In situ degradation of rapidly transported proteins in nerve terminals of retinal ganglion cells

The in situ degradation of rapidly transported proteins in nerve terminals of retinal ganglion cells was studied in pieces of the superior colliculus of the rabbit. Proteolytic degradation was found to be dependent upon extracellular calcium and intact calcium channels. Degradation was inhibited by leupeptin and SH-group blocking agents.     

A Double-Blind, Multicenter Immunotherapy Trial in Children, Using a Purified and Standardized Cladosporium herbarum Preparation II. In Vitro Results

This double-blind immunotherapy trial in children, using a purified and standardized Cladosporium herbarum allergen preparation, has shown that children with mould asthma and/or rhinoconjunctivitis, responded to immunotherapy with a decrease in specific IgE and a significant increase in specific IgG. There was a marked increase in the ratio specific IgG/specific IgE as a result of active treatment. IgE-CRIE radiostaining patterns showed no pronounced changes after 10 months' active treatment and no "new sensitivities" could be detected in the studied patients. IgG-CRIE radiostaining, primarily directed towards the important allergens, was significantly increased in the active group and particularly towards Ag-12 (partially identical to a previously described major allergen in Cladosporium herbarum, Ag-54). Children treated with histamine placebo showed no change in antibody patterns during 10 months of treatment.     

Enzyme-linked immunosorbent assay for immunological diagnosis of human tularemia.

The enzyme-linked immunosorbent assay (ELISA) was applied for immunological diagnosis of human tularemia, using lipopolysaccharide from Francisella tularensis as antigen. Sera collected from patients, healthy individuals, and vaccinated volunteers were investigated for antibodies against F. tularensis by ELISA and tube agglutination. In ELISA all sera were titrated with a polyspecific anti-immunoglobulin enzyme conjugate. A limited number of consecutive sera from individual patients were also investigated for immunoglobulin G (IgG) and IgM antibodies by means of immunoglobulin class-specific conjugates. On an average ELISA was more than 10-fold as sensitive as tube agglutination. Two weeks after onset of disease, sera from patients had significantly higher titers in ELISA than sera from healthy controls. High titers persisted after more than 2 years. Significant amounts of both IgG and IgM antibodies were present within 1 to 2 weeks after infection. The antibody activity increased during the first month, without any significant change of the relation between IgG and IgM titers. After 2.5 years the IgG/IgM titer ratio of sera from patients was significantly increased. Within 6 weeks after vaccination sera from about half of the vaccinees had significantly elevated titers in ELISA. Titers observed after vaccination were generally lower than those found after infection. An elevated ELISA titer can be of diagnostic importance by the end of the first week of illness. A significant increase of titer in consecutive serum samples indicates a diagnosis of tularemia. Determination of IgG and IgM antibodies may be of value in determing whether a positive titer of a single serum sample is of longstanding or recent origin.     

Development of porcine pancreatic hydrolases and their isoenzymes from the fetal period to adulthood

The appearance and activity of various porcine pancreatic hydrolases were studied during fetal and postnatal development. Quantitatively, the enzyme activities in activated pancreas homogenates were low but increased during the second half of the fetal period, using the substrates Bz-Arg-pNA for measuring anodal and cathodal trypsin, Suc-Phe-pNA (chymotrypsin A and C, and elastase II) and Suc-(Ala)3-pNA (elastase I and protease E). Postnatally, after an initial decrease during the first week, the enzyme activities increased markedly, especially from 10-14 weeks to 6 months. The individual hydrolases were identified after electrophoretic separation in agarose gel and staining with various substrates either directly in the gel or after transfer to nitrocellulose membranes (enzymoblotting). During the fetal period, chymotrypsin A and B, elastase II, carboxypeptidase A, and amylase appeared at approximately 65 days and anodal trypsin, at approximately 76 days. After birth, new proteinases appeared after the first week including chymotrypsin C, cathodal trypsin, and protease E, whereas elastase I was found from 5 weeks after birth. Concomitantly, unidentified "fetal proteinase(s)" with caseinolytic, Ac-Phe-beta NE and CBZ-Ala-beta NE activities began to diminish and disappeared 10-14 weeks after birth. This study showed a marked increase in the overall pancreatic enzyme activities, as well as an age-dependent expression of the variety of pancreatic hydrolases during porcine ontogeny.     

Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX®, Falls,and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis

Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height² (ALM/ht²) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX^®) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht² only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht²), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated ± fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Induction of circulating activated suppressor-like T cells by methimazole therapy for Graves' disease

Thyrostatic drug treatment of Graves' disease suppresses excessive thyroid hormone synthesis and causes a parallel decrease in serum thyroid autoantibody levels. The mechanism of this immunosuppression is unknown. We studied methimazole-induced immunoregulatory effects prospectively in 14 patients with Graves' disease treated for up to six months. The numbers of circulating activated, HLA-DR-positive T helper/inducer cells decreased gradually, from 8.3+1.7 percent (+SD) to 1.0+1.7 percent (P less than 0.001). HLA-DR-positive T suppressor/cytotoxic cells increased transiently at one month, from 2.0+1.9 percent to 12.6+6.4 percent (P less than 0.001), and returned to 2.9+3.7 percent at six months. Methimazole did not alter the HLA-DR expression of T cells in vitro. In two patients, the helper activity of T cells in inducing autoantibody secretion in vitro was substantially reduced after one month of methimazole treatment. Before treatment, large proportions of thyroid-infiltrating T-cell subsets expressed the activation markers HLA-DR, interferon-gamma, and interleukin-2 receptors, which were partially lost during therapy. Methimazole treatment was accompanied by a gradual reduction in circulating levels of thyrotropin-receptor, microsomal, and thyroglobulin autoantibodies. These results are compatible with the view that methimazole-induced immunoregulation in Graves' disease is mediated by a direct inhibitory effect on thyrocytes. This inhibition is in turn accompanied by marked changes in the proportions of activated T helper-like and T suppressor-like cells. This altered T-cell activation profile reflects, at least in part, the functional suppression of autoantibody production observed in methimazole-treated patients with Graves' disease.     

Clinical and genetic features of variegate porphyria in a Chinese patient

Acute porphyria is rare in orientals. We describe a Chinese woman with recurrent generalised tonic-clonic seizures and abdominal pain. Genomic DNA studies identified a heterozygous base substitution from guanine to adenine at nucleotide position 503, resulting in substitution of arginine by histidine at position 168 of the protein (R168H). This genetic abnormality is similar to the mutation reported in Caucasians with variegate porphyria. To the best of our knowledge, this is the first report in the English literature a Chinese patient with variegate porphyria with an identifiable mutation. A brief review of porphyria is presented.     

The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I. Results from a randomized trial

Background: Cost-effectiveness of routine postoperative radiotherapyafter breast-conserving surgery has not been prospectively evaluatedearlier. In times of rationing of medical resources, valid assessments ofcost-effectiveness are important for rational allocation of resources.Purpose: Cost and cost-effectiveness of routine postoperativeradiotherapy was calculated in a prospective randomized trial comparingsector resection plus axillary dissection with (XRT group) or without(non-XRT group) postoperative radiotherapy in breast cancer stage I. Threehundred eighty-one patients were included. After a median follow-up of fiveyears 43 local recurrences, six of them in the XRT-group occurred (P <0.0001). No difference in regional and distant recurrence (P = 0.23) orsurvival (P = 0.44) was observed.Patients and methods: Direct medical costs as well as indirect costs interms of production lost during the treatment period and travel expenseswere estimated from data in the medical records and the national insuranceregistry of each patient. Average costs of different treatment activitiesand measures were estimated for the XRT-group and the non-XRT grouprespectively. From these estimates differences in costs and effectivenessbetween the groups were calculated and marginal cost-effectiveness ratioswere estimated. For the construction of QALYs each life-year wasquality-adjusted by a utility value depending on which health state thepatient was considered to perceive.Results: Taking into account the cost of primary treatment, the cost offollow-up, the cost of treatment of a local recurrence, travel expenses andindirect costs (production lost) excluding costs for treatment of regionaland distant recurrence the cost per avoided local recurrence at five yearswas SEK 337,727 ($44,438, £27,018).Adjustment for quality of life showed a cost for every gained QALY to beSEK 1.6 million, ($210,526, £128,000), range SEK0.2–3.9 million ($26,315–513,158;£16,000–312,000).Conclusion: The cost of routine postoperative radiotherapy after sectorresection and axillary dissection in breast cancer stage I per avoided localrecurrence and gained QALY is high. The cost per gained QALY show greatvariation depending on utility value, which in this study was derived fromexternal observers and not from the patients themselves. These results stressthe importance of identifying risk factors for local recurrence, betterunderstanding of impact on quality of life of a local recurrence and addingcost evaluations to clinical trials in early breast cancer.     

The effects of different intravenous feeding regimens on the rates of synthesis of alpha1-antitrypsin after surgery

The effects of two nutritional regimens on the synthesis of alpha-1 antitrypsin were investigated postoperatively in gynaecological cancer patients. Total parenteral nutrition (TPN) or a hypocaloric amino acid mixture was administered on the day of surgery and continued for 3 days. The rate of synthesis of alpha-1 antitrypsin was estimated by a computer model from serial plasma concentrations of this protein and a reference protein, albumin. The hypocaloric amino acid mixture resulted in a more negative nitrogen balance than that produced during administration of TPN containing the same amount of nitrogen but more non-protein energy. Urinary excretion of 3-methylhistidine was significantly greater (p = 0.017) in the hypocaloric amino acid group (350 +/- 40 mumol/day; mean +/- SE) on the third postoperative day, as compared to the TPN group (240 +/- 20 mumol/day). In spite of this the synthesis of alpha-1 antitrypsin was apparently greater in the hypocaloric amino acid than in the TPN group. The accumulated plasma appearance rate of alpha-1 antitrypsin was significantly higher (p = 0.0465) in HAA group, at 70 h it was 490 +/- 40 compared to 400 +/- 20 times the pre-operative synthesis in the TPN group.     

Additional value of thallium-201 SPECT to a conventional exercise test for the identification of severe coronary lesions after an episode of unstable coronary artery disease

The additional value of thallium-201 SPECT to a conventional exercise test for the identification of patients with severe coronary lesions was evaluated in 170 men, one month after an episode of unstable coronary artery disease. Severe coronary lesions at coronary angiography — defined as three vessel disease, left main stenosis or proximal left anterior descending artery stenosis as part of two vessel disease — were observed in 45.9%. In the SPECT image, the left ventricular myocardium was divided into nine segments and each segment was classified as either normal (=0), reduced uptake (=1) or uptake defect (=2). The sum of gradings in all segments post-exercise was denoted SPECT score. The patients were divided into nine different groups regarding ST-depression during exercise (no ST-depression, ST-depression in 1–2 leads or 3 leads) and SPECT score (no SPECT score, 1–3 scores or 4 scores). Severe coronary lesions were, in 68% identified by SPECT score 4 and in 65% by ST-depression in 1 lead at exercise test. The specificity for identification of severe coronary lesions was, for both tests, 65%. SPECT score 4 and/or ST-depression in 3 leads identified 82% of the patients with severe coronary lesions with a specificity of 63%. Furthermore, SPECT score 3 identified more patients with isolated proximal left anterior descending artery stenosis than ST-depression alone at exercise test.