Mechanism of resistance to the phosphaturic effect of the parathyroid hormone in the hamster.

The effect of parathyroid hormone and calcitonin on the renal excretion of phosphate, calcium, and cyclic AMP was evaluated in the thyroparathyroidectomized hamster, a mammal apparently reisstant to the phosphaturic effect of parathyroid hormone. Parathyroid hormone did not increase phosphate excretion, although it decreased excretion of calcium and increased urinary excretion of cyclic AMP. This lack of a phosphaturic response to parathyroid hormone was not reversed by administration of 25-OH vitamin D or infusions of calcium or phosphate. Calcitonin, another potentially phosphaturic hormone, also vailed to increase phosphate excretion but markedly elevated urinary excretion of cyclic AMP. In hamsters pretreated with infusion of urinary ammonium chloride, which decreased plasma and urinary pH, both parathyroid hormone and calcitonin increased excretion of phosphate as well as that of cyclic AMP. Acetazolamide had no phosphaturic effect in ammonium chloride-loaded hamsters, and it decreased cyclic AMP and calcium excretion. Alkalinization of urine by acetazolamide did not prevent the phosphaturic effect of parathyroid hormone in ammonium chloride-loaded hamsters, but it blocked the increase in urinary cyclic AMP excretion. Parathyroid hormone and calcitonin both stimulated adenylate cyclase in a cell-free system (600-g pellet) from hamster renal cortex, elevated tissue cyclic AMP levels, and activated protein kinase in tissue slices from hamster renal cortex. In acid medium, the increase in cyclic AMP and activation of protein kinase in response to parathyroid hormone was diminished, but addition of acetazolamide restored responsiveness of both parameters to control values. Acetazolamide, on the other hand, did not influence adenylate cyclase or its response to parathyroid hormone or cyclic AMP phosphodiesterase activity. We conclude that the lack of a phosphaturic effect of parathyroid hormone and calcitonin in the hamster depends on steps in the cellular action of these hormones, steps that are sensitive to pH subsequent to cyclic AMP generation and protein kinase activation. In addition, acetazolamide may potentiate the phosphaturic effect of parathyroid hormone by promoting accumulation of cyclic AMP in tissue. Thus, the hamster is a particularly useful model for studies of syndromes in which there is renal resistance to phosphaturic hormones.

Effects of secretin on peritubular capillary physical factors and proximal fluid reabsorption in the rat.

The effects of secretin vasodilation on peritubular capillary Starling forces and absolute proximal reabsorption were examined in the rat. Secretin was infused at 75 mU/kg per min into the aorta above the left renal artery. Efferent plasma flow increased from 125 +/- 28 to 230 +/- 40 nl/min with secretin infusion. Single nephron filtration rate (44 +/- 6 vs. 44 +/- 7 nl/min) and absolute proximal reabsorption (21 +/- 5 vs. 21 +/- 4 nl/min) were not significantly changed. Peritubular capillary and interstitial hydrostatic pressures increased with secretin infusions (from 9 +/- 0.4 to 15 +/- 0.7 mmHg and from 3 +/- 0.2 to 4 +/- 0.2 mmHg, respectively). Both peritubular capillary and interstitial oncotic pressures decreased (from 25 +/- 2 to 20 +/- 2 mmHg and from 10 +/- 1 to 4 +/- 1 mmHg, respectively) during secretin infusion. The net reabsorption pressure for peritubular capillary uptake significantly decreased from 9 +/- 2 to 5 +/- 2 mmHg and the coefficient of reabsorption increased from 3 +/- 1 to 6 +/- 2 nl/min per mmHg. We conclude that although secretin causes a vasodilation and decreases net reabsorption pressure, absolute proximal reabsorption is unchanged. Peritubular capillary uptake is maintained, and since net reabsorption pressure is decreased, the coefficient of reabsorption is increased.

Depression of fractional sodium reabsorption by the proximal tubule of the dog without sodium diuresis.

The effect of infusions of hyperoncotic solutions on fractional sodium reabsorption by the proximal tubule of the dog was studied by the recollection micropuncture method. Tubule fluid to plasma inulin concentration ratios were measured for identified proximal tubule segments before and after infusion of 25% albumin or dextran solutions. Results were compared with changes in fractional reabsorption during saline diuresis. Plasma volume increased 66% +/- SE 5.8 after infusion of albumin solution and 94% +/- SE 8.2 after infusion of dextran solution. Fractional sodium reabosorption by the proximal tubule was depressed after infusion of both of these hyperoncotic solutions. Nevertheless, changes in sodium excretion after infusion of albumin and dextran were small. In contrast, after infusions of isotonic sodium chloride solution, which increased plasma volume 61% +/- SE 5.8, a decrease in fractional reabsorption of 50.7% +/- SE 7.2 was associated with large changes in sodium excretion.

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

A possible role for dopamine in phosphate handling by the dog kidney was investigated by intrarenal artery infusions of dopamine. Dopamine increased fractional phosphate excretion both in the presence and absence of control of parathyroid hormone and calcitonin. In addition, dopamine increased both renal blood flow and sodium excretion, however, the phosphaturia was independent of these changes; since 30 min after completion of dopamine infusion, renal blood flow and sodium excretion returned to control levels and phosphate excretion remained elevated. For comparison, the vasodilator isoproterenol increased renal blood flow and sodium excretion without a significant change in fractional phosphate excretion. Thus, the phosphaturic effect of dopamine is probably independent of its vasodilator effect. The phosphaturic effect of dopamine could not be accounted for by subsequent conversion to norepinephrine, since norepinephrine was antiphosphaturic in the dog. The effect of endogenous dopamine on renal phosphate excretion was investigated by intrarenal infusion of the precursor dopa. Dopa was phosphaturic both in the presence and absence of parathyroid hormone and calcitonin. In dogs pretreated with carbidopa, which blocks conversion of dopa to dopamine, dopa was no longer phosphaturic, although the kidney remained responsive to dopamine. It is postulated that dopamine may play a role in the intrarenal regulation of phosphate excretion.

Effect of volume expansion on sodium excretion in the presence and absence of increased delivery from superficial proximal tubules.

The role of the proximal tubule in the natriuresis after volume expansion was investigated by evaluating sodium excretion both in the presence and absence of increased delivery from the proximal tubule. Proximal delivery was calculated from fractional reabsorption in superficial proximal tubules determined by micropuncture and glomerular filtration rate of the micropunctured kidney. Infusion of Ringer's solution in six dogs increased delivery from the proximal tubule 4.7+/-1 ml/min (P < 0.01) and increased fractional sodium excretion 3.6+/-1.1% (P < 0.025). Infusion of hyperoncotic albumin into the renal artery during sustained volume expansion decreased delivery from the proximal tubule 6.5+/-0.9 ml/min (P < 0.01). Although proximal delivery was restored to below control levels, fractional sodium excretion was significantly increased 2.5+/-0.5% (P < 0.01) as compared with the hydropenic control period. Fractional phosphate excretion was increased 15.5+/-3.7% (P < 0.01) after Ringer's infusion and was decreased 10.5+/-1.6% (P < 0.005) after intrarenal albumin infusion, suggesting that changes in superficial nephron reabsorption were paralleled by changes in reabsorption in deeper nephrons. Similar results were found in six additional dogs in which other factors known to affect phosphate reabsorption were controlled; however, these studies cannot completely eliminate a role for deep nephrons in the natriuresis after intrarenal albumin infusion. Since 70% of the natriuresis after volume expansion was present without increased delivery from superficial proximal tubules, it is likely that increased delivery from the proximal tubule contributes a relatively minor fraction to the natriuresis of volume expansion.

Proximal tubule reabsorption after hyperoncotic albumin infusion. Role of parathyroid hormone and dissociation from plasma volume.

Preferential expansion of the plasma volume by infusion of salt-poor hyperoncotic albumin solution decreases sodium reabsorption by the proximal tubule. The present micropuncture studies test the thesis that albumin infusion depresses proximal reabsorption by an effect unrelated to expansion of the plasma volume, perhaps due to an effect of parathyroid hormone (PTH) on proximal sodium reabsorption. Infusion of salt-poor hyperoncotic albumin significantly decreased plasma ionized calcium, increased immunoreactive PTH (iPTH) in plasma, decreased sodium reabsorption by the proximal tubule, and increased phosphate clearance. In contrast, infusions of albumin, in which the ionized calcium was restored to normal plasma levels, had no significant effect on ionized calcium, iPTH, proximal reabsorption, or phosphate clearance in intact dogs. Similarly, in parathyroidectomized animals given a constant replacement infusion of PTH, albumin infusion had no significant effect on proximal reabsorption or phosphate clearance. Plasma volume was markedly expanded following albumin infusion in all groups of dogs. These findings (a) indicate that PTH plays a significant role in the decrease in sodium reabsorption by the renal proximal tubule after salt-poor hyperoncotic albumin infusion, and (b) dissociate preferential expansion of the plasma volume from decreases in sodium reabsorption by the proximal tubule.

The NHS breast screening programme (pathology) EQA: experience in recent years relating to issues involved in individual performance appraisal.

BACKGROUND: The original role of the National Health Service breast screening programme (pathology) external quality assessment (EQA) scheme was educational; it aimed to raise standards, reinforce use of common terminology, and assess the consistency of pathology reporting of breast disease in the UK. AIMS/METHODS: To examine the performance (scores) of pathologists participating in the scheme in recent years. The scheme has evolved to help identify poor performers, reliant upon setting an acceptable cutpoint. Therefore, the effects of different cutpoint strategies were evaluated and implications discussed. RESULTS/CONCLUSIONS: Pathologists who joined the scheme improved over time, particularly those who did less well initially. There was no obvious association between performance and the number of breast cancer cases reported each year. This is not unexpected because the EQA does not measure expertise, but was established to demonstrate a common level of performance (conformity to consensus) for routine cases, rather than the ability to diagnose unusual/difficult cases. A new method of establishing cutpoints using interquartile ranges is proposed. The findings also suggest that EQA can alter a pathologist's practice: those who leave the scheme (for whatever reason) have, on average, marginally lower scores. Consequently, with the cutpoint methodology currently used (which is common to several EQA schemes) there is the potential for the cutpoint to drift upwards. In future, individuals previously deemed competent could subsequently be erroneously labelled as poor performers. Due consideration should be given to this issue with future development of schemes.

Impact of a national external quality assessment scheme for breast pathology in the UK.

BACKGROUND: This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology. AIMS/METHODS: The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using kappa statistics. RESULTS: Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high-this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit-this included histological grading; (3) where consistency could be improved but only by changing the system of classification-this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved-this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming. CONCLUSIONS: These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.

The rising cost of glaucoma drugs in Ireland 1996-2003.

BACKGROUND: Glaucoma affects approximately 2% of the population in developed countries and is estimated to affect 67 million people worldwide. The authors investigated the effect of the introduction of new medications on the volume and cost of drugs for glaucoma in two countries, Northern Ireland (NI, population approximately 1.7 million) and the Republic of Ireland (ROI, population approximately 3.9 million) in the 8 years from 1996 to 2003. They also looked at the surgical rates for glaucoma within the same time period for the two countries. METHODS: A retrospective analysis was performed of drug costs, prescribing data, and operation rates for glaucoma in Ireland from January 1996 to December 2003. Information regarding costs and volume were obtained for each type of glaucoma drug and these were then grouped into the glaucoma treatment subsections as found in the British National Formulary. The drug information was obtained from the Central Services Agency in NI and IMS Health in the ROI and included both public and private prescriptions. The information on surgical rates for glaucoma was obtained from the Department of Health and Social Services in NI and the Hospital In-patient Enquiry (HIPE) data national files in the ROI. RESULTS: There was a 30% increase in prescription items for glaucoma in NI and a 59% increase in the ROI from 1996 to 2003. The costs increased more rapidly than the number of items: 227% in the ROI and 78% in NI from January 1996 to December 2003. In the ROI, there was an average 19% year on year increase in costs. In NI, new drugs accounted for 40% of the quantity of prescription items for glaucoma and 63% of the market cost in 2003. In the ROI new drugs accounted for 57% of the quantity and 77% of the market cost for glaucoma in 2003; prostaglandin analogue drugs alone accounted for 53% of the cost. The number of trabeculectomies performed decreased by more than 60% in both countries. CONCLUSION: Volume and cost of glaucoma drugs increased dramatically in both NI and the ROI from 1996 to 2003, probably the result of a combination of changing demographics and a changing approach towards the management of patients with glaucoma and ocular hypertension. In 2003 in the ROI, prostaglandin analogues were the most commonly prescribed class of drug for patients with glaucoma and/or ocular hypertension causing a profound rise in drug expenditure.

Conscious sedation and analgesia for oocyte retrieval during in vitro fertilisation procedures.

BACKGROUND: Various methods of sedation and analgesia have been used for pain relief during oocyte recovery in IVF/ICSI procedures. The choice of agents has also been influenced by quality of analgesia as well as by concern about possible detrimental effects on reproductive outcome. OBJECTIVES: To assess the efficacy of conscious sedation and analgesia versus alternative methods on pregnancy outcomes and pain relief in patients undergoing transvaginal oocyte retrieval. SEARCH STRATEGY: We searched the Specialised Register of the Menstrual Disorders and Subfertility Group, The Central Register of Controlled Trials (CENTRAL) , MEDLINE (1966 to present), EMBASE (1980 to present), CINAHL (1982 to present), the National Research Register, and Current Controlled Trials. There was no language restriction. All references in the identified trials and background papers were checked and authors contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials comparing conscious sedation and analgesia versus alternative methods for pain relief during oocyte recovery were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently scanned abstracts of the reports identified by electronic searching to identify relevant papers, extracted data and assessed trial quality. Interventions were classified and analysed under broad categories/strategies of pain relief comparing conscious sedation/analgesia with alternative methods and administration protocols. MAIN RESULTS: Our search strategy identified 390 potentially eligible reports and 12 papers met our inclusion criteria. There were no significant differences in clinical pregnancy rates per woman and patient satisfaction between the methods compared. Women's perception of pain showed conflicting results. Due to considerable heterogeneity, in terms of types and dosages of sedation or analgesia used, and tools used to assess the principal outcomes of pain and satisfaction, a meta-analysis of all the studies was not attempted. Of the three trials which compared the effect of conventional medical analgesia plus paracervical block versus electro-acupuncture plus paracervical block, there was no significant difference in clinical pregnancy rates per woman in the two groups (OR 1.01; 95% CI 0.73 to 1.4). For intra-operative pain score as measured by visual analogue scale (VAS), there was a significant difference (WMD -4.95; 95% CI -7.84 to -2.07), favouring conventional medical analgesia plus paracervical block . There was also a significant difference in intra-operative pain by VAS between patient-controlled sedation and physician-administered sedation (WMD 5.98; 95% CI 1.63 to 10.33), favouring physician -administered sedation. However, as different types and dosages of sedative and analgesic agents were used in these trials, these data should be interpreted with caution. For the rest of the trials, a descriptive summary of the outcomes was presented. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effect of different methods of pain relief when compared with conscious sedation and analgesia used during oocyte recovery. In this review, no one particular pain relief method or delivery system appeared to be better than the other. In future, greater consensus is needed to determine both the tools used to evaluate pain and the timing of pain evaluation during and after the procedure. Pain assessment using both subjective and objective measures may merit consideration. In addition, future trials should include intra- and post-operative adverse respiratory and cardiovascular events as outcomes.

Nicotinamide adenine dinucleotide and renal response to parathyroid hormone.

We tested the hypothesis that NAD plays a role in the cellular mechanism of action of parathyroid hormone (PTH) on phosphate transport. PTH significantly increased urinary cyclic AMP and phosphate excretions in thyroparathyroidectomized rats. The NAD+/NADH ratio, but not total NAD content, in renal cortical tissue was significantly higher in rats infused with PTH than in controls. The results demonstrate that the phosphaturic effect of PTH is associated with a shift in the renal cortical NADH to NAD+ and provides evidence for a role for NAD+ in the cellular regulation of phosphate transport.

Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems. State of the art lecture.

It has long been known that increments in renal perfusion pressure can induce an elevation of urine sodium excretion without changing renal blood flow or glomerular filtration rate. The mechanism underlying this pressure-related natriuresis remains undefined, although the interest in its elucidation has been stimulated by the notion that it may constitute the central phenomenon through which the kidney regulates blood volume and, thereby, blood pressure. Recently, the use of novel experimental techniques has disclosed some important clues about changes in renal hemodynamics that, along with changes in renal humoral regulators, allow us to visualize a possible sequence of events responsible for pressure-related natriuresis. According to this hypothesis, the autoregulatory responses responsible for maintaining glomerular filtration rate are elicited in preglomerular vasculature by changes in renal perfusion pressure. These myogenic responses are coupled through Ca2+ entry in juxtaglomerular cells with inversely related changes in the release of renin and, consequently, with the amount of angiotensin II generated in renal interstitium. The release of renin from juxtaglomerular cells is modulated by the synthesis of prostaglandin I2 from the adjacent endothelial cells. Interstitial angiotensin II could influence sodium tubular reabsorption directly by stimulating sodium transport in proximal renal tubules and indirectly by altering medullary blood flow and, thereby, medullary interstitial pressure. In the renal medulla, the effects of interstitial pressure on sodium reabsorption can be amplified by the release of prostaglandin E2 from interstitial cells. A deficient regulation of this relationship could result in a shift of the pressure-natriuresis curve, leading to hypertension.

Effects of long-term treatment with indomethacin on renal function.

The prolonged effects (42 days) of indomethacin treatment on the renin-angiotensin-aldosterone axis, renal hemodynamics, and renal excretory function in humans were studied. Indomethacin produced a 41% sustained depression in the 24-hour excretion of prostaglandin E2 and a mild (7%) decrease in inulin clearance but did not affect the clearance of p-aminohippurate, the 24-hour excretion of sodium and potassium, or the basal values of plasma aldosterone; however, it decreased the basal values of renin and prevented the stimulated (3 hours of walking) responses of plasma renin activity and plasma aldosterone. Indomethacin also produced a decrease in both the diuretic and saluretic response to furosemide and in the renal ability to concentrate urine. The indomethacin-induced hyporeninism and hypoaldosteronism were more pronounced when the subjects were receiving a sodium-restricted diet. This finding indicates that prolonged administration of anti-inflammatory drugs induces chronic hyporeninism and hypoaldosteronism. Prolonged treatment with indomethacin also produced some of the symptoms of a syndrome of hypoprostaglandinism, such as decreased plasma renin activity, plasma aldosterone, and urinary prostaglandin E2 in association with increases in plasma potassium levels and diastolic pressure.

Effect of furosemide on renal function in the stenotic and contralateral kidneys of patients with renovascular hypertension.

In a group of six patients diagnosed as having unilateral renovascular hypertension due to fibromuscular dysplasia, inulin glomerular filtration rate, (GFR) and PAH renal plasma flow, (RPF) clearances, urine flow (V), urine sodium (UVNa), potassium (UVK), urinary excretion of prostaglandin E2 (UVPGE2), thromboxane B2 (UVTxB2), and 6-keto prostaglandin F1 alpha (UVPGF1 alpha) were measured in each kidney before and after the i.v. administration of furosemide (20 mg). The basal values of GFR, RPF, UVNa, UVPGE2, UVTxB2, and UV6-keto-PGF1 alpha were lower (p less than 0.01) in the stenotic kidney. Furosemide increased RPF 11% and 50%, GFR 25% and 62%, and V 142% and 280% in the contralateral and stenotic kidney respectively. The increase of UVNa was similar in the two kidneys. In the stenotic kidney, both UVPGE2 and UV6-keto-PGF1 alpha increased significantly (p less than 0.01) with furosemide while UVTxB2 remained unchanged. Furosemide did not alter the rate of excretion of the three prostaglandins measured in the contralateral kidney. We conclude that furosemide significantly improves renal circulatory and excretory function of the stenotic kidney. Since prostaglandin excretions also increased, the vasodilatation in the stenotic kidney may be prostaglandin mediated.