Extraction of the

This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.

Severe Renal Allograft Rejection Resulting from Lenalidomide Therapy for Multiple Myeloma: Case Report.

Lenalidomide, a thalidomide analogue, is an immunomodulatory drug currently used as a chemotherapeutic agent in treating certain hematologic malignancies, including multiple myeloma. The antineoplastic effect of lenalidomide may be due to its ability to modulate different components of the immune system as well as its antiangiogenic, antiproliferative, and direct cytotoxic activity. Given its immunomodulatory effects, lenalidomide may potentially elicit unintended immune activity against allografts in solid organ transplant recipients. Here, we present a case of a renal transplant recipient who developed multiple myeloma after transplantation and was treated with the use of lenalidomide, which precipitated severe acute T-cell-mediated rejection. Lenalidomide was thought to be causative, and after cessation of the drug her renal function stabilized.

Measurement of the Electron Antineutrino Oscillation with 1958 Days of Operation at Daya Bay.

We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor ν[over ¯]_{e} inverse ß decay candidates observed over 1958 days of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative ν[over ¯]_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the inverted hierarchy.

Alterations in skeletal muscle structure are minimized with steroid withdrawal after renal transplantation.

BACKGROUND: Limitations in exercise capacity in kidney transplant recipients are thought to result in part from changes in muscle structure and function associated with immunosuppression therapy. METHODS: We compared the percent distribution of skeletal muscle fiber types, cross-sectional areas, and ultrastructural morphologies in kidney transplant recipients treated with standard prednisone maintenance therapy (n=21) to those undergoing rapid withdrawal of prednisone using Simulect (interleukin 2 receptor inhibitor) (n=13). Skeletal muscle biopsy specimens from the vastus lateralis were analyzed at 3 and 12 months after transplantation and compared with sedentary controls (n=15). RESULTS: Compared with the control group, the group receiving prednisone maintenance therapy had a significantly lower percentage of type I fibers and a higher percentage of type IIB/x fibers, evident at 3 and 12 months. Fiber type distribution in patients withdrawn from prednisone did not differ from controls. In patients withdrawn from prednisone, the cross-sectional areas of type I and IIA fibers were lower and the area of type IIB/x fibers was higher compared with controls. Likewise, ultrastructural studies revealed reduced volume densities of myofibrils and higher densities of interfibrillar and subsarcolemmal mitochondria. At 12 months there were no ultrastructural differences between the patients withdrawn from prednisone and controls. CONCLUSIONS: We conclude that prednisone maintenance therapy contributes to the lower exercise capacity by altering the ratio of type I to type IIB/x fibers and by reducing myofilament density. The increase in mitochondria in patients receiving prednisone may reflect a switch from carbohydrate to lipid metabolism resulting from the glucocorticoid therapy.

Health-related fitness and quality of life following steroid withdrawal in renal transplant recipients.

BACKGROUND: Exercise capacity increases significantly soon after transplantation; however, over time it does not further improve and patients remain low compared to normal levels. The limitations to exercise following transplantation have not been identified, but may be related to immunosuppression therapy regimens that include prednisone. METHODS: We studied health-related fitness measures (cardiorespiratory fitness, muscle strength, and body composition) and quality of life in renal transplant recipients randomized into two groups: those using standard maintenance immunosuppression, including prednisone therapy (N = 14); and those undergoing rapid withdrawal of steroids using Simulect[interleukin-2 (IL-2) receptor inhibitor] (N = 9). Testing was done at 3 and 12 months following transplant and the 12-month data were compared to 15 normal sedentary controls. RESULTS: Compared to those maintained on steroids, the steroid withdrawal group showed greater gains in VO2peak (P = 0.05) and quadriceps peak torque (P = 0.05) and greater gains in the vitality score and the Physical Composite Scale on the SF-36 questionnaire (P < 0.05). At 1 year, all patients had significantly lower exercise capacity compared to the sedentary controls (P = 0.01). No differences were observed in body composition, with both patient groups increasing in body weight (primarily body fat) over time. At 12 months, all patients were not different in body fat percentage compared to the sedentary controls. CONCLUSION: We conclude that prednisone is not the cause for increased body fat following transplantation; however, it may contribute to lower spontaneous improvements in exercise capacity possibly by limiting increases in muscle strength. The low exercise capacity in all transplant recipients studied at 1 year suggests a need for exercise training to optimize physical functioning following transplant.

Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise.

Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20-27 yr), 12 middle-aged (47-60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46-79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% (P < 0.05) from young to middle age and further decreased 50% (P < 0.05) from middle to old age. MHCIIx decreased 84% (P < 0.05) from young to middle age and 48% from middle to old age (P < 0.05). Exercise increased FSR of MHC by 47% (P < 0.01) and mixed muscle protein by 56% (P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.

Reduced synthesis of muscle proteins in chronic renal failure.

Muscle wasting and weakness occur frequently in patients with chronic renal failure. The mechanism(s) by which these abnormalities occur is unclear. We hypothesized that such findings were due to defective muscle protein synthesis. We measured synthetic rates of mixed muscle proteins, myosin heavy chain, and mitochondrial proteins in serial muscle biopsy samples during a continuous infusion of L[1-(13)C]leucine from 12 patients with chronic renal failure and 10 healthy control subjects under identical study conditions. Patients with chronic renal failure have significantly lower synthetic rates of mixed muscle proteins and myosin heavy chain (27 and 37% reductions, respectively, P < 0.05 and P < 0.02). Significant declines in the synthetic rates of muscle mitochondrial protein (27%) (P < 0.05), muscle cytochrome c-oxidase activity (42%) (P < 0.007), and citrate synthase (27%) (P < 0.007) were also observed in patients with chronic renal failure. The synthetic rates of muscle proteins and activity of mitochondrial enzymes were negatively correlated to the severity of renal failure. These results indicate that in chronic renal failure there is a decrease in the synthesis of muscle contractile and mitochondrial proteins and a decrease in muscle mitochondrial oxidative enzymes. Reduced synthetic rate of several muscle proteins is the likely biochemical basis of muscle loss and muscle weakness in people with chronic renal failure.

Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans.

A decline in muscle mass and contractile function are prominent features of the sarcopenia of old age. Because myosin heavy chain is an important contractile protein, it was hypothesized that synthesis of this protein decreases in sarcopenia. The fractional synthesis rate of myosin heavy chain was measured simultaneously with rates of mixed muscle and sarcoplasmic proteins from the increment of [13C]leucine in these proteins purified from serial needle biopsy samples taken from 24 subjects (age: from 20 to 92 yr) during a primed continuous infusion of L-[1-(13)C]leucine. A decline in synthesis rate of mixed muscle protein (P < 0.01) and whole body protein (P < 0.01) was observed from young to middle age with no further change with advancing age. An age-related decline of myosin heavy-chain synthesis rate was also observed (P < 0.01), with progressive decline occurring from young, through middle, to old age. However, sarcoplasmic protein synthesis did not decline with age. Myosin heavy-chain synthesis rate was correlated with measures of muscle strength (P < 0.05), circulating insulin-like growth factor I (P < 0.01), and dehydroepiandrosterone sulfate (P < 0.05) in men and women and free testosterone levels in men (P < 0.01). A decline in the synthesis rate of myosin heavy chain implies a decreased ability to remodel this important muscle contractile protein and likely contributes to the declining muscle mass and contractile function in the elderly.

Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle.

A progressive decline in muscle performance in the rapidly expanding aging population is causing a dramatic increase in disability and health care costs. A decrease in muscle endurance capacity due to mitochondrial decay likely contributes to this decline in muscle performance. We developed a novel stable isotope technique to measure in vivo rates of mitochondrial protein synthesis in human skeletal muscle using needle biopsy samples and applied this technique to elucidate a potential mechanism for the age-related decline in the mitochondrial content and function of skeletal muscle. The fractional rate of muscle mitochondrial protein synthesis in young humans (24 +/- 1 year) was 0.081 +/- 0.004%.h-1, and this rate declined to 0.047 +/- 0.005%.h-1 by middle age (54 +/- 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 +/- 0.004%.h-1) occurred with advancing age (73 +/- 2 years). The mitochondrial synthesis rate was about 95% higher than that of mixed protein in the young, whereas it was approximately 35% higher in the middle-aged and elderly subjects. In addition, decreasing activities of mitochondrial enzymes were observed in muscle homogenates (cytochrome c oxidase and citrate synthase) and in isolated mitochondria (citrate synthase) with increasing age, indicating declines in muscle oxidative capacity and mitochondrial function, respectively. The decrease in the rates of mitochondrial protein synthesis is likely to be responsible for this decline in muscle oxidative capacity and mitochondrial function. These changes in muscle mitochondrial protein metabolism may contribute to the age-related decline in aerobic capacity and muscle performance.

Evidence for a catabolic role of glucagon during an amino acid load.

Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.

Cardiopulmonary arrest in pregnancy: successful resuscitation of mother and infant following immediate caesarean section in labour ward.

Our patient experienced cardiopulmonary arrest secondary to profound hypotension and was unable to be resuscitated with external cardiac massage and assisted ventilation. This case demonstrates the need for continued vigilance by medical and nursing staff when epidural anaesthesia is being established. Resuscitation equipment should be available in the labour ward as cardiopulmonary resuscitation and immediate Caesarean section can be lifesaving in the event of a cardiopulmonary arrest.

Glomerulonephritis with associated hypocomplementemia and crescents: an unusual case of fibrillary glomerulonephritis.

Fibrillary glomerulonephritis is an unusual, but not rare cause of glomerulonephritis. Hypocomplementemia in association with fibrillary glomerulonephritis has been reported only once previously. A patient with hypocomplementemia and fibrillary deposits as demonstrated by electronmicroscopy is reported. The clinical and pathologic features of fibrillary glomerulonephritis and immunotactoid glomerulopathy are reviewed.

Smoking in pregnancy: relevance of maternal screening tests on fetal outcome.

A number of laboratory parameters were estimated in 54 pregnant women in order to assess whether changes induced by smoking could reflect weight gain in the fetus. There was a significant correlation between maternal weight gain index, oestriol levels, antithrombin III levels and reticulocyte synthesis with infant and placental weight gain. One or more of these tests was found abnormal in 27% of normal pregnant patients, 72% of light smokers, and 89% of heavy smokers. Several other parameters were found to be significantly altered in smoking compared to non-smoking pregnant patients; however, these bore no relationship to infant and placental parameters. These studies indicate that laboratory assessment of a number of maternal parameters could be of some value in determining the likelihood of depressed weight gain by infants of smoking mothers.

Contraception in the puerperium.

Choice of contraception in the puerperium is complicated by the normal factors of lactation, involuting uterus and emotional lability. The individual's previous contraceptive experience is important, and new agents and techniques change current practices. In the puerperium, failure for IUDs is increased, and tubal ligation has more hazards. During lactation the standard combined oral contraceptives are not advised, but the microdose progestagen-only pill may be a most satisfactory agent-changing to more routine methods when menstruation starts. In a population of normal women, progestagen-only therapy may show about a 25 per cent dropout because of an unacceptable bleeding pattern, but there is a small group of women who appear to be well suited by this form of oral contraception.