[Quantitative analysis of the degeneration of cervical spine and the correlation to the heterotopic ossification after artificial cervical disc replacement].

Objective: To investigate parameters related to quantifying the amount of degeneration in preoperative patients to identify ideal indication of artificial cervical disc replacement (ACDR) in patient with a minimum of 10 years of follow-up data. Methods: From January 2004 to August 2008, a total of 44 patients underwent single level Bryan cervical disk replacement performed by the same group of surgeons were involved in this retrospective study, and all of the patients in this group had at least 10 years of follow-up data. Heterotopic ossification (HO) was graded in radiographic images by using the McAfee classification. Preoperative degeneration of cervical spine was evaluated in radiographs based on a quantitative"9 points"scoring system. Univariate analysis and multifactor logistic regression were made to identify significant factors. To determine the cut-off points for the significant factors, a receiver operating characteristic (ROC) curve analysis was conducted. Results: The incidence of HO in study group was 61.4%. Based on univariate analysis results, there were significant differences in the scores of disc height, the presence of anterior osteophytes and endplate sclerosis between the HO group and non-HO group (all P<0.05), and the indices were included in the multivariate analysis. According to the logistic regression results, disc height and endplate sclerosis were identified as the independent risk factors for HO(OR(95%CI): 10.801(1.202-97.064), 37.870(1.581-907.237), respectively, both P<0.05). ROC analysis showed the area under the curve (AUC) of disc height and endplate sclerosis were 0.822 and 0.792, respectively. According to the scoring system, the ROC curve indicated that both the optimal cutoff points were 1.5. Conclusion: The incidence of postoperative HO is relatively high among the patients who had more than 10 years follow-up, and the amount of degeneration in the target level before surgery correlated with the incidence of HO.

[The correlation between the severity of uncovertebral joints degeneration and heterotopic ossification after single-level artificial cervical disc replacement].

Objective: To investigate the correlation between the severity of uncovertebral joints degeneration and heterotopic ossification (HO) after single-level artificial cervical disc replacement (ACDR). Methods: From January 2005 to January 2016, 70 patients who had undergone single-level ACDR in Peking University Third Hospital and had at least 5 years follow-up were included in this study. There were 35 males and 35 females with an average age of (42±8) years (range, 25-62 years). Cervical spine A-P X-rays were taken to assess the degeneration of uncovertebral joints and lateral X-rays were taken to assess the degeneration of intervertebral space. Cervical spine lateral and the flexion-extension X-rays at 5 years follow up were taken to assess HO. Degeneration of uncovertebral joints were evaluated by the classification system set-up in Peking University Third Hospital. Kellgren&Lawrence grading system was used to evaluate the degeneration of intervertebral space. HO was evaluated by the McAfee grading standards. The data were collected before surgery and at 5-years follow-up, then the correlation between degeneration of uncovertebral joints, degeneration of intervertebral space and HO was analyzed with Spearman non-parametric test. Results: The average follow-up time of 70 patients was (62.7±4.8) years (range, 52-74 months). There was a significant positive correlation between preoperative uncovertebral joints degeneration and HO after ACDR (r=0.585, P<0.01). There was a significant positive correlation between preoperative intervertebral space degeneration and HO (r=0.557, P<0.01). There was a significant positive correlation between preoperative intervertebral space degeneration and preoperative uncovertebral joints degeneration (r=0.727, P<0.01). Conclusion: There is a significant positive correlation between preoperative uncovertebral joints degeneration and HO after ACDR.

[Detection of circulating tumor DNA in epidermal growth factor receptor-TKI relapsed non-small cell lung cancer patients using next-generation sequencing and an analysis of the resistant mechanisms].

Objective: Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) samples from tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancers (NSCLC) and TKI-relapsed NSCLC to investigate the clinical value. Methods: A total of 381 plasma samples from patients who were diagnosed with lung cancer in Cancer Hospital Chinese Academy of Medical Sciences from March 2017 to May 2018 were enrolled in the study. NGS was performed using a custom-designed panel that covers 10 lung cancer-related driven genes. Paired plasma-tissue samples from 39 patients were collected to analyses the sensitivity and specificity of detecting driver gene mutations using ctDNA. NGS was also performed on plasma samples from TKI-relapsed patients to identify TKI resistance mechanisms. Results: Thirty-nine plasma samples collected from 39 NSCLC patients (including 21 female and 18 male) with corresponding tissue biopsies were analyzed for the sensitivity and specificity. The average age was 56 years (range 29 to 82 years). A high concordance of 84.62% (33/39) was observed between ctDNA and tissue biopsies. Compared with tissue biopsies, NGS sensitivity for ctDNA was 82.14% and specificity was 90.91%.Among these 39 patients, 34 were advanced stage patients (III-IV stage). The concordance, sensitivity, and specificity for ctDNA among the advanced stage patients were 88.24% (30/34), 86.36% (29/34) and 91.67% (31/34), respectively. Among the 381 plasma samples [including 231 TKI-naïve patients and 150 epithelial growth factor receptor(EGFR)-TKI relapsed patients], EGFR mutation was the most common driver gene among the 221 TKI-naïve lung adenocarcinoma patients (32.58%, 72/221). For 133 patients who progressed after first-generation EGFR-TKI, T790M was found to be the most frequent resistant mechanism (39.10%, 52/133), as well as bypass activation (3.01%, 4/133; such as MET amplification and ERBB2 amplification). Among those first-generation EGFR-TKI relapsed patients with EGFR sensitive mutations, T790M was detected in 53.06% (52/98). For the 17 patients who progressed after third-generation EGFR-TKI, C797S was found to be the most common resistant mechanism (4/17). Conclusions: The concordance, sensitivity and specificity between ctDNA and tissue biopsies are acceptable. ctDNA analysis provides valuable information for lung cancer patients' targeted treatment, especially for patients not fitted for biopsies.

[Midterm clinical outcomes and radiological results of surgical treatment for Hirayama disease].

OBJECTIVE: To assess the midterm clinical and radiological outcomes of internal fixation and fusion for the treatment of Hirayama disease and to evaluate the clinical significance and value of this procedure. METHODS: In the study, 36 patients were treated with anterior cervical internal fixation and fusion. The clinical outcomes including muscle strength and atrophy were recorded. The radiological outcomes including range of motion of cervical spine and the cross-sectional area of spinal cord at each level on MRI scan were measured before and at 3 month, 1 year and 2 years follow-up time points after surgery. RESULTS: (1) Clinical outcomes: all the patients showed no further progression of symptoms except one patient with mild progression of muscular weakness and atrophy. As the time passed by, the ratio of the patients with muscle strength and atrophy improvement increased. There were 26.5% of patients in 3 months, 36.0% in 1 year and 85.7% in 2 years who experienced muscle strength improvement. 8.8% of patients in 3 months, 24.0% in 1 year and 35.8% in 2 years felt muscle atrophy improvement. And 12 of the 14 patients showed improved muscle strength and atrophy at the end of 2 years period follow-up. (2) Radiological outcomes: the range of motion (ROM) of C2-C7 was significantly decreased after the operation. The ROM of preoperation was 62.25°±2.10° and that of 2 years postoperation was 13.67°±7.51°(P<0.01). The spinal cord was of no compression on flexion MRI. The cross-section area of spinal cord on MRI was significantly increased only at C6 level (P<0.05) at the end of three months follow-up. The level of increased cross-section area rose to C4-C5-C6 levels (P<0.01) in 1 year and to C4-C5-C6-C7 levels at the end of 2 years follow-up (P<0.05). The cross-section area increased 15.60% at C4, 19.08% at C5, 21.60% at C6 and 23.91% at C7 with significant difference (P<0.05) 2 years after the operation. CONCLUSION: Anterior cervical internal fixation and fusion is an effective surgical treatment for Hirayama disease and may provide preferable midterm clinical and radiological outcomes. This procedure has clinical significance and value in terms of control of the progression and outcome of this disease.

[Effects of percutaneous nephrolithotomy in the treatment of medullary sponge kidney with calculi].

Objective: To evaluate the effects of percutaneous nephrolithotomy (PNL) in the treatment of medullary sponge kidney with calculi. Methods: A total of 77 patients (91 renal units) of medullary sponge kidney with calculi (MSK group) and 77 patients (77 renal units) with common kidney stone (control group) received PNL at Department of Urology in Peking University People's Hospital from September 2006 to February 2016 were analyzed retrospectively. The MSK group included 33 males and 44 females with a mean age of (42.1±13.2) years, the mean stone burden was (3.9±1.8) cm. The control group included 36 males and 41 females with a mean age of (45.3±13.0) years, the mean stone burden was (3.6±1.5) cm. The numbers of tracts, the time of operation, the drop of hemoglobin, the change of creatine, the time of hospitalization, the stone free rate and major complications were compared between the two groups. The measurement data and numeration data were compared with t test and χ(2) test. Results: There were no significant differences in sex, age, preoperative urinary tract infection, stone type, and stone burden between the two groups (all P>0.05). The proportion of bilateral renal calculus in MSK group was higher (18.2% vs. 0, χ(2)=15.400, P=0.000). There were 159 percutaneous channels were established in MSK group while 90 percutaneous channels were established in control group. Compared with the control group, the operation time ((88.1±37.5) minutes vs. (68.5±30.1) minutes, t=3.543, P=0.000) and hospitalization time ((15.1±8.3) days vs. (10.1±3.6) days, t=4.816, P=0.000) were longer, the creatinine level increased ((101.2±62.6) µmol/L vs. (71.3±23.6) µmol/L, t=3.777, P=0.000), the rate of stone free decreased (27.5% vs. 83.1%, χ(2)=51.840, P=0.000) and the rate of complications increased (29.9% vs. 11.7%, χ(2)=8.114, P=0.004) in MSK group. There was no statistically difference in hemoglobin drop ((12.5±13.2) g/L vs. (13.0±10.9) g/L, t=-0.260, P=0.795). Conclusions: Using PNL for patients of MSK with calculi has a lower stone free rate and a higher complications. It is an effective method for patients of MSK with large and complex calculi.

[Reoperation for cervical myelopathy duo to progressing ossification of the posterior longitudinal ligaments in patients with expansive laminoplasty].

OBJECTIVE: To retrospectively analyze the clinical data of the patients with reoperation for cervical myelopathy due to progressing ossification of the posterior longitudinal ligaments, with previous open-door expansive laminoplasty, and to evaluate the outcomes. METHODS: From May 2006 to July 2012, a retrospective study was performed on a consecutive series of 17 patients with previous open-door expansive laminoplasty, who had received the reoperation for cervical myelopathy due to progressing ossification of the posterior longitudinal ligaments. The reoperation was performed based on the clinical manifestations and segments of responsibility. The anterior approaches were performed in 12 cases, and the posterior approaches in 5 cases. The correlation between the clinical factors and Japanese Orthopedic Association (JOA) scores or the JOA recovery rate was evaluated by Pearson or Spearman correlation test. The pre- and post-operative JOA scores were analyzed by repeated measures ANOVA and the JOA recovery rates were compared with paired t test. RESULTS: The mean follow-up was 137.5 months (range 60-348 months). There were no serious complications after surgical procedures. There was one case that had C5 palsy in the first operation and had recovery after one week. Another case had C5 palsy in the reoperation with posterior approach, which had recovery at the end of 6 months postoperation. Three cases had the cerebrospinal fluid leakage of the reoperation, with two cases in the anterior approaches and one case in the posterior approach. There was no significant correlation between the clinical variables and JOA scores or JOA recovery rates. The JOA scores of the patients in the first operation were improved from 9.4±4.1 to 12.8±2.8 (P<0.01), and the JOA recovery rate was 45.6%. The JOA scores of the reoperation were improved from 10.2±2.8 to 12.7±2.4 (P<0.05) at the end of 6 months and 14.3±1.9 (P<0.01) by the last follow-up. There were significant differences between the JOA recovery rates by the last follow-up (63.2%) and at the end of 6 months (39.3%) of the reoperation or 45.6% of the first operation (P<0.01). CONCLUSION: The reoperation for cervical myelopathy duo to progressing ossification of the posterior longitudinal ligaments can significantly promote the recovery of the spinal cord, based on the clinical manifestations combined with segments of responsibility of the imaging.

The efficacy and safety of leflunomide therapy in lupus nephritis by repeat kidney biopsy.

To evaluate the clinical and pathological efficacy, and safety of leflunomide as a new immunosuppressive medicine in lupus nephritis (LN). A total of 31 patients were all determined as LN by kidney biopsy. SLE disease activity index (SLEDAI), clinical and immunological tests of these patients were performed. Meanwhile, the pathological presentation and LN activity of before and after leflunomide therapy were evaluated by repeat biopsy. The patients of LN usually have a bit response by the first or second month visit and have a good response by the third month visit after leflunomide therapy. One year later SLEDAI scores of all patients were significantly improved and 13 patients of them were transformed from complex pathological types to simple types (the transformed ratio was 41.9%). For the other patients not transformed, the pathological presentation took a favorable turn, the pathological active index (AI) of LN were significantly improved. There was not anyone relapsed or aggravated. The side effects of leflunomide were less and mild, and could be improved by symptomatic management with or without decreasing dosage. The clinical and pathological activity of LN can be apparently inhibited and the relapse can be prevented through leflunomide therapy. The side effects of leflunomide are mild and transient. Leflunomide is now a new ideal immunosuppressive medicine in the therapy of LN.

Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study.

To evaluate the efficacy and safety of leflunomide in the treatment of proliferative lupus nephritis, a prospective multi-centre observational study was conducted. Patients with biopsy proven proliferative lupus nephritis were assigned to receive either leflunomide or cyclophosphamide with concomitant prednisone. Leflunomide was given orally with a loading dose of 1 mg/kg/day for 3 days followed by 30 mg/day. Intravenous cyclophosphamide was administered monthly at a dose of 0.5 g/m2 of body-surface area. A total of 110 patients were enrolled, 70 in the leflunomide group and 40 in the cyclophosphamide group. The complete remission rate in the leflunomide group was 21% and partial remission rate 52%, as compared with 18% and 55%, respectively, in the cyclophosphamide group. Renal parameters and systemic lupus erythematosus disease activity index improved significantly and similarly in both groups. Serum creatinine decreased or stabilized in both treatment groups. No significant difference was noted with respect to clinical outcome between groups. Repeat biopsy also showed a significant reduction of active lesions in kidney pathology after 6 months of leflunomide treatment. Major adverse events, similar in both treatment groups, included infection, alopecia and hypertension. Leflunomide, compared with cyclophosphamide, in combination with prednisone was effective in the induction therapy of proliferative lupus nephritis and was generally well-tolerated.

Citrate exudation from white lupin induced by phosphorus deficiency differs from that induced by aluminum.

Both phosphorus (P) deficiency and aluminum (Al) toxicity induce root exudation of carboxylates, but the relationship between these two effects is not fully understood. Here, carboxylate exudation induced by Al in Lupinus albus (white lupin) was characterized and compared with that induced by P deficiency. Aluminum treatments were applied to whole root systems or selected root zones of plants with limited (1 microM) or sufficient (50 microM) P supply. Aluminum stimulated citrate efflux after 1-2 h; this response was not mimicked by a similar trivalent cation, La(3+). P deficiency triggered citrate release from mature cluster roots, whereas Al stimulated citrate exudation from the 5- to 10-mm subapical root zones of lateral roots and from mature and senescent cluster roots. Al-induced citrate exudation was inhibited by P limitation at the seedling stage, but was stimulated at later growth stages. Citrate exudation was sensitive to anion-channel blockers. Al treatments did not affect primary root elongation, but inhibited the elongation of lateral roots. The data demonstrate differential patterns of citrate exudation in L. albus, depending on root zone, developmental stage, P nutritional status and Al stress. These findings are discussed in terms of possible functions and underlying mechanisms.

Nitrogen supply after removing the shoot apex increases the nicotine concentration and nitrogen content of tobacco plants.

BACKGROUND: and Aims High nicotine concentrations in leaves, especially in the upper leaves, offer a serious problem for the cultivation of tobacco (Nicotiana tabacum). Preliminary field experiments showed that rapid mineralization of soil N during late stages of growth may contribute to high nicotine concentrations in leaves. METHODS: A sand-culture experiment was carried out in the greenhouse. The N supply was controlled during the experiment, and different amounts of 15N were supplied during late stages of growth (after removal of the shoot apex), to investigate the contribution of the N taken up at this time to the N content of and nicotine concentration in tobacco plants. KEY RESULTS: Addition of 1.6 g or 4 g 15N-labelled NH4NO3 after removing the shoot apex and flushing out the 14N did not increase leaf dry weights; however, it did result in delayed leaf senescence, more lateral bud formation, and an increase in 15N as a proportion of total N, and nicotine-15N as a proportion of total nicotine-N in each organ. The nicotine concentration, 15N and nicotine-15N abundances were increased from the bottom to the top leaves. When more 15N-labelled NH4NO3 was supplied, the nicotine concentration in leaves increased, and so did the 15N abundance in nicotine-N. CONCLUSION: Enhanced N supply in the later growth stages (after removing the apex) increased N content and nicotine concentration in tobacco plants. Nicotine was synthesized de novo during the late growth stages.

Transpiration, potassium uptake and flow in tobacco as affected by nitrogen forms and nutrient levels.

BACKGROUND AND AIMS: Ammonium can result in toxicity symptoms in many plants when it is supplied as the sole source of N. In this work, influences of different nitrogen forms at two levels (2 and 15 mm N) on growth, water relations and uptake and flow of potassium were studied in plants of Nicotiana tabacum 'K 326'. METHODS: Xylem sap from different leaves was collected from 106-d-old tobacco plants cultured in quartz sand by application of pressure to the root system. Whole-shoot transpiration for each of the treatments was measured on a daily basis by weight determination. KEY RESULTS: Total replacement of NO(3)(-)N by NH(4)(+)-N caused a substantial decrease in dry weight gain, even when plants grew under nutrient deficiency. Increasing nutrient concentration resulted in a greater net dry weight gain when nitrogen was supplied as NO(3)(-) or NH(4)NO(3), but resulted in little change when nitrogen was supplied as NH(4)(+). NH(4)(+)-N as the sole N-source also caused reduction in transpiration rate, changes in plant WUE (which depended on the nutrient levels) and a decrease in potassium uptake. However, the amount of xylem-transported potassium in the plants fed with NH(4)(+) was not reduced: it was 457 % or 596 % of the potassium currently taken up at low or high nutrient level, respectively, indicating a massive export from leaves and cycling of potassium in the phloem. CONCLUSIONS: Ammonium reduces leaf stomatal conductance of tobacco plants. The flow and partitioning of potassium in tobacco plants can be changed, depending on the nitrogen forms and nutrient levels.

Evaluation of cadmium and other metal losses from various municipal wastes during incineration disposal.

The Japanese intake much more Cd through food than people in other countries, this may be partly caused by the activity of municipal waste incineration disposal. The present study was carried out to examine the behavior of Cd and to identify the other lost metals during municipal waste incineration. Thirty-eight waste samples, including food scraps (FS), animal wastes (AW), horticulture wastes (HW) and sewage sludges (SS) were collected from various places in Japan. Treatment temperatures of 500, 850, and 1000 degrees C were conducted to these samples in laboratory, and thirty-nine kinds of metals were examined. The results showed that average Cd losses were 69% (2.4 mg kg-1) and 74% (2.6 mg kg-1) at 850 and 1000 degrees C, respectively. Furthermore, the losses of 20 other metals were also found, i.e. Sn lost at 500 degrees C, K, Mg, Na, Bi, Cr, Ge, Li, Pb, Sn, Tl, Zn lost at 850 degrees C, and nine more metals, Al, Be, Cs, Nb, Sb, Sr, Th, Y, Zr lost at 1000 degrees C. The lost metals were considered to be transferred into the combustion flue gas, mainly in the forms of metallic chloride compounds, e.g. CdCl2, SnCl4, SnCl2, ZnCl2, PbCl2, etc. On the other hand, no significant losses for Ca, Fe, Ag, Ba, Co, Cu, Ga, Hf, Mn, Mo, Ni, Rb, Sc, Ta, Ti, U, V, W were found at 0.05 probability level. Total metal losses could be calculated at 9.9 and 20 g kg-1, in which major metal (Al, K, Mg, Na) losses were 9.5, 19 g kg-1 and minor and trace metal losses were 0.4, 0.6 g kg-1 at 850 and 1000 degrees C, respectively. Among the four types of waste materials, Cd losses were 0.8-3.7 mg kg-1, occupied about 60-80% at 850 degrees C, and 0.9-3.9 mg kg-1, occupied about 65-85% at 1000 degrees C. The total major metal losses from the four types of waste materials could be calculated at 6.5-15 g kg-1 at 850 degrees C, and 11-31 g kg-1 at 1000 degrees C, minor and trace metal losses were 0.03-1.3 g kg-1 at 850 degrees C, and 0.3-1.5 g kg-1 at 1000 degrees C, respectively.

Does aluminum inhibit pollen germination via extracellular calmodulin?

The effect of aluminum (Al) on pollen germination and its mechanism of action were investigated. Pollen germination and pollen tube elongation were inhibited by Al at pH 4.5. This inhibitory effect was reversed by the addition of purified calmodulin (CaM), whereas neither the calcium binding-protein S-100 nor Al chelator citric acid at the same concentrations had any obvious effect on Al-inhibited pollen germination. The presence of either the membrane-impermeable CaM inhibitor anti-CaM antiserum or Ca2+ chelator EGTA completely suppressed the effect of exogenous CaM. These results indicate the involvement of extracellular calmodulin in the short-term effects of Al on pollen germination and pollen tube elongation.

Parenteral vs enteral nutrition in tumor-bearing rats.

The development of cachexia may complicate cancer therapy, yet controversy exists concerning its nutritional management. For example, use of total parenteral nutrition (TPN) may not be appropriate because of gut atrophy, possible stimulation of tumor growth, and lack of total host protein repletion. In the present experiment, host and tumor responses were compared after identical parenteral or enteral nutritional supplementation (EN). Eighteen days after subcutaneous inoculation of adult male Fischer-344 rats with fresh methylcholanthrene-induced sarcoma (tumor-bearing [TB] rats), catheters were placed into either the external jugular vein or the stomach. Four days later, rats were started on an 11-day course of either TPN or EN with a Freamine-III-based formula (amino acids = 6%, dextrose = 21.5%, lipid = 1.5%). When the rats were killed, there was no difference in tumor weight between the various TB groups. Carcass weight was increased significantly in both the TB-TPN and TB-EN groups, and there was an elevation in gastrocnemius protein content in both groups compared with the TB-rat food group. Small intestine protein was preserved in the TB-EN group to the level observed in the control-rat food animals. Total lipids in the liver were increased in both TB-TPN and TB-EN groups; however, the magnitude of the increase was less in the TB-EN animals. Neither treatment resulted in complete protein repletion of tumor-bearing rats. EN may be more appropriate than TPN in that gut mass is preserved. The maintenance of gut mucosa may prove to be beneficial in the treatment of the depleted, immunocompromised, and metabolically stressed host.

Role of the root apoplasm for iron acquisition by wheat plants.

The role of the root apoplasm for iron acquisition was studied in wheat (Triticum aestivum L. cv Ares) grown in nutrient solution under controlled environmental conditions. To obtain different levels of Fe in the root apoplasm, plants were supplied in the dark for 5 hours (preloading period) with various (59)Fe-labeled Fe compounds [Fe(III) hydroxide; microbial siderophores: Fe rhodotorulic acid (FeRDA) and ferrioxamin (FeDesferal(3)), and synthetic Fe chelate (FeEDDHA)], each at a concentration of 5 micromolar. Large pools of apoplasmic Fe were formed after supplying Fe(III) hydroxide or FeRDA, but no such pools were observed after supplying FeDesferal or FeEDDHA. Depending on plant Fe nutritional status (preculture +/- 0.1 millimolar FeEDTA), apoplasmic Fe was used to different extent for translocation to the shoot. Under Fe deficiency, a much greater fraction of the apoplasmic Fe was utilized than in Fe-sufficient plants, as a result of the different rates of phytosiderophore release. Because of the diurnal rhythm in release of phytosiderophores in Fe-deficient plants, the utilization of the apoplasmic Fe for translocation into the shoot started 2 hours after onset of the light period and was dependent on the concentration of Fe in the apoplasm, which followed the order: Fe(III) hydroxide >> FeRDA >> FeDesferal = FeEDDHA. From these results, it can be concluded that in soil-grown plants the apoplasmic Fe pool loaded by various indigenous Fe compounds such as siderophores in the soil solution can be an important Fe source in graminaceous species, particularly during periods of limited Fe supply from the soil.

Reversal of cancer cachexia in rats by cimaterol and supplemental nutrition.

The anabolic beta 2-agonist cimaterol was used in conjunction with supplemental nutrition to reverse cancer-induced cachexia and malnutrition in tumor-bearing rats. Cimaterol was administered to tumor-bearing rats receiving total parenteral nutrition or enteral nutrition for 10 days, beginning 2 weeks after subcutaneous transplantation of methylcholanthrene sarcoma. A significant increase occurred in both muscle weight and muscle protein in animals receiving cimaterol in conjunction with either enteral or parenteral feeding, compared to food fed tumor-bearing animals. Muscle protein content was increased significantly by 16% in cimaterol-treated rats maintained on parenteral nutrition and by 11% in cimaterol-treated enterally fed rats compared with the respective tumor-bearing controls. Urinary concentrations of 3-methylhistidine, an estimation of muscle turnover or catabolism, were significantly reduced in both tumor-bearing groups treated with cimaterol compared to 3-methylhistidine levels of the untreated tumor-bearing groups. The anabolic effects of cimaterol were expressed in the presence of a large tumor burden resulting in reversal of muscle depletion and muscle breakdown regardless of the route of supplemental nutrition. Thus, beta 2-agonists may be considered as a possible therapy for cancer cachexia.

Clenbuterol treatment increases muscle mass and protein content of tumor-bearing rats maintained on total parenteral nutrition.

Treatment of tumor-bearing (TB) and control rats with the anabolic beta-2 agonist drug clenbuterol (CLE) for 14 days reduced food intake for 4 days initially. Feeding was increased in anorectic TB rats, however, during the last 7 days of drug administration. Since minimal muscle savings were observed in chow-fed TB rats treated with CLE, the anabolic effects of this drug were investigated in a second experiment on TB rats maintained on total parenteral nutrition (TPN). Sixteen days after the subcutaneous transplantation of methylcholanthrene-induced sarcomas rats was begun on a 2-week schedule of TPN. One group of these rats was treated daily for 14 days with CLE, while the remaining rats received injections of saline. Additional groups of TB and nonTB rats were maintained on rat chow for this period and treated with saline. Although TB rats maintained on rat chow or TPN and treated with saline exhibited significantly decreased gastrocnemius muscle weight and protein content, treatment of TB-TPN rats with clenbuterol normalized muscle mass and increased muscle protein content significantly and increased plasma concentrations of branched-chain amino acids. These results indicate that although nutritional support of TB organisms does not result in protein repletion, the addition of an anabolic drug renders the nutritional support highly efficacious.

Methionine sulfoximine intensifies cancer anorexia.

Consistent anorexia was first observed 33 days after inoculating Fischer 344 rats with methylcholanthrene-induced sarcoma. Daily treatment of a similar group of rats with the glutamine synthetase inhibitor, methionine sulfoximine, elicited significant reductions of feeding by day 29 at a dose that had no effect on nontumor-bearing rats. Blood concentrations of ammonia were elevated in both groups of tumor-bearing rats and brain ammonia level was increased in the methionine sulfoximine-treated tumor-bearing rats. Forebrain concentrations of tyrosine, tryptophan, DOPAC and 5-HIAA were elevated in both groups of tumor-bearing rats. Since ammonia is detoxified through the glutamine synthetase reaction, these results suggest that blood and brain ammonia concentrations are more important than the neurochemical consequences of ammonia detoxification for the etiology of cancer anorexia.