Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.     

Levels of acylation stimulating protein in obese women before and after moderate weight loss

Acylation stimulating protein (ASP) is a small (MW 14,000) basic (pI 9.0) protein which has only recently been purified from human plasma. Since ASP is the most potent known stimulant of triglyceride synthesis in human adipose tissue, the present study was designed to determine if plasma ASP was elevated in patients with moderate obesity, and if so, whether this level changed with weight loss. Fasting plasma ASP levels were determined by competitive ELISA immunoassay in 10 obese women before weight loss, immediately after weight loss, and 3 months after maintaining weight reduction. Their plasma ASP results were compared to 17 age and sex-matched lean controls. With weight loss, plasma ASP decreased significantly: 19.6 +/- 10.7 mg/dl before weight loss vs 15.0 +/- 9.5 mg/dl after weight loss vs 13.8 +/- 7.7 mg/dl 3 months after being weight stable, P less than 0.05 initial vs final value. Nevertheless, plasma ASP was significantly higher than the control value at all three times. Thus, before weight loss, the average ASP in the obese group was four times that in the control group (19.6 +/- 10.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005) while even 3 months after weight loss, it remained almost three times above the control group (13.8 +/- 7.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005). The data suggest, therefore, that an elevated plasma level of ASP is common in obesity, that the level of plasma ASP may reflect the fat cell mass present in an individual, and raises the possibilities that ASP may play a role in initiation or maintenance of the obese state.     

Growth promoting and metabolic activity of the human insulin analogue [Gly,Arg,Arg]insulin (HOE 901) in muscle cells

[Gly^A21,Arg^B31,Arg^B32]insulin (HOE 901) represents a biosynthetic human insulin analogue that, due to its isoelectric point, precipitates at neutral tissue pH leading to a retarded absorption rate and a corresponding longer duration of action. In the present investigation we have evaluated the growth promoting and metabolic activity of this analogue in muscle tissue using exponentially growing H9c2 cardiac myoblasts and adult rat ventricular cardiomyocytes. Equilibrium binding studies of ¹²⁵I-labelled IGF-I (insulin-like growth factor I) to differentiating myoblasts revealed the presence of 7×10³ IGF-I receptors per cell. In contrast, no specific binding of insulin could be detected. Competition binding experiments showed a slightly higher affinity of HOE 901 for the IGF-I receptor when compared to regular human insulin with IC₅₀ (half-inhibitory concentration) values of 70 and 101 nM, respectively. However, the supermitogenic insulin analogue [Asp^B10]insulin competed significantly more efficiently for IGF-I binding (IC₅₀: 44 nM). Maximum growth promoting activity of the peptides was then determined in serum-starved myoblasts by an incubation with the peptides (5×10⁻⁷ M) for 16 h in the presence of [³H]thymidine. [Asp^B10]Insulin produced a stimulation of DNA synthesis (about 3-fold) which was comparable to the effect of IGF-I and significantly (P<0.005) higher than the effect of HOE 901 with the latter being essentially equipotent to native insulin. Comparable results were obtained at lower concentrations of the peptides (10⁻⁹ to 10⁻⁸ M). Metabolic activity of HOE 901 was determined by measuring the dose-dependent stimulation of 3-O-methylglucose transport in adult cardiomyocytes. Maximum transport stimulation was identical for insulin and HOE 901 with EC₅₀ (half-effective concentration) values of 0.7×10⁻¹⁰ and 1.9×10⁻⁹ M, respectively. We concluded that the IGF-I receptor-mediated growth promoting activity of HOE 901 in muscle cells and the maximal metabolic activity of this analogue are not different from those of native human insulin. It is suggested that differential interaction with IGF-I receptors significantly contributes to the action profile of insulin analogues.     

Endoscopic cordectomy. a proposal for a classification by the Working Committee, European Laryngological Society

The European Laryngological Society is proposing a classification of different laryngeal endoscopic cordectomies in order to ensure better definitions of postoperative results. We chose to keep the word “cordectomy” even for partial resections because it is the term most often used in the surgical literature. The classification comprises eight types of cordectomies: a subepithelial cordectomy (type I), which is resection of the epithelium; a subligamental cordectomy (type II), which is a resection of the epithelium, Reinke’s space and vocal ligament; transmuscular cordectomy (type III), which proceeds through the vocalis muscle; total cordectomy (type IV); extended cordectomy, which encompasses the contralateral vocal fold and the anterior commissure (type Va); extended cordectomy, which includes the arytenoid (type Vb); extended cordectomy, which encompasses the subglottis (type Vc); and extended cordectomy, which includes the ventricle (type Vd). Indications for performing those cordectomies may vary from surgeon to surgeon. The operations are classified according to the surgical approach used and the degree of resection in order to facilitate use of the classification in daily practice. Each surgical procedure ensures that a specimen is available for histopathological examination. Received: 29 December 1998 / Accepted: 2 July 1999     

Training the "clinical scientist" through a combined industrial/academic fellowship

A novel two-year fellowship program is described which provides specialized training both in clinical drug research and drug development methodology for pharmacists with previous clinical experience. Pharmaceutical industry, university and hospital research facilities are used as the training laboratories, and collectively offer theoretical as well as practical research skills development. Traditional didactic and laboratory training are provided within university and hospital environments with emphasis in the conduct of clinical trials. Extramural experience with pharmaceutical industry provides a corollary experience which includes exposure to ethical, legal and regulatory issues involving both investigational and marketed drugs. Following successful completion of the fellowship, the pharmacist is expected to have developed the fundamental skills necessary for a career in academia, pharmaceutical industry, or clinical practice.     

Malignant laryngotracheal obstruction: a way to treat serial stenoses of the upper airways

BACKGROUND: Six patients known to have inoperable esophageal carcinoma presented with stridor due to both malignant tracheal stenosis (n = 6) and bilateral vocal cord paralysis. Two patients also had respiratory-digestive fistula. METHODS: Patency was restored by endotracheal stenting plus unilateral cordectomy. Four patients had immediate relief. Two patients required enlargement of the cord incision. One of them declined reoperation and underwent tracheotomy. RESULTS: Stent function was uneventful. There was no dislodgement or mucous impaction. Fistula seal was complete. There was no aspiration through the new-shaped glottic orifice. Peak expiratory flow increased from 24.4% +/- 9.7% predicted normal before to 40.5% +/- 13.7% after the procedure, whereas the dyspnea score decreased from 74.2 +/- 12.7 to 24.2 +/- 14.0. CONCLUSIONS: Restoration of airway continuity in serial laryngotracheal stenoses using a combined approach is a feasible technique in end-stage cancer patients. It effectively relieves respiratory distress and ensures voice preservation. In addition, it may avoid the risks of tracheotomy.     

Survival for rectal cancer patients and international comparisons.

BACKGROUND: Population-based cancer registry data are important because they reflect routine care, present long-term follow-up, can show differences in treatment, outcomes and health care over time, and can be used for comparisons between regions and countries. PATIENTS AND METHODS: Details of all cancer patients in the Munich region are recorded by the Munich Cancer Registry. Rectal cancer patients with an invasive primary tumor diagnosed between 1996 and 1998 were included in this analysis (n=936). Observed and relative survival are presented. Observed survival was also investigated with a Cox proportional hazards regression model. RESULTS: Median follow-up time of survivors was 5.7 years. Five-year relative survival for the whole sample was 62.2%. International Union Against Cancer (UICC) stage was the most important prognostic factor in the multivariate analysis. Compared with the 1992-1999 Surveillance Epidemiology and End Results (SEER) data (62.4%), relative survival for each disease stage and the whole sample were very similar. In comparison with other European registries, Munich patients had slightly higher survival rates per stage (for example, 5-year relative survival in UICC III was 58.3% in Munich, 54.6% in South East Netherlands, 33.3% in Modena and 47.4% in Cote d'Or); however, more patients in Munich were in higher disease stages with worse prognoses, indicating poorer early detection. CONCLUSIONS: These results indicate that treatment of rectal cancer in Munich is good, but early detection could be improved. Cancer registries should publish their population-based stage data to ensure quality of care and provide regular feedback to health-care workers and decision makers. Comparisons between countries without stage data should be conducted cautiously.     

Wertigkeit der Feinnadelpunktionszytologie bei Neoplasien der Glandula parotis

BACKGROUND: In many parts of Germany fine-needle aspiration biopsy (FNAB) is still not part of the routine preoperative diagnostic evaluation of salivary gland neoplasms. Most opponents consider the study unnecessary and recommend that all salivary gland neoplasms should be excised. OBJECTIVE: Because of this an evaluated the ability of FNAB to provide an accurate diagnosis of parotid gland neoplasms. PATIENTS AND METHOD: Between January 1992 and October 1995, 336 patients referred for operative therapy of salivary gland neoplasms underwent retrospective analysis of preoperative FNAB compared with the excised tumor histology. RESULTS: Results showed that the FNAB had a sensitivity of 93.1%, a specificity of 99.2%, a positive predictive value of 93.1%, a negative predictive value of 99.2% and an accuracy of 98.6%. Complications were observed in less than 1%. DISCUSSION: Our findings demonstrated that the FNAB is a safe diagnostic tool that has a reliable sensitivity and high specificity for the assessment of salivary gland pathology. Since many malignant salivary gland neoplasms present with a virtual lack of symptoms indicating actual malignancy we believe that there is need for FNAB in routine preoperative diagnostic testing.