Semi-supervised clustering of quaternion time series: Application to gait analysis in multiple sclerosis using motion sensor data.

Recent approaches in gait analysis involve the use of wearable motion sensors to extract spatio-temporal parameters that characterize multiple aspects of an individual's gait. In particular, the medical community could largely benefit from this type of devices as they could provide the clinicians with a valuable tool for assessing gait impairment. Motion sensor data are however complex and there is an urgent unmet need to develop sound statistical methods for analyzing such data and extracting clinically relevant information. In this article, we measure gait by following the hip rotation over time and the resulting statistical unit is a time series of unit quaternions. We explore the possibility to form groups of patients with similar walking impairment by taking into account their walking data and their global decease severity with semi-supervised clustering. We generalize a compromise-based method named hclustcompro to unit quaternion time series by combining it with the proper dissimilarity quaternion dynamic time warping. We apply this method on patients diagnosed with multiple sclerosis to form groups of patients with similar walking deficiencies while accounting for the clinical assessment of their overall disability. We also compare the compromise-based clustering approach with the method mergeTrees that falls into a sub-class of ensemble clustering named collaborative clustering. The results provide a first proof of both the interest of using wearable motion sensors for assessing gait impairment and the use of prior knowledge to guide the clustering process. It also demonstrates that compromise-based clustering is a more appropriate approach in this context.

A Novel Walking Activity Recognition Model for Rotation Time Series Collected by a Wearable Sensor in a Free-Living Environment.

Solutions to assess walking deficiencies are widespread and largely used in healthcare. Wearable sensors are particularly appealing, as they offer the possibility to monitor gait in everyday life, outside a facility in which the context of evaluation biases the measure. While some wearable sensors are powerful enough to integrate complex walking activity recognition models, non-invasive lightweight sensors do not always have the computing or memory capacity to run them. In this paper, we propose a walking activity recognition model that offers a viable solution to this problem for any wearable sensors that measure rotational motion of body parts. Specifically, the model was trained and tuned using data collected by a motion sensor in the form of a unit quaternion time series recording the hip rotation over time. This time series was then transformed into a real-valued time series of geodesic distances between consecutive quaternions. Moving average and moving standard deviation versions of this time series were fed to standard machine learning classification algorithms. To compare the different models, we used metrics to assess classification performance (precision and accuracy) while maintaining the detection prevalence at the level of the prevalence of walking activities in the data, as well as metrics to assess change point detection capability and computation time. Our results suggest that the walking activity recognition model with a decision tree classifier yields the best compromise in terms of precision and computation time. The sensor that was used had purposely low computing and memory capacity so that reported performances can be thought of as the lower bounds of what can be achieved. Walking activity recognition is performed online, i.e., on-the-fly, which further extends the range of applicability of our model to sensors with very low memory capacity.

Smoothing method for unit quaternion time series in a classification problem: an application to motion data.

Smoothing orientation data is a fundamental task in different fields of research. Different methods of smoothing time series in quaternion algebras have been described in the literature, but their application is still an open point. This paper develops a smoothing approach for smoothing quaternion time series to obtain good performance in classification problems. Starting from an existing method which involves an angular velocity transformation of unit quaternion time series, a new method which employ the logarithm function to transform the quaternion time series to a real three-dimensional time series is proposed. Empirical evidences achieved on real data set and artificially noisy data sets confirm the effectiveness of the proposed method compared with the classical approach based on angular velocity transformation. The R functions developed for this paper will be provided in a Github repository.

Human papillomavirus (HPV) DNA triage of women with atypical squamous cells of undetermined significance with cobas 4800 HPV and Hybrid Capture 2 tests for detection of high-grade lesions of the uterine cervix.

The triage of women with high-risk (HR) human papillomavirus (HPV)-positive smears for atypical squamous cells of undetermined significance (ASC-US) to colposcopy is now an integrated option in clinical guidelines. The performance of cobas 4800 HPV and that of Hybrid Capture 2 (HC2) for HR HPV DNA detection in cervical samples in PreservCyt were compared in 396 women referred to colposcopy for ASC-US. Of these, 316 did not have cervical intraepithelial neoplasia (CIN), 47 had CIN1, 29 had CIN2 or CIN3 (CIN2+), and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 149 (37.6%) samples with HC2 and cobas 4800 HPV, respectively (P = 0.15). The clinical sensitivities and specificities for detecting CIN2+ were 89.7% (95% confidence interval [CI], 72.8 to 97.2%) and 66.7% (95% CI, 61.7 to 71.3%) with cobas 4800 HPV and 93.1% (95% CI, 77.0 to 99.2%) and 72.2% (95% CI 67.4 to 76.5%) with HC2. The performance of cobas 4800 HPV was similar to that of HC2 for identifying women with ASC-US who would benefit the most from colposcopy.

Comparison of human papillomavirus testing and cytology for cervical cancer screening in a primary health care setting in the Democratic Republic of the Congo.

OBJECTIVES: We compared the screening performance of conventional Pap cytology and two human papillomavirus (HPV) DNA assays, the original Hybrid Capture 2 (HC2) and an expanded version that tests for 4 additional HPV types (HC2+4; Qiagen Corporation), in the detection of cervical neoplasia among unscreened women in a primary care setting in a suburb of Kinshasa, Democratic Republic of the Congo. METHODS: All women 30 years or older residing in the area were invited to participate, and 1528 were evaluated by Pap cytology and the two HPV assays, conducted at a European and US reference laboratory, respectively, followed by colposcopy. Cervical biopsies were obtained from all women with abnormal colposcopy and from 290 randomly chosen women with normal colposcopy (to correct for verification bias). RESULTS: Using a relative light unit of 1 as the cutoff for positivity, 169 and 168 (11%) women tested positive using HC2 and HC2+4, respectively. HC2 and HC2+4 were in agreement in 98.6% of cases (Kappa=0.94; 95% confidence interval: 0.91-0.96). Both assays were sensitive (~83%) and specific (~91%) for the detection of cervical intraepithelial neoplasia-2 or worse disease. Irrespective of the cutoff point used to define positivity, Pap cytology was both less sensitive and more specific than HC2 or HC2+4. For instance, cytology was 63% sensitive and 97% specific when a cutoff point of low-grade squamous intraepithelial lesions or worse was used. CONCLUSIONS: Among unscreened women, HC2 and HC2+4 had similar screening accuracy for cervical neoplasia, and both were more sensitive but less specific than Pap cytology.

Human papillomavirus (HPV) DNA triage of women with atypical squamous cells of undetermined significance with Amplicor HPV and Hybrid Capture 2 assays for detection of high-grade lesions of the uterine cervix.

Up to 20% of women having a cytology smear showing atypical squamous cells of undetermined significance (ASC-US) and infected with high-risk human papillomavirus (HR HPV) have high-grade cervical intraepithelial neoplasia (CIN 2/3). Results obtained with the Amplicor HPV and Hybrid Capture 2 (HC-2) assays for HR HPV DNA detection in women referred to colposcopy for an ASC-US smear were compared. Cervical samples in PreservCyt were tested for the presence of 13 HR HPV types with HC-2, with Amplicor at three cutoffs for positivity (0.2, 1.0, and 1.5 optical density units), and for 36 genotypes with the Linear Array (LA). Of 396 eligible women, 316 did not have CIN, 47 had CIN 1, 29 had CIN 2/3, and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 164 (41.4%) samples with HC-2 and Amplicor HPV (cutoff, 0.2), respectively (P = 0.01). Overall, 112 specimens were positive and 215 were negative with the HC-2 and Amplicor HPV assays (agreement of 82.6%; 95% confidence interval [CI], 78.5 to 86.0). The clinical sensitivity and specificity of Amplicor HPV at cutoffs of 0.2, 1.0 and 1.5 and of HC-2 for detection of CIN 2/3 were 89.7% (95% CI, 72.8 to 97.2) and 62.5% (95% CI, 57.5 to 52.4), 89.7% (95% CI, 72.8 to 97.2) and 64.5% (95% CI, 59.4 to 69.2), 89.7% (95% CI, 72.8 to 97.2) and 64.7% (95% CI, 59.7 to 69.5), and 93.1% (95% CI, 77.0 to 99.2) and 72.2% (95% CI, 67.4 to 76.5), respectively. Both HR HPV detection tests identified women with ASC-US who would benefit the most from colposcopy. Women with persistent HR HPV infection need further investigation despite a first normal colposcopy.

Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study.

BACKGROUND: Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. METHODS: In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V), sentinel-node detection was done in patients with T1-T2 (<4 cm) squamous-cell vulvar cancer, followed by inguinofemoral lymphadenectomy if metastatic disease was identified in the sentinel node, either by routine examination or pathological ultrastaging. For the present study, sentinel nodes were independently reviewed by two pathologists. FINDINGS: Metastatic disease was identified in one or more sentinel nodes in 135 (33%) of 403 patients, and 115 (85%) of these patients had inguinofemoral lymphadenectomy. The risk of non-sentinel-node metastases was higher when the sentinel node was found to be positive with routine pathology than with ultrastaging (23 of 85 groins vs three of 56 groins, p=0.001). For this study, 723 sentinel nodes in 260 patients (2.8 sentinel nodes per patient) were reviewed. The proportion of patients with non-sentinel-node metastases increased with size of sentinel-node metastasis: one of 24 patients with individual tumour cells had a non-sentinel-node metastasis; two of 19 with metastases 2 mm or smaller; two of 15 with metastases larger than 2 mm to 5 mm; and ten of 21 with metastases larger than 5 mm. Disease-specific survival for patients with sentinel-node metastases larger than 2 mm was lower than for those with sentinel-node metastases 2 mm or smaller (69.5%vs 94.4%, p=0.001). INTERPRETATION: Our data show that the risk of non-sentinel-node metastases increases with size of sentinel-node metastasis. No size cutoff seems to exist below which chances of non-sentinel-node metastases are close to zero. Therefore, all patients with sentinel-node metastases should have additional groin treatment. The prognosis for patients with sentinel-node metastasis larger than 2 mm is poor, and novel treatment regimens should be explored for these patients.

The Meaning-Making intervention (MMi) appears to increase meaning in life in advanced ovarian cancer: a randomized controlled pilot study.

OBJECTIVE: This pilot study aimed to provide supportive evidence for the acceptability and usefulness of the Meaning-Making intervention (MMi) in patients newly diagnosed with Stage III or IV ovarian cancer, and to provide estimates of parameters needed to design a full-scale study. METHODS: A randomized controlled trial with 24 patients (12 experimental and 12 control) was conducted. Existential well-being (primary outcome), overall quality of life, distress, anxiety, depression and self-efficacy were measured. RESULTS: Compared to the control group, patients in the experimental group had a better sense of meaning in life at one and three months post-intervention. CONCLUSION: The MMi seems a promising intervention for advanced cancer patients, and a full randomized controlled trial is warranted to further investigate its efficacy.

Primary abdominal wall clear cell carcinoma: case report and review of literature.

BACKGROUND: The development of a mass in a surgical scar poses a diagnostic dilemma due to similarities in appearance to hernias, abscesses, hematomas or desmoid tumors. Scar endometriosis is uncommon and malignant change within this ectopic tissue is rare. CASE REPORT: The case of a 55-year-old woman with an isolated clear cell adenocarcinoma in an area of scar endometriosis more than 17 years after a cesarean section is presented. Initially, this tumor was thought to be a chronic abscess, but was finally diagnosed as clear cell carcinoma. This case highlights the difficulties in preoperative diagnosis as well as the poor prognosis of these tumors. CONCLUSION: Accurate diagnosis of a lump within a scar is important to define the prognosis and treatment. Further data are needed for the management of this pathology.

Positive adnexal or uterine serosal involvement in stage IIIC endometrial cancer is an adverse factor for recurrence.

OBJECTIVES: Clinical and pathological significance of stage IIIC endometrial cancer is unclear. Our study was designed to determine the risk of recurrence among patients with stage IIIC endometrial cancer according to different pathological findings. METHODS: We retrospectively reviewed all patients with FIGO IIIC endometrial carcinoma (n = 48) treated in our institution between 1996 and 2005. Patients without comprehensive surgical staging were excluded. Patients were classified into two groups: with adnexae and/or uterine serosal metastasis (group A, n = 18) and without metastasis (group B, n = 20). Cox proportional hazards model was used for multiple regression analysis. RESULTS: Mean age was 64 years (range 46-90). Eighteen patients received adjuvant chemotherapy and pelvic radiotherapy, 17 received pelvic radiotherapy alone, and 11 received chemotherapy or hormonotherapy. At a median follow-up of 26.7 months, 12 had recurrence of the disease. Serosal and/or adnexal involvement was a negative independent prognostic factor for disease-free survival [relative risk = 3.75 (1.01-13.9); p = 0.04], whereas histological type, grade, depth of invasion and age at diagnosis had no influence. CONCLUSION: Patients with stage IIIC endometrial cancer and metastasis to adnexae and/or serosa have a higher risk of recurrence than those with node metastasis alone. Optimal adjuvant therapy for these groups remains unclear.

Haemorheological disturbances in hypertensive type 2 diabetic patients--influence of antihypertensive therapy.

Haemorheological changes have been described in hypertension as well as in diabetes mellitus. Antihypertensive treatment improves rheology in hypertensive patients. The aim of this study was to describe the haemorheological profile and its impact on shear stress in hypertensive type 2 diabetes mellitus patients (HT + DM) and to investigate the effect of antihypertensive therapy on blood rheology using a double-blind randomized protocol, comparing the calcium antagonist amlodipine with the angiotensin-converting enzyme (ACE) inhibitor enalapril. A total of 144 patients with hypertension and type 2 diabetes (64 of transversal study and 80 of randomized clinical trial) were compared with 92 controls belonging to a transversal study. Secondarily, in a separate analysis, therapeutic effects of calcium antagonist amlodipine and ACE inhibitor enalapril were compared in a longitudinal, randomized trial in the patients. We assessed whole-blood viscosity, plasma viscosity, partial and total disaggregation times, haematocrit and fibrinogen. Radial artery systolic flow velocity was measured by pulsed Doppler. Shear stress was calculated as the product of flow velocity x whole-blood viscosity. Compared with controls, patients had significantly higher whole-blood viscosity for all shear rates (P < 0.001) as well as higher arterial diameter and systolic blood flow velocity (2.8 +/- 0.3 vs. 2.6 +/- 0.3 mm, P < 0.001; and 50.8 +/- 11.6 vs. 45.6 +/- 9.8 cm/s, P = 0.01, respectively). Whole-blood viscosity at shear rate gamma = 128/s tended to increase with amlodipine (+1.13%) and decrease with enalapril (-2.47%) (P = 0.028 for inter-group difference). In hypertensive diabetic patients, hyperviscosity contributes to increased shear stress. Haemorheological disturbances in these patients are not significantly influenced by blood pressure lowering with antihypertensive therapy by ACE inhibitor enalapril or calcium antagonist amlodipine. Other factors potentially contributing to rheology and arterial changes may be more critical in HT + DM patients and need further investigation.

Logic programming reveals alteration of key transcription factors in multiple myeloma.

Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP. These repairs could represent cancer mutations leading to GEP variability. With this reasoning, unmeasured protein states can be inferred, and we can simulate the impact of a protein perturbation on the RN behavior to identify therapeutic targets. We showed that JUN/FOS and FOXM1 activities are altered in almost all MM patients and identified two survival markers for MM patients. Our results suggest that JUN/FOS-activation has a strong impact on the RN in view of the whole GEP, whereas FOXM1-activation could be an interesting way to perturb an MM subgroup identified by our method.

Aggressive angiomyxoma of the vulva or perineum: report of three patients.

BACKGROUND: Aggressive angiomyxoma is a rare, locally aggressive soft tissue tumour that chiefly involves the vulvoperineal region of young female patients. Treatment is wide surgical excision. Frequent relapses are common. CASES: We present three patients who each had an aggressive angiomyxoma treated initially for another presumed diagnosis. Two patients required immediate repeat surgical procedures for incomplete tumour excision. The third patient developed a recurrence two years after the initial surgery. In one patient, hormonal therapy was used postoperatively because the evaluation of the tumour margins was uncertain. Harpoon markers were used to aid in tumour localization in another patient prior to resection. CONCLUSION: Clinicians should consider the diagnosis of aggressive angiomyxoma when a patient presents with an atypical vulvoperineal mass, as an incorrect diagnosis may lead to repeated surgical procedures.

Accuracy of an electrochemical sensor for measuring capillary blood ketones by fingerstick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients.

OBJECTIVE: This study was designed to test the accuracy of capillary ketonemia for diagnosis of ketosis after interruption of insulin infusion. RESEARCH DESIGN AND METHODS: A total of 18 patients with type 1 diabetes treated by external pump were studied during pump stop for 5 h. Plasma and capillary ketonemia and ketonuria were determined every hour from 7:00 A.M. (time 0 min = T0) to 12:00 P.M. (time 300 min = T300). Plasma beta-hydroxybutyrate (beta-OHB) levels were measured by an enzymatic end point spectrophotometric method, and capillary beta-OHB levels were measured by an electrochemical method (MediSense Optium meter). Ketonuria was measured by a semiquantitative test (Ketodiastix). Positive ketosis was defined by a value of >/=0.5 mmol/l for ketonemia and >/=4 mmol/l (moderate) for ketonuria. RESULTS: After stopping the pump, concentrations of beta-OHB in both plasma and capillary blood increased significantly at time 60 min (T60) compared with T0 (P < 0.001), reaching maximum levels at T300 (1.30 +/- 0.49 and 1.23 +/- 0.78 mmol/l, respectively). Plasma and capillary beta-OHB values were highly correlated (r = 0.94, P < 0.0001). For diagnosis of ketosis, capillary ketonemia has a higher sensitivity and negative predictive value (80.4 and 82.5%, respectively) than ketonuria (63 and 71.8%, respectively). For plasma glucose levels >/=250 mg/dl, plasma and capillary ketonemia were found to be more frequently positive (85 and 78%, respectively) than ketonuria (59%) (P = 0.017). The time delay to diagnosis of ketosis was significantly higher for ketonuria than for plasma ketonemia (212 +/- 67 vs. 140 +/- 54 min, P = 0.0023), whereas no difference was noted between plasma and capillary ketonemia. CONCLUSIONS: The frequency of screening for ketosis and the efficiency of detection of ketosis definitely may be improved by the use of capillary blood ketone determination in clinical practice.

Evolution of analytical performance in portable glucose meters in the last decade.

OBJECTIVE: To assess and compare the technical accuracy of portable glucose meters during the last decade. RESEARCH DESIGN AND METHODS: One-thousand preprandial (pre) and postprandial (post) capillary whole-blood glucose values measured with meters owned mainly by diabetic patients were compared with a single laboratory method yearly from 1989 to 1999. A total of 21,950 capillary measurements and their corresponding laboratory reference values were analyzed at our clinic. RESULTS: The lowest mean absolute difference was found in 1989 (pre: 2 +/- 22 mg/dl, post: 9 +/- 31 mg/dl) (mean +/- SD). The highest mean absolute difference was observed in 1993 (pre: 31 +/- 33 mg/dl) and 1996 (post: 50 +/- 35 mg/dl). The highest mean relative deviation was observed in 1990 (pre: 16.4%) and 1996 (post: 20.6%). The highest percentage of readings that were within a 5% deviation limit were observed in 1998 (pre: 44.5%) and in 1997 (post: 36.7%). Based on blood glucose levels within +/-5 and +/-10% of laboratory values, the technical accuracy of meters was similar for 1989 and 1999 (P = 0.27 and 0.52, respectively). The percentage of pre values in zone A of Clarke's error grid analysis was >90% in 1989, 1997, 1998, and 1999. CONCLUSIONS: The analytical performance of glucose meters decreased between 1990 and 1996 but was restored between 1997 and 1999. Nevertheless, our data suggest that the technical accuracy of glucose meters has not significantly improved during the last decade. Complementary studies taking into account the preanalytical improvements of the recent meters, as well as their calibration method, appear necessary.

Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs.

OBJECTIVE: Performance criteria have been established for in vitro blood glucose monitoring, particularly for the self-monitoring of blood glucose using glucose meters. Devices intended for use in the future, such as the continuous glucose monitoring system (CGMS), should satisfy similar criteria, particularly in diabetic patients under intensive therapy. RESEARCH DESIGN AND METHODS: The analysis was conducted on 18 type 1 diabetic patients (not controlled, HbA(1c) >7.5%) treated by external pump using insulin analogs. Each patient received a glucose sensor for 3 days during his/her hospitalization and was instructed in its operation. Medtronic criteria were used to determine the accuracy of the CGMS. In addition, the data were analyzed according to American Diabetes Association (ADA) criteria, Clarke Error Grid analysis, and method of residuals, with the glucose oxidase method using a Beckman analyzer used as the reference method. Specificity and sensitivity were evaluated from the viewpoint of accuracy in the detection of hypoglycemia. For nine patients, two glucose sensors were simultaneously inserted into an abdominal site to determine the reproducibility of the system. RESULTS-Among the 33 glucose sensors inserted, 6 (18%) were nonfunctional. The mean duration of CGMS recording was 63 +/- 12 h. From all of the 692 sets of data that paired glucose readings and CGMS, the coefficients of correlation ranged from 0.87 to 0.92 and the mean absolute error ranged from 12.8 to 15.7%. The time experienced in hypoglycemia (<55 mg/dl) was reported at 86 +/- 62 min/day. Only 39% of the CGMS values satisfied the ADA precision criteria to within +/-10%, and 19% of these values satisfied the future ADA precision criteria of accuracy to within +/-5%. The means of difference method showed that the CGMS slightly underestimated the plasma glucose values (mean = -12 mg/dl). Error grid analysis showed only 77% of the glucose sensor values were in zone A, and 98.9% were in zones A and B. Two values fell in zone C and a single value fell in zone D. The sensitivity and specificity of the CGMS to detect hypoglycemia were 33 and 96%, respectively. A total of 6666 paired sensor values were recorded with a coefficient of correlation of 0.84 with a coefficient of variation of 8.25%. CONCLUSIONS: CGMS could be useful in routine clinical practice to provide much more information on the glucose profile than intermittent self-monitoring of blood glucose (SMBG). However, CGMS cannot be used as a replacement for glucose meters because it does not satisfy the conventional performance goals set down for in vitro glucose measurements and could therefore lead to clinically incorrect treatment decisions.

The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients.

OBJECTIVE: This study was designed to assess the insulin-sparing effect of oral administration of metformin along with a continuous subcutaneous insulin infusion (CSII) for the treatment of type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 62 patients (25 women and 37 men) were studied in a monocenter, randomized, double-blind placebo-controlled study, comparing metformin (850 mg b.i.d.) with placebo in association with CSII during a 6-month period. RESULTS: Treatment with metformin was associated with a reduction in daily insulin requirements between V0 and V6 of -4.3 +/- 9.9 units (-7.8 +/- 18%) compared with an increase with placebo treatment of 1.7 +/- 8.3 units (2.8 +/- 12.7%) (P = 0.0043). A decrease in basal requirement of insulin was also observed in patients treated with metformin of -2.6 +/- 3.2 units (-7.9 +/- 23.8%) compared with an increase with placebo treatment of 1.9 +/- 5.7 units (8.8 +/- 27.1%) (P = 0.023). HbA(1c) remained unchanged in treatment with metformin and placebo between V0 and V6. The number of hypoglycemic events (<60 mg/dl) was similar in both groups. Significant reductions of total cholesterol (P = 0.04) and LDL cholesterol (P = 0.05) were observed in patients treated with metformin. Gastrointestinal events, including diarrhea and abdominal pain, were reported in three patients in the metformin group who discontinued the trial. Mild or moderate gastrointestinal side effects were also reported in eight patients treated with metformin and two patients treated with placebo (P = 0.069). CONCLUSIONS: Metformin was found to be a safe insulin-sparing agent, when used in combination with CSII for the treatment of type 1 diabetes.

Effects of sibutramine on ventricular dimensions and heart valves in obese patients during weight reduction.

BACKGROUND: Obesity enhances hemodynamic alterations that predispose to a subsequent increase in left ventricular (LV) wall stress leading to LV hypertrophy. In obese subjects, weight reduction regresses LV mass (LVM), regardless of blood pressure. Sibutramine can increase blood pressure and heart rate, which may attenuate the reductions in LVM associated with weight loss. METHODS: Outpatients (n = 184, age 18-65 y, body mass index > or =30 to <40 kg/m2) were randomly assigned to 6 months of once daily double-blind treatment with sibutramine 10 mg or 20 mg, or placebo. LV dimensions, status and function of the valves, weight loss, blood pressure, heart rate, and electrocardiogram were assessed. RESULTS: For end point data sets, the mean +/- SD LVM index (LVM/height) changes were -3.0 +/- 11.9 g/m for placebo (n = 56), -4.4 +/- 10.7 g/m for sibutramine 10 mg (n = 61), and -4.3 +/- 10.9 g/m for sibutramine 20 mg (n = 56). The reductions observed in the sibutramine groups were statistically significant compared with baseline (P <.01), but pairwise comparison results with placebo were not statistically significant. There was no difference in overall status of the cardiac valves. A statistically significant greater weight loss was found in patients on both doses of sibutramine compared with placebo (P <.001). No statistically significant differences between the groups were observed in respect to blood pressure and electrocardiographic intervals, but a statistically significant increase in pulse rate (7 beats/min) was noted for patients with sibutramine treatment. CONCLUSION: A 6-month treatment with sibutramine does not affect ventricular dimensions, heart valves, and electrocardiogram variables.

Erythrocyte membrane phospholipid composition is related to hyperinsulinemia in obese nondiabetic women: effects of weight loss.

The complex mechanisms by which obesity predisposes to insulin resistance are not clearly understood. According to a cell membrane hypothesis of insulin resistance, the defects in insulin action could be related to changes in membrane properties. The purpose of this work was to examine the relationship between 2 markers of insulin resistance (fasting plasma insulin [FPI] and homeostasis model assessment [HOMA IR]) and erythrocyte membrane lipid composition. In the first cross-sectional study, 24 premenopausal nondiabetic overweight women (body mass index [BMI], 32.5 +/- 0.9 kg/m(2); age, 35.7 +/- 2.2 years) were compared to 21 lean healthy women (BMI, 21 +/- 0.4 kg/m(2); age, 35.4 +/- 2.2 years). The second study examined whether a 3-month diet-induced weight loss, which usually improves insulin resistance, could also affect the membrane phospholipid (PL) composition and fluidity in the overweight group. Overweight women had significantly higher FPI levels (P <.0001), HOMA IR (P <.0001), membrane sphingomyelin (SM) (P <.05), and cholesterol (P <.05) contents than lean women. Baseline FPI and HOMA IR were positively correlated with membrane SM (P <.005), phosphatidylethanolamine (PE) (P <.005), and phosphatidylcholine (PC) (P <.05) contents, and negatively with phosphatidylinositol (PI) (P <.05) contents in the whole population. Multivariate regression analyses showed that 2 membrane parameters, PE and SM, were among the independent predictors of FPI or HOMA IR in the whole population, but also in the lean and the obese groups separately. Intervention induced a significant reduction in body weight (-5.7% +/- 0.7%), fat mass (-11.3% +/- 1.4%), and FPI (-10.2% +/- 5.4%). An improvement in membrane lipid composition was only observed in the insulin resistant subgroup (FPI > 9.55 mU/L). The reduction in FPI or HOMA IR was directly associated with reduction in SM and PE contents, a finding independent of the reduction in fat mass. A stepwise multiple regression analysis indicated that the changes in SM accounted for 26.6% of the variance in the changes in FPI as an independent predictor, with the changes in fat mass and PE as other determinants (27.8% and 20%, respectively, adjusted r(2) =.704, P <.0001). These results suggest that the abnormalities in the membrane PL composition could be included in the unfavorable lipid constellation of obesity which correlated with impaired insulin sensitivity.

Sentinel node dissection is safe in the treatment of early-stage vulvar cancer.

PURPOSE: To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. PATIENTS AND METHODS: A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). CONCLUSION: In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.