Predicting therapeutic response and degree of pituitary tumour shrinkage during treatment of acromegaly with octreotide LAR

BACKGROUND/AIMS: The efficacy of transsphenoidal surgery in the treatment of patients with acromegaly is largely dependent on tumour size. A reduction in pituitary tumour volume by medical therapy might therefore improve subsequent surgical cure rates. This study prospectively determined the effects of the depot somatostatin analogue octreotide LAR on pituitary tumour size, GH and IGF-I levels and clinical symptoms in a cohort of previously untreated patients with acromegaly. METHODS: Six patients newly diagnosed with acromegaly (mean age 53 years; range 42-76 years) received intramuscular octreotide LAR every 28 days for 6 months. The initial dose of LAR was 20 mg, but increased to 30 mg after the initial 3 injections if mean GH levels were >5 mU/l. Prior to commencing LAR therapy, each patient received 3 injections of subcutaneous octreotide (50, 100 and 200 mug) in a randomized order on separate days, and the serum GH response was measured. Pituitary tumour volume was calculated from MRI or computed tomography scans at baseline, then 3 and 6 months after initiation of treatment, and assessed by a 'blinded' radiologist in random order. At baseline, 4 patients had a macroadenoma and 2 patients had a microadenoma. For the latter, the whole gland volume was measured. RESULTS: Serum GH levels decreased from 29.6 +/- 19.2 mU/l (mean +/- SD) at baseline to 12.1 +/- 10.5 mU/l at 3 months and 10.4 +/- 9.3 mU/l at 6 months. Three patients achieved a mean serum GH level of <5 mU/l. In these patients, the serum GH had declined to <5 mU/l in response to a single 100 mug subcutaneous octreotide injection. Serum IGF-I levels decreased by a mean of 45 +/- 7.4%. Tumour volume decreased in all patients: mean baseline volume 2,175 mm(3) (range 660-6,998) decreasing to 1,567 mm(3) (range 360-4,522) at 3 months (p < 0.05) and 1,293 mm(3) (range 280-4,104) at 6 months (p < 0.002). The mean percentage decrease in size was 29% (range -54 to +4%) at 3 months (p < 0.02) and 47% (range 21-97%) at 6 months (p < 0.002). There was no statistically significant correlation between GH response and tumour shrinkage. CONCLUSIONS: A single test dose of subcutaneous octreotide may be useful in predicting the subsequent efficacy of octreotide LAR. Octreotide LAR results in significant shrinkage of pituitary tumours of newly diagnosed patients with acromegaly. Whether its administration to such patients for 6-12 months can improve the efficacy of subsequent transsphenoidal surgery will require further study.     

The treatment of multinodular large non-toxic goiter using repeated doses of radioiodine (preliminary report)

INTRODUCTION: The aim of study was to establish the effectiveness of radioiodine therapy using 131I in the group of patients with multinodular large non-toxic goiter. MATERIAL AND METHODS: Therapy was undertaken in female patients disqualified from surgery due to high risk and these patients who didn't agree to surgery. Studies were performed in 7 women (age range: 62-82 yrs) with large goiters (2nd degree according to WHO classification and goiter volume assessed by USG over 100 cm(3)). Serum TSH, fT4, fT3, antithyroid antibodies (TPOAb, TgAb, TRAb) levels, urinary iodine concentration (UIE) were estimated in all patients parallel with radioiodine uptake test (after 5 and 24 hours), 131I thyroid scintigraphy and fine needle biopsy to exclude neoplasmatic transformation. These studies and therapy with 22 mCi 131I were repeated every 3 months. RESULTS: Before therapy median thyroid volume was approximately 145 cm(3) and during therapy gradually decreased to 76 cm(3) after 6 months and to 65 cm(3) after 12 months. Increase of TRAb can be a inhibiting factor of thyroid volume reduction. Other antithyroid antibodies showed marked tendency to rise but without significant correlation with radioiodine uptake and goiter reduction. After 12 months we found 2 patients with clinical and laboratory hypothyroidism. CONCLUSIONS: In some cases of multinodular large non-toxic goiter, the radioiodine therapy can be the best alternative way for L-thyroxine treatment or surgery therapy. The fractionated radioiodine therapy of multinodular large non-toxic goiter is safe and effective method but continuation of nodules observation is necessary.     

An accelerated approach to tissue expansion for breast reconstruction: experience with intraoperative and rapid postoperative expansion in 370 reconstructions

Breast reconstruction with tissue expansion is a well-established technique that offers satisfactory aesthetic results with minimal patient morbidity. The traditional period of expansion, however, continues to be a significant source of patient inconvenience and dissatisfaction. The objective of this study was to develop and evaluate a protocol for rapid tissue expansion. A total of 370 breast reconstructions in 314 patients who underwent rapid tissue expansion were retrospectively reviewed. Contraindications to rapid expansion were considered to be previous radiation, mastectomy skin flaps of questionable viability, and an excessively tight skin envelope. All expanders were placed submuscularly and filled to 40 to 50 percent of tissue expander volume. Office expansion was undertaken within 10 to 14 days after the operation and continued on a weekly basis. Each expansion was limited by patient tolerance up to a maximal pressure of 40 mm of water or a volume of 120 cm3. Expansion was considered complete once the expanded breast was 30 to 50 percent larger than the contralateral breast. If required, postoperative chemotherapy was given during the expansion period. Mean patient age was 48 years (range, 23 to 73 years). Two hundred fifty-eight patients had unilateral reconstructions. Three hundred two patients had immediate reconstruction. Mean tissue expander size was 583 cm3 (SD, 108 cm3). Mean intraoperative expansion was 271 cm3, or 46 percent (SD, 9 percent) of the tissue expander size. The first expansion was started 12 days (SD, 3 days) after the operation. The mean volume of each expansion was 88 cm3 (SD, 23 cm3). Expansion was completed in 4.7 office visits (SD, one visit). Mean final expander volume was 672 cm3 (SD, 144 cm3). The expanders were overexpanded by 15.3 percent (SD, 8.4 percent). The mean time between expander placement and the final expansion was 6.6 weeks (SD, 3 weeks). The overall complication rate was 4 percent. Ten patients developed cellulitis, five patients had hematomas requiring drainage, and one expander became exposed. A total of eight expanders were removed: four for cellulitis, one for a hematoma, one because of locally recurrent disease, one because of expander exposure, and one at the patient's request for no medical reason. Intraoperative and rapid postoperative tissue expansion is a safe and reliable technique that offers a significant improvement over conventional techniques. In this accelerated protocol, expansion may be completed in less than 7 weeks. The result is decreased patient morbidity and delays in adjuvant therapy at no detriment to the final surgical outcome.     

Effects of the aromatase inhibitor testolactone on human benign prostatic hyperplasia

The aromatase inhibitor testolactone was used for endocrine treatment of benign prostatic hyperplasia (BPH). Thirteen patients (mean age 79 years) with complete urinary retention (BPH stage IV) without improvement after 4 weeks of bladder drainage by suprapubic catheter were treated with testolactone 100 mg, b.i.d., for 6 months. Nine men (mean age 80 years) with identical conditions who did not receive hormonal therapy served as controls. Results, treatment group: In 7 patients spontaneous micturation reoccurred after an average treatment period of 8 weeks (group A); 6 patients continued to need the catheter (group B). Prostatic volume decreased in all patients, and an average volume reduction of 26% was found in group A, whereas in group B the decrease averaged 15%. Finally, the testosterone/estradiol ratio significantly increased in all patients during treatment. Control group: Prostatic volume did not change nor did spontaneous micturation occur during the whole observation period.     

Medical Research Council of Canada therapeutic trial of human growth hormone: first 5 years of therapy.

The Medical Research Council of Canada has initiated human growth hormone (hGH) therapy in 151 patients with documented complete hGH deficiency that was idiopathic in 76% of cases, secondary to craniopharyngioma (organic) in 17% and of varied cause in 7%. Approximately 50% of the patients with idiopathic disease had isolated hGH deficiency; during therapy thyroid deficiency developed in five patients and cortisol deficiency in three. A similar increase in mean height velocity occurred in the first treatment phase for patients less than 12 years old (0.93 plus or minus 0.30 cm/mo) and those 12 years and older (0.86 plus or minus 0.29 cm/mo). Although subsequent courses of hGH therapy yielded significantly diminished response in both age groups, this diminution was not progressive: the height velocity of the younger patients returned to 0.82 plus or minus 0.26 cm/ml in the fifth therapy phase. The mean height velocity attained at the optimal dosage (0.20 to 0.29 units/kg three times per week) for each age group did not differ significantly. Despite therapy being carried out for only 6 months of the year, normal increment ratios for height age and bone age against chronologic age were observed in the patients with idiopathic disease. In only four patients did treatment failure occur, and three of these were more than 20 years old. The addition of fluoxymesterone (10 mg/d) to the hGH therapeutic regimen (15 units/wk), when diminished response to hGH alone became evident, promoted an enhanced growth response in 9 of 11 older patients. These data indicate that age of the patient and dosage of hGH, but not diagnostic category, were important influences on the response to therapy. Younger patients responded best and maintained a higher mean growth velocity than older patients during intermittent hGH therapy     

Predicting a relapse of Graves' hyperthyroidism in adults during the early phase of treatment with anti-thyroid drugs

INTRODUCTION: The long-term effectiveness of anti-thyroid drugs (ATD) in the treatment of Graves' hyperthyroidism (GH) is still unsatisfactory and difficult to predict. The aim of this study was to evaluate the usefulness of a determination of serum level of thyrotropin-binding inhibiting immunoglobulins (second generation TBII assay) in predicting the possibility of relapse in the early phase of pharmacological treatment. MATERIAL AND METHODS: We investigated 37 patients within the 20-60 age range with the first occurrence of GH. All patients were treated with thiamazole for 12 months. Clinical assessment, ultrasound estimation of thyroid volume and determination of serum thyrotropin, free thyroxine, free triiodothyronine, thyroid autoantibodies and TBII levels were carried out at the onset and after 1, 3, 6, 9 and 12 months of ATD treatment. RESULTS: The mean follow-up period after ATD withdrawal was 27.24 +/- 5.81 months. Of 37 patients 12 (32%) had a relapse of hyperthyroidism (mean time 8.17 +/- 6.91 months after drug withdrawal). The difference in TBII levels between the relapse and the remission group was found to be significant after the first month of therapy until the end of ATD treatment. We observed that patients with TBII above 14 IU/L after 3 months and above 8 IU/L after 6 months of therapy relapsed more frequently than patients with lower levels (sensitivity 50% and specificity 92 and 96%, respectively). CONCLUSIONS: The study confirmed that TBII estimation in the early phase of ATD could be useful in the proper planning of GH therapy and early qualification to more radical treatment (radioiodine or surgery).     

Percutaneous ethanol injections in the treatment of secondary hyperparathyroidism

INTRODUCTION: Renal insufficiency is the most common etiology of secondary hyperparathyroidism. In case of resistance for conservative treatment, methods of choice are surgical intervention or percutaneous ethanol injections. AIM OF THE STUDY: The aim of the study was to evaluate usefulness of percutaneous ethanol injection therapy in the treatment of patients with secondary hyperparathyroidism. MATERIAL AND METHODS: We performed percutaneous 96% ethanol injections under USG guideance in 51 patients: 22 women (mean age 49.6 years) and 29 men (46.6 yrs). The base level of parathormone was 689.35 pg/ml. We managed to visualize one parathyroid gland in 34 patients, 2 in 12, 3 in 5 patients. The mean volume of a single gland was 0,8 cm3. All the injections were performed with the use of needle number 6. We repeated injections in case of no effects. One injection was performed in 18 patients, 2 in 18, 3 in 13, 5 in 1 and 6 in 1 patient. Before and after the treatment patients were examined with USG, scintigraphy and densitometry. Serum levels of calcium (Ca), phosphorus (P), parathormone (PTH) and alkaline phosphatase (FA) activity were also obtained. The main criteria for success was decrease in parathormone level of 50% or more in comparison with pre-injection level or to less than 200 pg/ml. RESULTS: In the whole group of patients after the first month, positive results were observed in 67%. There were no changes in 23%, and PTH level increased in 10%. After 6 months-positive results in 53%, no change in 35% and increase in 12%. We noted the best results in patients with PTH less than 800 pg/ml-72% of them had positive results after 1 as far as after the 6 month. CONCLUSIONS: Percutaneous ethanol injections are valuable method of treatment of secondary hyperparathyroidism. The best results can be obtained if PTH level is less than 800 pg/ml, one parathyroid gland dominating over the rest is visualised in USG, and if patient responds after 1 or at least 2 injections.     

Androgen therapy in constitutional delay of growth

BACKGROUND/AIMS: Two modalities of androgen therapy prevail in the treatment of constitutional delay of growth (CDG): monthly injections of testosterone or daily tablets of the non-aromatizable oxandrolone. The present study was undertaken to prospectively compare both compounds and dose. METHODS: Thirty patients with CDG were the subjects of this study. The protocol required that they all be at age 12-14 years with a bone age delay of more than 2 'years', height less than -2 SDS and growth velocity less than -0.5 SDS. The subjects were at a Tanner stage 1 or 2 and testicular volume were no larger than 4 ml. They were randomly assigned into 3 treatment groups: group 1 patients received monthly injections of 25 mg testosterone propionate-enanthate; group 2 patients received monthly injections of 50 mg testosterone propionate-enanthate; group 3 patients received oral oxandrolone at a weekly dose of 0.7 mg/kg. Treatment was given for a period of 6 months and follow-up commenced 6 months later and yearly thereafter for 2 years. RESULTS: Height velocity and height increased significantly only in groups 2 and 3. Bone age advanced most in group 2. Puberty progressed faster in that group as compared with group 3. The predicted adult height before and 2 years after completion of treatment remained unchanged in the two testosterone groups. It increased significantly in the oxandrolone group from a mean 169.8 cm before therapy to a mean 177.5 cm 2 years after completion of therapy. Peak GH levels were significantly higher on both testosterone 50 mg and oxandrolone, as compared to pretreatment levels. The increment was significantly greater in group 2 as was the increment in serum IGF-1 and IGFBP3. CONCLUSIONS: These results imply that 6 months of testosterone injections at a dose of 50 mg, but not 25 mg, is an effective and safe treatment for patients with CDG, with no considerable impact on final height prediction. On the other hand, daily oxandrolone treatment, starting at age 12-14 years, may increase the predicted final adult height.     

Partial abolition of seasonal variations of testicular weight in rams by decreasing the photoperiod

Under moderate latitudes all breeds of rams undergo seasonal variations in testicular weight with a maximum during summer under decreasing daylength ([1]-[4]). Similarly, in rams submitted to a 6-month artificial light regime [5] or to an alternation of long (16L:8D) and short (8L:16D) days [6] an increase in testicular weight occurred following a decrease in daylength and vice versa. However this effect is transitory, a phenomenon which can be referred as photorefractoriness. In the present study the influence of the period of the light cycle on variation in testicular weight in the ram was investigated. 4 groups of 6 adults Ile-de-France rams were submitted to artificial light cycles where the daylength varied between 8-16 hrs. and the period (T) was 6, 4, 3, or 2 months respectively (Groups T6, T4, T3, and T2). Testicular volume was measured fortnightly using an orchidometer, Variations in testicular volume were submitted to harmonic regression analysis following the model y(t)=mu + a sin(2(pi t/tau) + phi). Cyclic changes in testicular volume were seen with each light cycle, at least in groups T6, T4, and T3 (Fig.). Analysis (Table) showed that: (1) the coefficient of determination R2 was high in the groups (2) mean testicular volume has increased from 258 to 294 cm3 when the period of the light cycle decreased from 6 to 2 months; (3) conversely, the amplitude decreased from 66.5 to 26.5 cm3 as the period decreased; (4) maximal testicular volumes (mean plus amplitude) were similar in all groups (range: T4, 312,5-T6,324 cm3) while minima (mean less amplitude) differed significantly (P<0.000,1) between groups (range: T6 and T4 about 190, T2 267.5 cm3) and (50 th computed periods of testicular volumes cycles were almost identical to the imposed light cycles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-Staged Gamma Knife Stereotactic Radiosurgery for Large Cerebral Arteriovenous Malformations: A Preliminary Report

ObjectiveWe retrospectively analyzed our experience with time-staged gamma knife stereotactic radiosurgery (GKS) in treating large arteriovenous malformation(AVM)s;≥ 10 cm³).MethodsForty-five patients who underwent time-staged GKS (2-stage, n = 37;3-stage,n = 8) between March 1998 and December 2011 were included. The mean volume treated was 20.42±6.29 cm³ (range, 10.20–38.50 cm³). Obliteration rates of AVMs and the associated complications after GKS were evaluated.ResultsMean AVM volume (and median marginal dose) at each GKS session in the 37 patients who underwent 2-stage GKS was 19.67±6.08 cm³ (13 Gy) at session 1 and 6.97±6.92 cm³ (17 Gy) at session 2. The median interval period was 39 months. After follow-up period of 37 months, the complete obliteration rate was 64.9%. The mean AVM volume (and median marginal dose) at each GKS session in the 8 patients who underwent 3-stage GKS was 23.90±6.50 cm³ (12.25 Gy), 19.43±7.46 cm³ (13.5 Gy), 7.48±6.86 cm³ (15.5 Gy) at session 1, 2, and 3, respectively. The median interval duration between each GKS session was 37.5 and 38 months, respectively. After a median follow-up period of 47.5 months, 5 patients (62.5%) achieved complete obliteration. Postradiosurgical hemorrhage developed in 5 patients (11.1%) including one case of major bleeding and 4 cases of minor bleeding. No patient suffered from clinically symptomatic radiation necrosis following radiation.ConclusionTime-staged GKS could be an effective and safe treatment option in the management of large AVMs.     

苦参碱注射液对急性病毒性心肌炎的治疗作用

目的:观察苦参碱注射液治疗急性病毒性心肌炎(AVM)的临床疗效.方法:将AVM患者120例随机分为治疗组63例及对照组57例,对照组采用常规疗法,治疗组在对照组基础上给予苦参碱注射液治疗,连用2周.观察临床疗效.结果:治疗组总有效率90.5%,对照组总有效率73.7%,两组比较有显著性差异.治疗组治疗后血清肌酸磷酸激酶(CPK)、天冬氨酸转氨酶(AST)及血清乳酸脱氢酶(LDH)较对照组治疗后明显降低,差异有统计学意义(P＜0.05).结论:苦参碱对急性心肌炎有良好疗效.     

Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial

Background

Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the effect of rapamycin in reducing the volume of AML in TS.

Methods

Twenty four-month prospective open-label, single arm, unicentre Phases II andIII study. The primary endpoint was to evaluate the effect of treatment on the reduction of at least 50% AML volume from baseline at 24 months. The secondary endpoints were: average tumour reduction, surgical complications, skin lesions and drug safety.The study population comprised 17 patients, aged >10 years who were diagnosed with TS and had ≥1 renal AML >2 cm of diameter and had a serum creatinine < 2mg/dl and urine protein/creatinine ratio < 22.6 mg/mmol. The trial was conducted at Fundació Puigvert. Rapamycin was given to achieve stable plasma levels between 4 and 8 ng/ml. AML volume was estimated using orthogonal measurements by MRI at baseline, 6, 12 and 24 months.

Results

Ten out of 17 patients were success responders for the main outcome ?58.8%, 95%CI: 32.9% to 81.6%-. After 6 months of therapy, the mean volume decrease was 55.18% (5.01 standard error (SE); p<0.001) and 66.38% (4.41 SE; p<0.001) at year 1. There was no significant decrease between year 1 and 2. According to RECIST criteria, all patients achieved a partial response at year 1 and all but two had already achieved this partial response after 6 months.The main analysis was performed according to the intention-to-treat principle analysis. Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis. We used the baseline tumour volume as a covariate for the absolute change and percentage change from baseline data. The analysis was performed using SAS version 9.2 software, and the level of significance was established at 0.05 (two-sided).

Conclusions

This study show that mTOR inhibitors are a relatively safe, efficacious and less aggressive alternative than currently available options in the management of AML in TS.

Trial registration

EudraCT number: 2007-005978-30, ClinicalTrials.gov number: NCT0121712

     

Comparison of evening and morning dosing of travoprost 0.004%/timolol 0.5% fixed combination in 6 month period

An open label, multi-center, 6 months observational study of new fixed combination (travoprost 0.004%/timolol 0.5%), in order to evaluate both efficacy (intraocular pressure lowering) and tolerability (patient and investigator satisfaction) of two dosing regimens--evening (PM) and morning (AM). After screening for enrollment, to 40 patients (79 eyes with primary open angle glaucoma or ocular hypertension), new fixed combination travoprost 0.004%/timolol 0.5% was prescribed once a day in the evening (PM). Patients were enrolled according to each investigator decision on indication for travoprost 0.004%/timolol 0.5% fixed combination once a day, without washout period after previous medication. Intraocular pressure was measured at 9 AM at all time control points: at baseline, after 1 month, after 3 months and after 6 month. After 1 month, screening for nonresponders (criteria: 20% intraocular pressure lowering) and subjects with major side effects was performed. At second control visit, after 3 months PM dosing, intraocular pressure was measured and patients were instructed to continue once a day the same medication, but in the morning (AM) for consequent 3 months. After 1 month, reduction in mean intraocular pressure value was 21.66%. At the visit after 3 month, the mean intraocular pressure was 15.67 +/- 2.17 mm Hg (reduction 21.14%). 3 month after dosing regimen changed to AM (6 month after beginning of travoprost 0.004%/timolol 0.5% combination therapy), reduction in intraocular pressure value was 19.86%. The differences (mean +/- standard deviation) in intraocular pressure values after 1, 3 and 6 month were all highly statistically significant compared to baseline values. The tolerability was evaluated in five steps (Likert scale) ranging from unsatisfactory to excellent by both patient and investigator--taken at 3 and 6 month control visit. 95% of patients and 100% of investigators were satisfied with the possibility of choosing dosing regimen for travoprost 0.004%/timolol 0.5% fixed combination. Travoprost 0.004%/timolol 0.5% fixed combination proved sufficient intraocular pressure control dosed either PM or AM with no statistically significant difference between two dosing regimens. Possibility to choose between two dosing regimens gives each practitioner additional reassurance that glaucoma therapy will be individualised to needs of each patient.     

A study of replacement of timolol-pilocarpine with latanoprost in pseudoexfoliation glaucoma

The aim of the study was to evaluate the efficacy of replacing current dual local therapy (timolol and pilocarpine) with latanoprost 0.005% in 71 pseudoexfoliation glaucoma patients with controlled intraocular pressure (IOP). 39 patients switched to latanoprost 0.005%) and 32 patients continued timolol-pilocarpine therapy. Mean diurnal (IOP) was measured at baseline, after 0.5, 1, 3 and 6 months of treatment. After 6 months 38 patients with latanoprost and 30 patients with timolol-pilocarpine had completed the study. At baseline the mean diurnal IOP was 20.4 +/- 2.0 mmHg for patients in latanoprost treatment group and 21.4 +/- 2.1 mmHg for patients in timolol-pilocarpine group. At the end of the study, after 6 months of treatment, the mean diurnal IOP values were 16.6 +/- 2.4 and 17.9 +/- 2.0 mmHg respectively. IOP was statistically significantly reduced from baseline (p < 0.001). The mean diurnal IOP change from baseline was -3.3 +/- 0.5 mmHg (mean +/- SEM, ANCOVA) for the patients treated with latanoprost and -3.2 +/- 0.4 mmHg for the patients treated with timolol + pilocarpine. This difference in IOP reduction between groups was not statistically significant (z = 0.69; p = 0.49). This study showed that combination therapy (timolol plus pilocarpine) in pseudoexfoliation glaucoma can effectively be replaced by latanoprost monotherapy.     

Improved Glycaemia Correlates with Liver Fat Reduction in Obese,Type 2 Diabetes,Patients Given Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months’ GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA₁c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m² (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA₁c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy (¹H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA_1c reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (−59.3, −16.5%). The relative reduction in IHL correlated with that in HbA₁c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.     

阿维菌素B1a对土壤微生物和蚯蚓的影响

研究了不同阿维菌素B_1a浓度对种土壤微生物生长和呼吸强度的影响及对土壤中蚯蚓的急性毒性.结果表明,土壤中阿维菌素B_1a浓度在83.3 mg·kg^-1以上时对种土壤细菌均表现出明显的抑制作用,但对土壤真菌不表现抑制作用.高浓度阿维菌素B_1a对土壤微生物的呼吸强度有抑制作用,并且在不同土壤其作用有差异.采用滤纸接触试验和人工土壤试验测定阿维菌素对蚯蚓的急性毒性(半数致死量,LD₅₀),接触毒性LD₅₀为.63μg·cm^-2,土壤法试验测定的LD₅₀在处理后第7 d和第1 d分别为2.13和17.06 mg·kg^-1.     

Evidence for a role of hyaluronan in the spacing of fibrils within collagen bundles in rabbit synovium

Synovial hydraulic resistance is vital for the retention of intra-articular fluid, and originates within the matrix of biopolymers in the intercellular gaps. Specific digestion of hyaluronan resulted in a increase in synovial hydraulic permeability from 0.478+/-0.24 microl min(-1) cm H(2)O(-1) in control tissue to 4.561+/-0.40 microl min(-1) cm H(2)O(-1) (mean+/-S.D., n=6 rabbits, P<0.001 t test). To investigate whether hyaluronidase also altered the interstitial ultrastructure, morphometry of hyaluronidase treated synovium was carried out. The most striking novel finding was that hyaluronidase treatment reduced extrafibrillar volume fraction within the synovial collagen bundles from 50.5+/-11.1% to 36.8+/-15.5% (mean+/-S.D., n=6 rabbits, P<0.001, two-way anova). This was accompanied by a reduction in interfibrillar centre to centre spacing from 101+/-11 (control) to 84+/-6 nm (mean+/-S.D.; n=6 rabbits, P<0.001) in enzyme-treated bundles. Individual fibrils showed a small but highly significant reduction in cross-sectional diameter from 76.9+/-6.3 to 72.5+/-6.3 nm (mean+/-S.E.; P<0.001) after hyaluronidase treatment. The findings indicate that hyaluronan chains have a major organisational role within the collagen bundle itself. The trans-synovial pathway comprises bundles and substantial areas of intervening, bundle-free matrix, and it is possible that bundle collapse contributes to a rise in overall permeability by increasing the inter-bundle space.     

Routine use of ancillary investigations in staging diffuse large B-cell lymphoma improves the International Prognostic Index (IPI)

Objective

Curative surgery is not an option for many patients with clinical stage I non-small-cell lung carcinoma (NSCLC), but radical radiosurgery may be effective.

Methods

Inoperable patients with small peripheral clinical stage I NSCLC were enrolled in this study. Three-to-five fiducial markers were implanted in or near tumors under CT guidance. Gross tumor volumes (GTVs) were contoured using lung windows. The GTV margin was expanded by 5 mm to establish the planning treatment volume (PTV). A dose of 42–60 Gy was delivered to the PTV in 3 equal fractions in less than 2 weeks using the CyberKnife radiosurgery system. The 30-Gy isodose contour extended at least 1 cm from the GTV. Physical examination, CT imaging and pulmonary function testing were completed at 6 months intervals for three years following treatment.

Results

Twenty patients with an average maximum tumor diameter of 2.2 cm (range, 1.1 – 3.5 cm) and a mean FEV1 of 1.08 liters (range, 0.53 – 1.71 L) were treated. Pneumothorax requiring tube thoracostomy occurred following CT-guided fiducial placement in 25% of the patients. All patients completed treatment with few acute side effects and no procedure-related mortality. Transient chest wall discomfort developed in 8 of the 12 patients with lesions within 5 mm of the pleura. The mean percentage of the total lung volume receiving a minimum of 15 Gy was 7.3% (range, 2.4% to 11.3%). One patient who received concurrent gefitinib developed short-lived, grade III radiation pneumonitis. The mean percent predicted DLCO decreased by 9% and 11% at 6 and 12 months, respectively. There were no local failures, regional lymph node recurrences or distant metastases. With a median follow-up of 25 months for the surviving patients, Kaplan-Meier overall survival estimate at 2 years was 87%, with deaths due to COPD progression.

Conclusion

Radical CyberKnife radiosurgery is a well-tolerated treatment option for inoperable patients with small, peripheral stage I NSCLC. Effective doses and adequate margins are likely to have contributed to the optimal early local control seen in this study.     

Cellular and biochemical characteristics of semen obtained from pubertal chimpanzees by masturbation

Semen characteristics were studied in 6 wild-born chimpanzees with dental ages ranging approximately from 6 to 12 years. The animals formed 2 groups, early pubertal (EP, N = 3, 6-9 years) and late pubertal (LP, N = 3, 11-12 years). Mean body weight, testicular volume and serum androgen concentration were significantly lower in Group EP (32.2 +/- 1.6 kg, 34.0 +/- 7.7 cm3, 2.1 +/- 0.1 ng/ml) than in Group LP (55.7 +/- 5.7 kg, P less than 0.01; 100.5 +/- 11.9 cm3, P less than 0.01; 3.6 +/- 0.7 ng/ml, P less than 0.05). Ejaculates were obtained by masturbation in all subjects. The mean ejaculate volume was lower in Group EP (0.56 +/- 0.20 ml) than in Group LP (3.77 +/- 0.73 ml, P less than 0.01). In Group EP, 2 animals were azoospermic while the third produced semen with means of 57.1 x 10(6) spermatozoa per ml, 20% motility and 40% vitality. These values were low when compared with the mean values of Group LP (376 x 10(6) spermatozoa per ml, 67% motility and 78% vitality). Mean total sperm count was correlated with testicular volume (r = 0.84) and serum androgen concentration (r = 0.96). The mean concentrations of L-carnitine, fructose, citrate and acid phosphatase for the two groups were not significantly different; but, related to the differences in ejaculate volumes, their total amounts in total ejaculate were lower in Group EP than in Group LP. These results suggest that, in chimpanzees, mechanisms of seminal plasma production and ejaculation are functional early in the reproductive life and that the emission of spermatozoa occurs later.     

Middle cerebral artery blood velocity during a valsalva maneuver in the standing position.

Occasionally, lifting of a heavy weight leads to dizziness and even to fainting, suggesting that, especially in the standing position, expiratory straining compromises cerebral perfusion. In 10 subjects, the middle cerebral artery mean blood velocity (V(mean)) was evaluated during a Valsalva maneuver (mouth pressure 40 mmHg for 15 s) both in the supine and in the standing position. During standing, cardiac output decreased by 16 +/- 4 (SE) % (P < 0.05), and at the level of the brain mean arterial pressure (MAP) decreased from 89 +/- 2 to 78 +/- 3 mmHg (P < 0.05), as did V(mean) from 73 +/- 4 to 62 +/- 5 cm/s (P < 0.05). In both postures, the Valsalva maneuver increased central venous pressure by approximately 40 mmHg with a nadir in MAP and cardiac output that was most pronounced during standing (MAP: 65 +/- 6 vs. 87 +/- 3 mmHg; cardiac output: 37 +/- 3 vs. 57 +/- 4% of the resting value; P < 0.05). Also, V(mean) was lowest during the standing Valsalva maneuver (39 +/- 5 vs. 47 +/- 4 cm/s; P < 0.05). In healthy individuals, orthostasis induces an approximately 15% reduction in middle cerebral artery V(mean) that is exaggerated by a Valsalva maneuver performed with 40-mmHg mouth pressure to approximately 50% of supine rest.