Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

BACKGROUND & AIMS: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB. METHODS AND RESULTS: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat. We calculated the homeostasis model assessment index (HOMA-IR) and whole body insulin sensitivity from oral glucose tolerance tests and measured intramyocellular fat by magnetic resonance spectroscopy. BCAAs and 3-HIB plasma concentrations were inversely related to insulin sensitivity but not to intramyocellular fat content at baseline. With 7.4 ± 4.5% weight loss mean BCAA and 3-HIB plasma concentrations did not change, irrespective of dietary macronutrient content. Individual changes in 3-HIB with 6-month diet but not BCAAs were correlated to the change in whole body insulin sensitivity and HOMA-IR independently of BMI changes. CONCLUSIONS: 3-HIB relates to insulin sensitivity but is not associated with intramyocellular fat content in overweight to obese individuals. Moreover, changes in 3-HIB rather than changes in BCAAs are associated with metabolic improvements with weight loss. Registration number for clinical trials: ClinicalTrials.gov Identifier: NCT00956566.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects.

BACKGROUND & AIMS: Amino acids may interfere with insulin action, particularly in obese individuals. We hypothesized that increased circulating branched-chain and aromatic amino acids herald insulin resistance and ectopic fat storage, particularly hepatic fat accumulation. METHODS AND RESULTS: We measured fasting branched-chain and aromatic amino acids (tryptophan, tyrosine, and phenylalanine) by mass spectrometry in 111 overweight to obese subjects. We applied abdominal magnetic resonance imaging and spectroscopy to assess adipose tissue distribution and ectopic fat storage, respectively. Plasma branched-chain amino acids concentrations were related to insulin sensitivity and intrahepatic fat independent from adiposity, age and gender, but not to abdominal adipose tissue or intramyocellular fat. CONCLUSIONS: In weight stable overweight and obese individuals, branched-chain amino acid concentrations are specifically associated with hepatic fat storage and insulin resistance.

Determinants of exercise-induced fat oxidation in obese women and men.

Endurance training at an intensity eliciting maximal fat oxidation may have a beneficial effect on body weight and glucose metabolism in obese patients. However, the exercise intensity at which maximal fat oxidation occurs and the factors limiting fat oxidation are not well studied in this population. Obese, otherwise healthy men (n=38) and women (n=91) performed an incremental exercise test up to exhaustion on a cycle ergometer. Substrate oxidation was estimated using indirect calorimetry. Magnetic resonance tomography and spectroscopy were conducted to assess body fat distribution and intramyocellular fat content. We determined the exercise intensity at which maximal body fat oxidation occurs and assessed whether body composition, body fat distribution, intramyocellular fat content, or oxidative capacity predict exercise-induced fat oxidation. Maximal exercise-induced fat oxidation was 0.30+/-0.02 g/min in men and 0.23+/-0.01 g/min in women (p<0.05). Exercise intensity at the maximum fat oxidation was 42+/-2.2% VO (2 max) in men and 43+/-1.7% VO (2 max) in women. With multivariate analysis, exercise-induced fat oxidation was related to fat-free mass, percent fat mass, and oxidative capacity, but not to absolute fat mass, visceral fat, or intramyocellular fat content. We conclude that in obese subjects the capacity to oxidize fat during exercise appears to be limited by skeletal muscle mass and oxidative capacity rather than the availability of visceral or intramyocellular fat.

Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial).

BACKGROUND: Arteriogenesis (collateral artery growth) is nature's most efficient rescue mechanism to overcome the fatal consequences of arterial occlusion or stenosis. The goal of this trial was to investigate the effect of external counterpulsation (ECP) on coronary collateral artery growth. MATERIALS AND METHODS: A total of 23 patients (age 61 +/- 2.5 years) with stable coronary artery disease and at least one haemodynamic significant stenosis eligible for percutaneous coronary intervention were prospectively recruited into the two study groups in a 2 : 1 manner (ECP : control). One group (ECP group, n = 16) underwent 35 1-h sessions of ECP in 7 weeks. In the control group (n = 7), the natural course of collateral circulation over 7 weeks was evaluated. All patients underwent a cardiac catheterization at baseline and after 7 weeks, with invasive measurements of the pressure-derived collateral flow index (CFIp, primary endpoint) and fractional flow reserve (FFR). RESULTS: In the ECP group, the CFIp (from 0.08 +/- 0.01 to 0.15 +/- 0.02; P < 0.001) and FFR (from 0.68 +/- 0.03 to 0.79 +/- 0.03; P = 0.001) improved significantly, while in the control group no change was observed. Only the ECP group showed a reduction of the Canadian Cardiovascular Society (CCS, P = 0.008) and New York Heart Association (NYHA, P < 0.001) classification. CONCLUSION: In this study, we provide direct functional evidence for the stimulation of coronary arteriogenesis via ECP in patients with stable coronary artery disease. These data might open a novel noninvasive and preventive treatment avenue for patients with non-acute vascular stenotic disease.

Transapical aortic stenting: an initial case series.

AIMS: The standard approach for thoracic endovascular aortic repair (TEVAR) is transfemoral; however, calcifications and tortuosity of the access vessels might be so extensive as to increase the operative risk markedly or preclude the procedure. This study evaluates the transapical approach as an alternative route for TEVAR in such patients. METHODS AND RESULTS: From June 2011 to July 2013, the institution's interdisciplinary board for aortic diseases initially denied TEVAR for eight patients with thoracic aortic pathology due to extensive calcification and tortuosity of the distal vessels. The transapical approach was suggested and approved by the board. All procedures were performed in a hybrid operating room through a left mini-thoracotomy. The stent grafts were implanted in either the proximal descending or the ascending aorta. The deployment was performed under rapid ventricular pacing. Procedural success was 100%. There were no intraoperative complications. One patient needed re-exploration. There was no 30-day mortality. In follow-up, one patient suffered type 1B endoleak, which required surgery after one year. CONCLUSIONS: The transapical approach for TEVAR (TaTEVAR) is a feasible option for patients with distal aorta/iliac vessels unsuitable for transfemoral access. It might be even more beneficial for TEVAR of the ascending aorta.

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine.

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q2cv of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q2cv values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.

Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D(3) subtype.

To evaluate nonaromatic catechol bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as the key reaction step. Subsequent receptor binding studies at the dopamine receptor subtypes D(1), D(2 long), D(2 short), D(3), and D(4) showed highly interesting binding profiles for the enynes 1a and 1b when compared to dopamine. At the guanine nucleotide-sensitive high-affinity binding site of the D(3) receptor, the target compound 1b (K(i) = 5.2 nM) was 10-fold more potent than dopamine but less potent at the D(2) and D(4) subtypes. In contrast to dopamine the agonists 1a and 1b showed strong selectivity for the receptors of the D(2) family (D(2)-D(4)). As far as we know, this study represents the first report on nonaromatic dopamine agonists. Comparison of molecular electrostatic potentials, derived from semiempirical molecular orbital calculations, and lipophilicity maps was performed.

Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213).

Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the intrinsic activity of the regioisomers investigated is controlled by the ability of the heterocyclic unit to interact with both elements of the D4 binding-site crevice, the aromatic microdomain in TM6, and a serine residue in TM5.

A high-efficiency microwave thermoablation system for the treatment of benign prostatic hyperplasia: results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical trial.

OBJECTIVES: To determine the effectiveness, safety, and impact on patient quality of life (QOL) of a novel transurethral microwave thermoablation system for the treatment of benign prostatic hyperplasia (BPH). METHODS: A total of 169 patients with BPH were randomized to undergo a 1-hour microwave (n = 125) or sham (n = 44) procedure using the Urologix Targis thermoablation system on an outpatient basis, without general or regional anesthesia. Symptoms, flow rates, and QOL scores were determined before the study procedure and periodically thereafter up to 6 months. RESULTS: Mean American Urological Association (AUA) score in the microwave group diminished 50% (P <0.0005) by the 6-month evaluation (10.5, 95% confidence interval [CI] 9.2 to 11.8) compared with baseline values (20.8, 95% CI 19.8 to 21.9). The sham group also exhibited lower postprocedural AUA scores; however, the magnitude of the postprocedural decline in AUA score in the microwave group was significantly greater (P <0.01) than that in the sham group. Half the microwave group had an AUA score of less than 9 by 6 months, and the decrease in symptoms was similar among patients with initially moderate versus initially severe symptoms. Mean peak urinary flow rate (Qmax) in the microwave group increased 51% (P <0.0005) by 6 months to 11.8 mL/s (95% CI 10.7 to 13.0) versus a pretreatment value of 7.8 mL/s (95% CI 7.4 to 8.2). The magnitude of the postprocedural increase in Qmax was significantly greater in the microwave than the sham group (P <0.05). In nearly half the microwave group (47%), Qmax increased 50% or more by 6 months compared with 24% of the sham group. Microwave treatment resulted in a significantly greater (P <0.05) positive impact on patient QOL than did the sham procedure. By 6 months, the QOL score in microwave-treated patients (2.2, 95% CI 1.9 to 2.4) averaged 48% lower (P <0.0005) than that at baseline (4.2, 95% CI 4.0 to 4.4). Significantly greater durability of treatment effects was also evident with microwave than with sham treatment, as judged by the higher proportion of microwave-treated patients (98.4%) requiring no further treatment during the 6-month study period versus 83.3% of sham control patients (P <0.0005). Microwave treatment was well tolerated, and complications were generally minor, readily manageable, and transitory. CONCLUSIONS: The microwave thermoablation system proved to be an effective and safe treatment modality for BPH, with a positive impact on patient QOL.

[Clinical aspects of osteomyelitis sicca (pseudo-Paget)]. / Zur Klinik der Osteomyelitis sicca (Pseudo-Paget).

Osteomyelitis sicca of the mandible in its dry, tumour-producing form was described clinically and radiologically as pseudo-Paget's disease by Axhausen in 1934. In 1969, Hoppe et al. were able to corroborate in animal experiments different stages of this disease, previously outlined by Hoppe in a pathological histological study in 1964. Empirically, an anti-rheumatic treatment offers itself with which an exacerbation can be cut short and complete remission obtained later.

[Bone regeneration over plastic implants after mandibular resection breaking the continuity]. / Knochenregeneration bei Kunststoffimplantaten nach Unterkieferkontinuitätsresektion

In young patients, bone regeneration may start from the region of the temporo-mandibular joint and from the peripheral mandibular stump in cases of continuity defects of the mandible. A resin graft implanted for soft tissue reconstruction is collar-like surrounded by bone which is developing into a functionally and anatomically full regenerate over many years, in correspondence to periosteal and desmal growth stimuli. In adults, regeneration is minimal.

[Clinical aspects and pathology of tumors of the temporomandibular joint]. / Zur Klinik und Pathologie von Kiefergelenktumoren

Two primary tumors of the temporo-mandibular joint are presented. Because of their unspecific clinical symptoms, the diagnosis could be confirmed by surgical intervention and histopathology only after a long period of observation. Benign temporo-mandibular joint tumors can still be managed, while in malignant tumors the further course of the disease is characterized by a poor prognosis.

Multifocal dermal-type basal cell adenomas of parotid glands with co-existing dermal cylindromas.

A basal cell adenoma of the parotid gland accompanied by multiple developing microadenomas of the same type and three dermal cylindromas, all observed in a 54-year-old woman, were examined by light microscopy. The histological structure of the basal cell adenomas shows striking similarities to co-existing dermal cylindromas, suggesting a common histogenesis of both tumors. We suggest that the term "basal cell adenoma of dermal type" should be used for these lesions. Multifocal ductal proliferations with nascent adenomas in the glandular parenchyma allow us to trace the development of these tumors. Studies of the literature reveal four additional cases in which there are co-existing basal cell adenomas of salivary glands and dermal adnexal tumors.

[Results of conservative and surgical treatment of jaw fractures]. / Ergebnisse konservativer und operativer Kieferbruchbehandlung

In the majority of the patients with fractures of the jaws treated in the period covered by this study, conservative therapy has shown satisfying results. In intraoral splinting, periodontal lesions could largely be avoided by adequate oral hygiene. Surgery must still be applied in those cases where conservative methods failed to be successful.

[Transsinusal repositioning and retention of zygomatic fractures]. / Transsinusale Reposition und Retention von Jochbeinfrakturen

In the treatment of impression fractures of the zygoma transsinusal repositioning of the fragments and their retention by means of a simple inflatable balloon catheter has proved successful. This method not only permits retention and drainage of the maxillary sinus but also postoperative correction of visual disturbances, if necessary.

Suture entrapment and secondary ureteral obstruction.

During the 6-year period ending in 1988, suture entrapment and secondary postoperative ureteral obstruction occurred in 18 (0.33%) of the 5379 patients who underwent major pelvic operations for benign conditions. Sixteen cases occurred after vaginal surgery and two after abdominal hysterectomy. Placement of the McCall suture or sutures for elevation of a bladder neck caused ureteral entrapment most frequently. Early diagnosis was facilitated by comparison of preoperative and postoperative serum creatinine levels. The mean change in serum creatinine level in patients with unilateral obstruction was an increase of 0.8 mg/dl. Treatment by either antegrade placement of ureteral stents or abdominal exploration with deligation or ureteroneocystotomy was successful in all cases. Retrograde placement of ureteral stents was unsuccessful.

Migration and granulomatous reaction after periurethral injection of polytef (Teflon).

Although patients with urinary incontinence have been treated successfully by periurethral injection of polytef paste, this study in continent animals demonstrates migration of polytef particles from the injection site. We injected polytef paste periurethrally into female dogs and male monkeys. Particles were found at 50 to 70 days in pelvic nodes in six of seven animals and lungs in four of seven (the kidneys and brain were not studied); and at 10 1/2 months in pelvic nodes, lungs, and brain in seven of seven; kidneys in four of seven; and spleen in two of seven. X-ray microanalysis confirmed that the particles were polytef. At 10 1/2 months, polytef granulomas were found at all injection sites and some sites of distant migration. Since these granulomas signify chronic foreign-body reaction, we believe that until the long-term effects in humans are known, polytef paste should not be used in children or young adults with normal life expectancy.