[Four cases of acute renal injury caused by acute dimethyl oxalate poisoning].

Objective: To investigate the clinical features, non-dialysis treatment and prognosis of acute renal injury caused by acute dimethyl oxalate (DMO) poisoning. Methods: Retrospective analysis was performed on the occupational data, clinical manifestation, laboratory examination, treatment methods and prognosis of 4 patients with acute DMO poisoning in July 2020. Results: A large number of white DMO crystals were observed in the workplace. Four patients had acute onset, presenting symptoms such as fatigue, abdominal distension, abdominal cramps and nocturia to varying degrees. Laboratory tests all showed acute kidney injury. Serum creatinine of patients at the onset were 119-835 µmol/L. Patients were given early treatment including rest, protection of renal function, hydration and alkalization of urine, Bailing capsule. Renal function of 4 patients returned to normal, and clinical prognosis was good. Conclusion: Acute DMO poisoning leads to acute renal injury, mainly with renal tubulointerstitial lesions such as hypogravity uria and aseptic leucuria. Active treatment in the early stage has a good short-term clinical prognosis.

Critical role of astrocytic interleukin-17 A in post-stroke survival and neuronal differentiation of neural precursor cells in adult mice.

The brain and the immune system interact in complex ways after ischemic stroke, and the long-term effects of immune response associated with stroke remain controversial. As a linkage between innate and adaptive immunity, interleukin-17 A (IL-17 A) secreted from gamma delta (γδ) T cells has detrimental roles in the pathogenesis of acute ischemic stroke. However, to date, the long-term actions of IL-17 A after stroke have not been investigated. Here, we found that IL-17 A showed two distinct peaks of expression in the ischemic hemisphere: the first occurring within 3 days and the second on day 28 after stroke. Our data also showed that astrocyte was the major cellular source of IL-17 A that maintained and augmented subventricular zone (SVZ) neural precursor cells (NPCs) survival, neuronal differentiation, and subsequent synaptogenesis and functional recovery after stroke. IL-17 A also promoted neuronal differentiation in cultured NPCs from the ischemic SVZ. Furthermore, our in vitro data revealed that in primary astrocyte cultures activated astrocytes released IL-17 A via p38 mitogen-activated protein kinase (MAPK). Culture media from reactive astrocytes increased neuronal differentiation of NSCs in vitro. Blockade of IL-17 A with neutralizing antibody prevented this effect. In addition, after screening for multiple signaling pathways, we revealed that the p38 MAPK/calpain 1 signaling pathway was involved in IL-17 A-mediated neurogenesis in vivo and in vitro. Thus, our results reveal a previously uncharacterized property of astrocytic IL-17 A in the maintenance and augment of survival and neuronal differentiation of NPCs, and subsequent synaptogenesis and spontaneous recovery after ischemic stroke.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Effect of heme oxygenase­endogenous carbon monoxide on mortality during septic shock in rats.

AIM: To investigate the effect of HO­CO on mortality during septic shock in rats. METHOD: Eighty rats were randomly divided into group-control, group ZnPP-IX, group SS, and group LZ. RESULTS: Death was significantly lower in group SS than in group LZ (P < 0.05). The MAP was significantly higher in the group LZ than in the group SS (P < 0.05). ALT, AST, Cr and BUN, MDA, and the lung EB contents, were significantly lower in the group SS than that in the group LZ (all P < 0.05). And CO and SOD activities were significantly higher in group SS than that in the group LZ (all P < 0.05). HO-1 mRNA, and HO-1 protein were significantly lower in the group LZ than in the group SS (P < 0.05), whereas HO-2 mRNA, and HO-2 protein were not significantly different among four groups (all P > 0.05). CONCLUSION: The increased oxidative stress and end-organ damage is related to mortality during septic shock; while the hypotension partly contributing to HO-1 protein and CO has no obvious relation with it.

Protective effects of propofol on lipopolysaccharide-activated endothelial cell barrier dysfunction.

BACKGROUND: Propofol has been widely used in intravenous anesthesia. It possesses antioxidant and immunomodulating effects. This study aimed to investigate whether propofol may attenuate lipopolysaccharide (LPS)-induced endothelial cell barrier dysfunction and the possible mechanisms of such modulation. METHODS: Cultured human umbilical vein endothelial cells (HUVECs) were used to assess the following treatments: (i) no additives (negative control), (ii) LPS alone (1 and 10 microg/ml), (iii) propofol alone (20 microg/ml), (iv) intralipid (a solvent of propofol) alone (20 microg/ml), (v) LPS (10 microg/ml) combination with propofol (4 and 20 microg/ml) and (vi) LPS (10 microg/ml) combination with intralipid (20 microg/ml). Changes of cell permeability and filamentous actin (F-actin) were determined. Expression of nitrotyrosine proteins and activity of nuclear factor kappaB (NF-kappaB) were analyzed by Western blot and immunocytochemistry. Expression of endothelial nitric-oxide synthase (eNOS) and inducible nitric-oxide synthase (iNOS) were analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: LPS markedly increased the permeability of endothelial cells, the formation of peroxynitrite and depolymerization of F-actin in HUVECs. LPS also significantly increased mRNA of iNOS, protein level of NF-kappaB and decreased mRNA of eNOS (P < 0.05). Propofol at both concentrations (4 and 20 microg/ml) significantly inhibited the LPS-induced increase in cell permeability and alteration in F-actin organization. Propofol also reduced the LPS-enhanced iNOS mRNA and NF-kappaB protein levels whilst it increased eNOS mRNA expression (P < 0.05). CONCLUSION: This study demonstrated that propofol, both at therapeutic concentrations and 5 times therapeutic concentrations, inhibited NF-kappaB activation in LPS-stimulated endothelial cells and was found to protect endothelial cells against LPS-induced barrier dysfunction.

Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-kappaB.

BACKGROUND: Treatment of neuropathic pain remains a challenge. The current study investigated the therapeutic effect of intrathecal administration of NF-kappaB antisense oligodeoxynucleotides (ODNs) on mechanical allodynia and thermal hyperalgesia in a chronic constriction injury (CCI) model of rats. METHODS: Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats and a CCI model was established. Thermal and mechanical nociceptive thresholds were assessed with paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The phosphorothioate-modified antisense ODNs to p65 subunit of NF-kappaB were administered intrathecally on each of five consecutive days post-CCI. Nuclear NF-kappaB p65 expression was assessed by western blot. RESULTS: CCI induced mechanical allodynia and thermal hyperalgesia and significantly increased NF-kappaB p65 protein expression. Intrathecal injection of antisense ODN markedly suppressed the expression of NF-kappaB p65 protein and significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CONCLUSION: The activation of NF-kappaB pathway may contribute to neuropathic pain in CCI rats. Suppression of NF-kappaB could be a potential new strategy for the treatment of neuropathic pain.

Stellate ganglion block inhibits formalin-induced nociceptive responses: mechanism of action.

BACKGROUND AND OBJECTIVE: Stellate ganglion block has been extensively used in clinical practice for the management of painful conditions such as cephalic, facial and upper limb pains yet its mechanism of action and its analgesic efficacy are poorly understood. METHOD: Formalin (3% 0.2 mL) was injected into the plantar region of the right upper limb paw in rabbits and 50 min after this injection, saline or bupivacaine 2.5% 0.5 mL was administered via a chronic implantation catheter near the right stellate ganglion. Behavioural modification, changes in heart rate and plasma norepinephrine release at different time points after formalin and bupivacaine or saline injection were observed. Finally, the cervical spinal cord was harvested and immunostaining for substance P and c-Fos was performed. RESULTS: Formalin caused stress noxious behavioural changes and a significant increase in heart rate and norepinephrine release. These changes were inhibited by bupivacaine stellate ganglion block but not by saline injection. Immunoreactants of substance P were significantly decreased by formalin injection compared with that in controls. However, with bupivacaine injection, substance P levels were restored though not reaching the levels seen in the controls. Formalin injection also caused a significant increase of c-Fos expression in cervical spinal cord. This increase was not affected by stellate ganglion block. CONCLUSION: Stellate ganglion block can effectively alleviate nociceptive responses induced by formalin injection. The mechanism of its action may involve reduction of substance P in the spinal cord and plasma catecholamine release caused by noxious stimuli.

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma, reduces pulmonary inflammatory response in a rat model of endotoxemia.

OBJECTIVE: The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, on pulmonary inflammation in endotoxemia was investigated. MATERIALS AND METHODS: Male Wistar rats were given either lipopolysaccharide (LPS, 6 mg/kg i.v.) or saline, pretreated with rosiglitazone (0.3 mg/kg i.v.) or its vehicle (dimethyl sulphoxide) 30 min before LPS. The selective PPAR-gamma antagonist GW9662 (0.3 mg/kg i.v.) was given 20 min before rosiglitazone. Wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) as well as TNF-alpha and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-kappaB p65 and PPAR-gamma were also determined by immunohistochemistry or Western blot analysis. RESULTS: Rosiglitazone pretreatment significantly attenuated the increases in W/D ratio, MPO activity and MDA levels, and reduced pulmonary overproduction of TNF-alpha and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-kappaB and up-regulated the expression of PPAR-gamma protein. The specific PPAR-gamma antagonist GW9662 abolished the effect of rosiglitazone. CONCLUSION: These findings suggest that PPAR-gamma agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia.

A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies.

This Phase I study was performed to assess the feasibility of administering L-778,123, a peptidomimetic farnesyl protein transferase (FPTase) inhibitor, as a continuous i.v. infusion for 7 days every 3 weeks and to determine the recommended dose for subsequent disease-directed trials. This study also sought to characterize the pharmacological behavior of L-778,123 and to determine whether the desired biological effect, inhibition of protein farnesylation, could be detected and assessed during treatment. Patients with advanced solid malignancies were treated with L-778,123 as a continuous i.v. infusion for 7 days every 3 weeks at doses ranging from 35 to 1120 mg/m(2)/day. On the basis of preclinical studies, toxicity assessments included cardiac telemetry, electrocardiograms, and electroretinograms in addition to more routine safety monitoring laboratory tests. Plasma sampling was performed to characterize the pharmacokinetics of L-778,123, and peripheral blood mononuclear cells (PBMCs) were sampled to detect and monitor the inhibitory effects of L-778,123 on the prenylation of HDJ2, a chaperone protein that undergoes farnesylation. Twenty-five patients received 51 complete courses of L-778,123. An unacceptably high incidence of dose-limiting toxicities, consisting of grade 4 thrombocytopenia, significant prolongation of the QT(c) interval, and profound fatigue, was observed at the 1120 mg/m(2)/day dose level. At the next lower L-778,123 dose level, 560 mg/m(2)/day, seven new patients had no unacceptable toxicity. Instead, myelosuppression was mild to moderate and QT(c) prolongation was negligible. Pharmacokinetics were linear, and L-778,123 plasma concentrations at steady-state (mean, 8.09 +/- 3.11 microM at 560 mg/m(2)/day) exceeded IC(50) values (range, 0.07-5.35 microM) required for growth inhibition and cytotoxicity in preclinical studies. The systemic clearance of L-778,123 averaged 106.4 +/- 45.6 ml/min/m(2), and the terminal half-life of elimination was 2.8 +/- 1.0 h. L-778,123 inhibited HDJ2 prenylation for the duration of the drug infusion in a dose-dependent manner, but seemed to plateau above 560 mg/m(2)/day. At the 560 mg/m(2)/day dose level, the mean percentage of HDJ2 protein in its unprenylated form increased from 1.41% +/- 1.71% (pretreatment) to 28.76% +/- 6.10% (day 4) and 30.86 +/- 4.96 (day 8) and declined to 2.28% +/- 2.11% one week after drug discontinuation (day 16). L-778,123 administered as a continuous 7-day i.v. infusion for 7 days every 21 days is well tolerated at doses of 560 mg/m(2)/day and results in biologically relevant concentrations and consistent inhibition of HDJ2 prenylation in PBMCs. Although the relationship between drug-related inhibition of HDJ2 prenylation in PBMCs and both prenylation of relevant proteins and growth inhibition in tumor cells is unknown, serial analyses of HDJ2 prenylation provide a pharmacodynamic marker of protein prenylation that may be useful in optimizing the development of drugs targeting FPTase.

Subcellular expression of UGT1A6 and CYP1A1 responsible for propofol metabolism in human brain.

AIM: To observe the subcellular expression of UDP-glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P-450 1A1 (CYP1A1) mRNA in the human brain and investigate the effect of brain on extrahepatic metabolism of propofol. METHODS: Fifteen patients scheduled for craniotomy under propofol anesthesia were selected. Brain tis sue was taken and blood samples from the radial artery and the internal jugular vein were drawn simultaneously. PCR technique was used to detect UGT1A6 and CYP1A1 mRNA in the microsomes and mitochondria. Enzymatic activities were assayed. Blood propofol and propofol-glucuronide concentrations were measured with HPLC and GC, respectively. RESULTS: UGT1A6 mRNA was located mainly in the microsomes, and CYP1A1 mRNA was mainly in the mitochondria. The higher blood concentration of propofol and lower blood concentration of propofol-glucuronide were observed from the radial artery than from the internal jugular vein, respectively. The Km of UGT1A6 and CYP1A1 was (0.74 +/- 0.21) mmol and (548 +/- 50) mmol, respectively. The Vmax was (536 +/- 98) nmol . h-1 . mg-1 and (37 +/- 5) nmol . h-1 . mg-1, respectively. CONCLUSION: The human brain is an important organ for extrahepatic metabolism of propofol. The metabolism occurs within microsomes and mitochondria in brain.

Interval after prostate specific antigen testing and subsequent risk of incurable prostate cancer.

PURPOSE: Studies of the potential effect of prostate specific antigen (PSA) screening on a less than yearly basis have been limited to computer simulations using relatively small sample sets. Primary clinical data on this relationship have not been generally available. We examined the relationship of less frequent testing and the risk of nonlocalized incurable cancer. The effect of testing frequency on the risk of prostate biopsy in men ultimately diagnosed with cancer was also assessed. MATERIALS AND METHODS: The study included a population based sample of 36,422 men 65 years old or older residing in 9 geographic areas with newly diagnosed prostate cancer during 1989 to 1993. The primary end point was the risk of nonlocalized cancer, as determined by logistic regression. Patient age, geographic region, year of diagnosis and race were included as covariates. RESULTS: In men who would be diagnosed with prostate cancer the risk of nonlocalized cancer did not differ in those tested 2 or 3 years compared with the risk in those tested 1 year before diagnosis (relative risk 1.00, 95% confidence interval 0.84 to 1.20 and 1.02, 95% confidence interval 0.74 to 1.41, respectively). However, the risk of prostate biopsy in these men was directly related to the number of PSA tests performed (test for trend p = 0.0061). CONCLUSIONS: Patients who choose to undergo PSA testing may be tested on a biennial instead of annual basis without an increased risks of nonlocalized cancer. Decreasing the frequency of PSA testing may lead to fewer prostate biopsies.

Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial.

BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay.

BACKGROUND: Despite the large number of prostatectomies performed annually, few data exist regarding relationships between the volume of prostatectomies handled by a hospital, the length of a patient's stay in the hospital, and patient outcomes. We examined the effect of hospital prostatectomy volume and changes in the hospital volume on patient outcomes and the length of a patient's stay. METHODS: We collected data on 101 604 prostatectomies from Medicare claims filed from 1991 through 1994. By use of logistic regression and analysis of variance, we examined relationships between hospital load of prostatectomies, length of a patient's hospital stay, surgical complications, readmission rate, and mortality rate in a 30-day period following surgery. Statistical tests were two-sided. RESULTS AND CONCLUSIONS: Cross-sectional analyses revealed that, compared with high-volume hospitals, low-volume, medium-low-volume, and medium-high-volume hospitals had higher relative risks of readmission by 30% (95% confidence interval [CI] = 21%-39%), 16% (95% CI = 7%-25%), and 8% (95% CI = -1% to 17%), respectively; higher relative risks of serious complications by 43% (95% CI = 37%-48%), 25% (95% CI = 19%-31%), and 9% (95% CI = 3%-15%), respectively; and higher relative risks of mortality by 51% (95% CI = 25%-77%), 43% (95% CI = 17%-69%), and 42% (95% CI = 16%-68%), respectively. The mean length of a patient's stay in a low-volume hospital was 9% longer than that in a high-volume hospital (8.51 days [95% CI = 8.47-8.56] versus 7.81 days [95% CI = 7.77-7.85]; P for trend across all volume categories =.0001). Within-hospital longitudinal analyses revealed that hospitals with a relative increase in prostatectomy volume had a 57% greater reduction in the length of a patient's stay compared with those with a relative decrease in volume (P =.005). Changes in prostatectomy volume did not affect the frequency of complications, mortality, and readmission. These findings suggest that an increase in a given hospital's prostatectomy volume may facilitate a decrease in the length of a patient's stay without an adverse impact on patient outcomes.

Effect of age and surgical approach on complications and short-term mortality after radical prostatectomy--a population-based study.

OBJECTIVES: To use population-based data to accurately delineate the types and incidence of complications, risk of readmission, and influence of age and surgical approach on short-term mortality after radical prostatectomy. METHODS: Medicare claims from 1991 to 1994 were used to identify and quantify the types and risks of complications, rehospitalization within 90 days, and mortality at 30 and 90 days after perineal or retropubic prostatectomy. Logistic regression was used to determine the relationships between age, surgical approach, and short-term outcomes while adjusting for potential confounders. RESULTS: On the basis of data from 101,604 men, complications affected 25.0% to 28.8% of patients treated with the perineal or retropubic approach. The retropubic approach had a higher risk of respiratory complications (relative risk [RR] = 1.53, 95% confidence interval [CI] 1.37 to 1.71) and miscellaneous medical complications (RR = 1.77, 95% CI 1.60 to 1.97) and a lower risk of miscellaneous surgical complications (RR = 0.86, 95% CI 0.78 to 0.94). Differences in medically related gastrointestinal complications partially accounted for the differences in miscellaneous medical complications. Rectal injury with the perineal approach was only approximately 1% to 2%. Readmission within 90 days was necessary for 8.5% to 8.7% of patients who underwent the retropubic or perineal approach. The 30-day mortality was less than 0.5% for men aged 65 to 69; it approached 1% for men aged 75 and older. CONCLUSIONS: Complications and readmission after prostatectomy are substantially more common than previously recognized. Notable differences exist in the incidence of respiratory and nonsurgical gastrointestinal complications, although many short-term outcomes are comparable for the two approaches. Older age is associated with elevated surgical mortality and complications.

Use of radical prostatectomy among Medicare beneficiaries before and after the introduction of prostate specific antigen testing.

PURPOSE: We monitored the use of radical prostatectomy in medicare beneficiaries before and after the introduction of prostate specific antigen (PSA) testing. MATERIALS AND METHODS: Radical prostatectomies performed on medicare beneficiaries between 1984 and 1995 were identified through the medicare claims data base. Medicare enrollment files were used to define the population at risk and age-adjusted rates were standardized to the 1990 United States medicare population. RESULTS: Rates of radical prostatectomy have steadily increased since 1984. A sharp increase in radical prostatectomy rates followed the institution of PSA testing after which a prominent decrease, particularly among older age groups, was evident. During the peak year of 1992 the age-adjusted rates of radical prostatectomy for white and black men 65 to 79 years old in the United States were 461.2 and 294.5/100,000 men. Between 1992 and 1995 the rates of radical prostatectomy among white men decreased by 22, 47 and 69% for patients 65 to 69, 70 to 74 and 75 to 79 years old, respectively. The corresponding changes among black men were +6, -18 and -47%, respectively. Differences in the age-adjusted rates between white and black men have narrowed in recent years, ranging from 166.7 (1992) to 29.7 (1995)/100,000 men. CONCLUSIONS: Recent years have been marked by a rapid increase in the use of radical prostatectomy, which peaked in 1992. Subsequent to 1992 a sharp decrease occurred, which was particularly evident in older and white men. Racial differences in the use of radical prostatectomy have narrowed in recent years.

Population-based study of long-term survival in patients with clinically localised prostate cancer.

BACKGROUND: Choice of treatment in localised prostate cancer has been hampered by a lack of unbiased, representative data on outcome. Most existing data have come from small cohorts at specialised academic centres; precise overall and cancer-grade-specific data are not available, and the data are subject to differential staging bias. Randomised clinical trials have been undertaken, but the results will not be available for another decade. We have carried out a large population-based study to ascertain overall and prostate-cancer-specific survival in men treated by prostatectomy, radiotherapy, or conservative management. METHODS: Data for 59,876 cancer-registry patients aged 50-79 were analysed. We examined the effect of differential staging of prostate cancer by analysing the data both by intention to treat and by treatment received. Estimated survival was calculated by the Kaplan-Meier method. FINDINGS: By the intention-to-treat approach, 10-year prostate-cancer-specific survival for grade 1 cancer was 94% (95% CI 91-95) after prostatectomy, 90% (87-92) after radiotherapy, and 93% (91-94) after conservative management. The corresponding survival figures in grade 2 cancers were 87% (85-89), 76% (72-79), and 77% (74-80); those in grade 3 cancer were 67% (62-71), 53% (47-58), and 45% (40-51). Although the intention-to-treat and treatment-received analyses yielded similar results for radiotherapy and conservative management, the 10-year disease-specific survival after prostatectomy differed substantially (83% [81-84] by intention to treat vs 89% [87-91] by treatment received). INTERPRETATION: The overall and cancer-grade-specific survival found in this study differ substantially from those in previous studies. Previous studies that used a treatment-received approach have generally overestimated the benefits of radical prostatectomy. We found that grade 3 tumours are highly aggressive irrespective of stage.

Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases.

The induction of apoptosis by the Fas/APO-1 receptor is important for T-cell-mediated cytotoxicity and down-regulation of immune responses. Binding of Fas ligand to the Fas/APO-1 receptor transduces an apoptotic signal that requires activation of interleukin 1beta-converting enzyme (ICE) and CPP32beta, members of a family of cysteine proteases that are evolutionarily conserved determinants of cell death. We report here that Fas/APO-1-triggered apoptosis involves ICE-mediated activation of p34cdc2 kinase. Ligation of the Fas receptor resulted in the rapid stimulation of ICE proteolytic activity and activation of p34cdc2 kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala-Asp-chloromethylketone) or CPP32beta (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas antibody-mediated activation of p34cdc2 and inhibited apoptosis. Inhibition of p34cdc2 activity by transient overexpression of a dominant-negative cdc2 construct or human WEE1 kinase inhibited Fas-mediated apoptosis. These results suggest that activation of p34cdc2 kinase is a critical determinant of cell death mediated by Fas and ICE family proteases.

Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase.

The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.

Soluble normal and mutated DNA sequences from single-copy genes in human blood.

Healthy individuals have soluble (extracellular) DNA in their blood, and increased amounts are present in cancer patients. Here we report the detection of specific sequences of the cystic fibrosis and K-ras genes in plasma DNA from normal donors by amplification with the polymerase chain reaction. In addition, mutated K-ras sequences are identified by polymerase chain reaction utilizing allele-specific primers in the plasma or serum from three patients with pancreatic carcinoma that contain mutated K-ras genes. The mutations are confirmed by direct sequencing. These results indicate that sequences of single-copy genes can be identified in normal plasma and that the sequences of mutated oncogenes can be detected and identified with allele-specific amplification by polymerase chain reaction in plasma or serum from patients with malignant tumors containing identical mutated genes. Mutated oncogenes in plasma and serum may represent tumor markers that could be useful for diagnosis, determining response to treatment, and predicting prognosis.

Prevalence of vitamin B12 deficiency among geriatric outpatients.

BACKGROUND: Healthy people can have low levels of cobalamin (vitamin B12) without symptoms or signs of cobalamin deficiency. Early detection of deficiency is imperative for treatment to be effective. Development of radioimmunoassay tests has greatly improved accurate determination of cobalamin (Cbl) levels. Nevertheless, results of studies of Cbl deficiency vary widely because of the variety of populations studied. METHODS: In a prospective study, we tested 100 consecutive, unselected geriatric outpatients in a primary care setting to determine the prevalence of cobalamin deficiency. All patients, 65 years of age or older, who visited the office of one of the authors during a period of 11 consecutive working days, had their serum Cbl level checked. If the level was 299 pg/mL or lower, serum intrinsic factor and parietal cell antibodies, serum gastrin, part 1 Schilling test, serum methylmalonic acid, and total homocysteine were done, when possible, for the diagnosis of type A gastritis and intracellular Cbl deficiency. RESULTS: Sixteen percent of geriatric outpatients had serum Cbl levels of 200 pg/mL or below, and 21% had levels between 201 and 299 pg/mL. Among the 16 patients with levels < or = 200 pg/mL, 2 patients had macrocytic anemia, 3 patients had peripheral neuropathy, and 8 patients had type A gastritis. Among the 21 patients with levels of 201 to 299 pg/mL, 2 patients had peripheral neuropathy, 9 patients had type A gastritis, and none of the patients had macrocytic anemia. Among the patients whose methylmalonic acid and total homocysteine levels were determined, the results were high in 80% of those with Cbl levels < or = 200 pg/mL and in 33% of those with levels from 201 to 299 pg/mL. CONCLUSIONS: The prevalence of Cbl deficiency in geriatric outpatients was found to be higher than in any recent report. The lower limit of the normal range for Cbl level should be increased to 300 pg/mL.