Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations.

INTRODUCTION: This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended release (ER) with SITA + MET sustained release (SR) and DAPA + MET ER in patients with type 2 diabetes poorly controlled with metformin. METHODS: This phase 3, randomized, open-label, active-controlled study included adult patients with glycated hemoglobin (HbA1c) ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol), randomized in 1:1:1 ratio to receive either FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets once daily (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). Primary endpoint was mean change in HbA1c from baseline to week 16. RESULTS: Mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group. At week 16, adjusted mean reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER (- 1.73% [- 19.0 mmol/mol]) compared to SITA + MET SR (- 1.28% [- 14.1 mmol/mol]; difference of - 0.46% [- 5.1 mmol/mol], p < 0.001) and DAPA + MET ER (- 1.33% [- 14.6 mmol/mol]; difference - 0.4% [4.4 mmol/mol], p < 0.001). Similarly, at week 12, reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0006) and DAPA + MET ER (p = 0.0276). At week 16, DAPA + SITA + MET ER showed significant reduction in postprandial blood glucose compared to DAPA + MET ER (p = 0.0394) and significant reduction in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0226). The proportion of patients achieving HbA1c < 7.0% (53 mmol/mol) at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) (p < 0.001) and DAPA + MET ER (21.3%) (p = 0.0023). All study medications were well tolerated. CONCLUSION: Triple FDC of DAPA + SITA + MET ER tablets once daily was significantly better in achieving glycemic control versus dual combination once daily in patients with type 2 diabetes poorly controlled with metformin without any significant safety concerns. TRIAL REGISTRATION: CTRI/2021/11/038176, registered on 22 November 2021.

Type 2 diabetes is a progressive disease in which the risks of microvascular and macrovascular complications and mortality are strongly associated with hyperglycemia. Achieving glycemic control remains the main goal of treatment to prevent these complications. Estimates in 2019 showed that 77 million individuals had diabetes in India, which is expected to rise over 134 million by 2045. Considering the progressive nature of the disease, many guidelines recommend use of dual or triple drug therapy based on glycated hemoglobin (HbA1c) level. Use of fixed-dose combination (FDC) helps to improve therapy compliance and can provide optimum therapeutic benefits. Mechanisms of action of dipeptidyl peptidase 4 (DPP4) and sodium­glucose cotransporter 2 (SGLT2) inhibitors are complementary to that of metformin with low risk of hypoglycemia. Studies have shown beneficial effects of adding both DPP4 inhibitors and SGLT2 inhibitors after metformin monotherapy. This phase 3 study was designed to assess efficacy and safety of triple FDC of dapagliflozin + sitagliptin + metformin extended release in comparison with combipack of sitagliptin + metformin sustained release and FDC of dapagliflozin + metformin ER in patients with type 2 diabetes inadequately controlled with metformin monotherapy. The study demonstrated superiority of triple FDC of dapagliflozin + sitagliptin + metformin ER over dual combinations in terms of reduction in HbA1c and percentage of patients achieving target HbA1c at the end of week 16. The current study provides evidence for considering triple FDC of dapagliflozin + sitagliptin + metformin ER as an alternative option with minimal risk of hypoglycemia and weight gain, while considering oral triple-combination therapy for patients to achieve their glycemic target.

One-year safety and effectiveness of insulin degludec in patients with diabetes mellitus in routine clinical practice in India-TRUST (Tresiba real-world use study).

Objective: This post-authorization safety study (PASS) was conducted to evaluate the long-term safety and effectiveness of insulin degludec in patients with diabetes mellitus (DM) requiring insulin therapy in routine clinical practice in India. Methods: Data on glycated hemoglobin (HbA1c) and adverse events (AEs) were collected up to 12 months after insulin degludec initiation. Results: A total of 1057 adult patients with DM were enrolled, including 60.07% males with the mean duration of 22.2 ± 21.90 years with type 1 DM and 10.1 ± 7.37 years with type 2 DM and the mean HbA1c of 9.6 ± 1.9%. Insulin degludec was prescribed to improve HbA1c and fasting plasma glucose (FPG). Insulin degludec daily dose was increased from 14.8 ± 8.0 U to 18.0 ± 9.46 U over 12 months resulting in a significant decrease of HbA1c by 1.8 ± 1.68% compared with baseline. There were 84 events of confirmed hypoglycemia in 51 patients during the 12-month follow-up period, and 44 AEs were reported in 2.6% of patients, of which 2 AEs were serious and unrelated to the drug. Conclusion: Insulin degludec is well tolerated in patients with DM. It improves glycemic control with reduced HbA1c, FPG, and postprandial glucose, with a low risk of hypoglycemia.

I2DNet - Design and Real-Time Evaluation of Appearance-based gaze estimation system.

Gaze estimation problem can be addressed using either model-based or appearance-based approaches. Model-based approaches rely on features extracted from eye images to fit a 3D eye-ball model to obtain gaze point estimate while appearance-based methods attempt to directly map captured eye images to gaze point without any handcrafted features. Recently, availability of large datasets and novel deep learning techniques made appearance-based methods achieve superior accuracy than model-based approaches. However, many appearance- based gaze estimation systems perform well in within-dataset validation but fail to provide the same degree of accuracy in cross-dataset evaluation. Hence, it is still unclear how well the current state-of-the-art approaches perform in real-time in an interactive setting on unseen users. This paper proposes I2DNet, a novel architecture aimed to improve subject- independent gaze estimation accuracy that achieved a state-of-the-art 4.3 and 8.4 degree mean angle error on the MPIIGaze and RT-Gene datasets respectively. We have evaluated the proposed system as a gaze-controlled interface in real-time for a 9-block pointing and selection task and compared it with Webgazer.js and OpenFace 2.0. We have conducted a user study with 16 participants, and our proposed system reduces selection time and the number of missed selections statistically significantly compared to other two systems.

Effect of added calcium and heat setting on gel forming and functional properties of Sardinella fimbriata surimi.

Present study evaluates the effect of calcium and heat setting on gel characteristics of lesser sardine (Sardinella fimbriata) surimi. Total seven formulations were made namely, S. fimbriata minced meat without heat setting (A1), minced meat with heat setting (A2), S. fimbriata surimi control (without addition of calcium) without heat setting (B1), control (without addition of calcium) with heat setting (B2), surimi added with 0.3% calcium without heat setting (C1) and surimi added with calcium with heat setting (C2) and refiner meat without addition of calcium and with addition of sodium bicarbonate (D). C1 exhibited gel strength of 329 g cm (Grade KA) whereas C2 sample exhibited gel strength of 556.2 g cm (Grade AA) as a result of gel setting at 35 °C for 45 min. Textural parameters such as hardness, chewiness, gumminess and cohesiveness were improved in C2 when compared with all other formulations. Addition of calcium and sodium bicarbonate significantly improved whiteness of surimi with gel setting in comparison to other treatments (p < 0.05). C2 samples exhibited reduced thio barbituric acid (TBA) values indicating lower oxidation. Results indicated potential for use of fish species with high fat content and darker meat for surimi manufacture with gel setting of sol and addition of sodium bicarbonate and calcium as ingredients.

Food grade zinc oxide bulk particle composite can replace the toxic zinc oxide nano composite towards the control of pathogenic and spoilage bacteria.

ZnO-Nanoparticle-Chitosan (ZnO-NP-CH) composite has potential biomedical and food applications due to its better antimicrobial activity. However, the presence of nano-metal-oxide in the composite makes the material unsuitable for any food applications. Moreover, the cost involved in the preparation of Zinc Oxide-Nano-Particle (ZnO-NP) is a major limitation for commercial food applications. Hence a suitable alternative for ZnO-NP is highly needed for food application. Since ZnO-Bulk Particles (ZnO-BP) are food grade and there is no study on the composite prepared from ZnO-Bulk Particle-Chitosan (ZnO-BP-CH), in the present study, antimicrobial activity was assessed for ZnO-BP-CH and compared with ZnO-NP-CH. Based on the study, it was observed that in the individual form of ZnO-NP possessed significantly higher antimicrobial activity than ZnO-BP. The composite form of ZnO-NP-CH and ZnO-BP-CH possessed higher antimicrobial activity than chitosan. However, no significant difference was observed between the composite forms. Hence, ZnO-BP-CH could be recommended as a suitable alternative to ZnO-NP-CH for future studies related to chitosan with ZnO composite to avoid costly nanomaterials preparation.

Characterization of chitin extracted from enzymatically deproteinized Acetes shell residue with varying degree of hydrolysis.

Acetes shrimp is an unexploited tiny shrimp mainly landed as bycatch which is a good source for the recovery of protein and chitin. In the present study, the residual shell obtained after the hydrolysis of Acetes was used for the extraction of chitin by combining enzymatic and chemical treatments. Enzymatic hydrolysis with Alcalase was performed at different rates. Results showed that the protein removal efficiency increases with the increase in DH and the maximum deproteinzation was achieved at 30 % DH (93.68 %). The FTIR spectra showed two sharp bands for chemically prepared chitin and 30 % DH chitin at 1627-1629 and 1664-1665 cm-1 indicating that its alpha amorphous structure. The degree of N-acetylation was found to be higher in enzymatically prepared chitin in all different hydrolytic treatment rather than chemically prepared. The surface morphologies of chitin revealed the porous and nanofibrous structures for 30 % DH chitin and chemically prepared chitin.

Blood-pressure Lowering Efficacy and Safety of Perindopril / Indapamide / Amlodipine Single-pill Combination in Hypertensive Patients: Phase III Trial in India.

BACKGROUND: Hypertension is the biggest contributor to global burden of disease and mortality. Increasing compliance with antihypertensive treatment and achieving a wide BP control in the population represents a major challenge for clinical practice. The benefits of single pill combination versus free-equivalent combination has been demonstrated in several meta-analyses and is now strongly supported by the latest 2018 ESC/ESH guidelines. The RAAS blocker with CCB and thiazide like diuretic is proposed as the optimal combination in patients inadequately controlled by two drugs. OBJECTIVE: To assess the blood pressure control rate, safety, tolerability and quality of life with triple-drug SPC in patients with grade II/ III hypertension. METHODS: Hypertensive patients uncontrolled (BP ≥ 140/90 mmHg) on two-drug therapy were recruited in an open-label, phase III clinical trial conducted in outpatient setting in India with 6 months treatment period. No other antihypertensive medication except the study medication was received by the patients. RESULTS: Out of 218 evaluable patients the observed average blood pressure reduction achieved from baseline to end of study at 6 months was Systolic Blood Pressure (SBP) 28.5 mm Hg / Diastolic Blood Pressure (DBP) 13.8 mm Hg. The quality of life (QoL) questionnaire demonstrated improvement in QoL for all patients. CONCLUSION: This study showed the clinical efficacy, safety and acceptability of the perindopril/indapamide/amlodipine SPC in patients with grade 2/3 hypertension inadequately controlled with two-drug therapy. The clinical effectiveness was observed in more than 96 % patients. The benefit of single-pill combination (SPC) therapy in hypertension control was reconfirmed in this study.

Bioaccumulation of heavy metals in different organs of Labeo rohita, Pangasius hypophthalmus, and Katsuwonus pelamis from Visakhapatnam, India.

The bioaccumulation of heavy metals (Zn, Pb, Cd, Co, Cu, and Fe) in fish tissues was determined using Atomic Absorption Spectrometer (spectra 220) and Mercury (Hg) content was estimated by using a mercury analyzer. Various organs (eye, gill, gut, gonad, liver, skin, and muscle) of three fish species, i.e., Labeo rohita, Pangasius hypophthalmus and Katsuwonus pelamis, from Visakhapatnam were analyzed. Young and aged fish were chosen based on their length: LR-32, LR-49 (Rohu); PH-33, PH-56 (Pangasius); and KP-18, KP-52 (Skipjack). In both the small and big size of L. rohita and P. hypophthalmus, the metal concentration was in the order Fe > Zn > Cu whereas Pb, Hg, and Co were below detectable limit (BDL). Concentrations in K. pelamis was Fe > Zn > Cu > Cd and Pb, Hg, and Co were BDL. In conclusion, the metal concentrations in the examined fish species available in Visakhapatnam fall below the maximum permissible limit (MPL) for human consumption recommended by FAO, WHO, MAFF, and EC.

Association between High Levels of Parathyroid Hormone and Frailty: The Nepean Osteoporosis and Frailty (NOF) Study.

BACKGROUND: Frailty is associated with poor outcomes hence identification of risks factors is pivotal. Since the independent role of parathyroid hormone (PTH) in frailty remains unexplored, we aimed to determine this in a population of older individuals with a history of falling. DESIGN: Cross-sectional study. SETTING: Falls and Fracture Clinic, Nepean Hospital (Penrith, Australia). PARTICIPANTS: 692 subjects (mean age=79, 65% women) assessed between 2009-2015. MEASUREMENTS: Assessment included clinical examination, mood, nutrition, grip strength, gait velocity, bone densitometry and posturography. Chemistry included serum PTH, calcium, vitamin D (25(OH)D3), creatinine and albumin. Normocalcemic subjects were divided into 4 groups: (1) Normal: 25(OH)D3 >50nmol/L and PTH between 1.6-6.8pmol/L; (2) PTH responsive: low 25(OH)D3 (<50nmol/L) and high PTH (>6.8pmol/L); (3) PTH unresponsive: low 25(OH)D3 and normal PTH; (4) Hyper PTH (>6.8pmol/L) with normal 25(OH)D3. Frailty was defined using Fried's criteria. Difference between the groups was assessed using one-way ANOVA and X2 analysis. Multinomial logistic regression evaluated the association between the groups and the number of Fried's criteria adjusted for age, BMI, renal function, 25(OH)D3 levels, and albumin. RESULTS: 22.6% subjects had high PTH levels (>6.8pmol/L). All subjects in the high PTH groups had significantly lower grip strength, gait velocity, limits of stability, and higher BMI. The PTH responsive group had a higher risk of pre-frailty (ß=3.8, 95% CI = 3.42 - 5.22, p≷ 0.01) and frailty (ß=8.26, 95% CI = 2.8-16.1, p<0.01). The risk of frailty was also higher in the Hyper PTH group (ß=2.3, 95% CI = 1.74-4.32, p<0.01). CONCLUSION: We have reported an independent association of high PTH levels with high number of falls and with the clinical components of physical frailty in community dwelling older persons. Our results suggest a possible role of PTH in frailty that deserves further exploration.

Distribution and pathological features of pancreatic, ampullary, biliary and duodenal cancers resected with pancreaticoduodenectomy.

BACKGROUND: Pancreatic cancer (PC) has the worst survival of all periampullary cancers. This may relate to histopathological differences between pancreatic cancers and other periampullary cancers. Our aim was to examine the distribution and histopathologic features of pancreatic, ampullary, biliary and duodenal cancers resected with a pancreaticoduodenectomy (PD) and to examine local trends of periampullary cancers resected with a PD. METHODS: A retrospective review of PD between January 2000 and December 2012 at a public metropolitan database was performed. The institutional ethics committee approved this study. RESULTS: There were 142 PDs during the study period, of which 70 cases were pre-2010 and 72 post-2010, corresponding to a recent increase in the number of cases. Of the 142 cases, 116 were for periampullary cancers. There were also proportionately more PD for PC (26/60, 43% pre-2010 vs 39/56, 70% post-2010, P = 0.005). There were 65/116 (56%) pancreatic, 29/116 (25%), ampullary, 17/116 (15%) biliary and 5/116 (4%) duodenal cancers. Nodal involvement occurred more frequently in PC (78%) compared to ampullary (59%), biliary (47%) and duodenal cancers (20%), P = 0.002. Perineural invasion was also more frequent in PC (74%) compared to ampullary (34%), biliary (59%) and duodenal cancers (20%), P = 0.002. Microvascular invasion was seen in 57% pancreatic, 38% ampullary, 41% biliary and 20% duodenal cancers, P = 0.222. Overall, clear margins (R0) were achieved in fewer PC 41/65 (63%) compared to ampullary 27/29 (93%; P = 0.003) and biliary cancers 16/17 (94%; P = 0.014). CONCLUSIONS: This study highlights that almost half of PD was performed for cancers other than PC, mainly ampullary and biliary cancers. The volume of PD has increased in recent years with an increased proportion being for PC. PC had higher rates of nodal and perineural invasion compared to ampullary, biliary and duodenal cancers.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Bangalore cohort of the A1chieve study.

BACKGROUND: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. MATERIALS AND METHODS: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Bangalore, India. RESULTS: A total of 1533 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1262), insulin detemir (n = 165), insulin aspart (n = 86), basal insulin plus insulin aspart (n = 11) and other insulin combinations (n = 2). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 9.2%) and insulin users (mean HbA1c: 8.8%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naïve: -1.3%, insulin users: -1.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. CONCLUSION: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Genetic diversity and population genetic analysis of bovine MHC class II DRB3.2 locus in three Bos indicus cattle breeds of Southern India.

The present study was performed to evaluate the genetic polymorphism of BoLA-DRB3.2 locus in Malnad Gidda, Hallikar and Ongole South Indian Bos indicus cattle breeds, employing the PCR-RFLP technique. In Malnad Gidda population, 37 BoLA-DRB3.2 alleles were detected, including one novel allele DRB3*2503 (GenBank: HM031389) that was observed in the frequency of 1.87%. In Hallikar and Ongole populations, 29 and 21 BoLA-DRB3.2 alleles were identified, respectively. The frequencies of the most common BoLA-DRB3.2 alleles (with allele frequency > 5%), in Malnad Gidda population, were DRB3.2*15 (10.30%), DRB3*5702 (9.35%), DRB3.2*16 (8.41%), DRB3.2*23 (7.01%) and DRB3.2*09 (5.61%). In Hallikar population, the most common alleles were DRB3.2*11 (13.00%), DRB3.2*44 (11.60%), DRB3.2*31 (10.30%), DRB3.2*28 (5.48%) and DRB3.2*51 (5.48%). The most common alleles in Ongole population were DRB3.2*15 (22.50%), DRB3.2*06 (20.00%), DRB3.2*13 (13.30%), DRB3.2*12 (9.17%) and DRB3.2*23 (7.50%). A high degree of heterozygosity observed in Malnad Gidda (H(O) = 0.934, H(E) = 0.955), Hallikar (H(O) = 0.931, H(E) = 0.943) and Ongole (H(O) = 0.800, H(E) = 0.878) populations, along with F(IS) values close to F(IS) zero (Malnad Gidda: F(IS) = 0.0221, Hallikar: F(IS) = 0.0127 and Ongole: F(IS) = 0.0903), yielded nonsignificant P-values with respect to Hardy-Weinberg equilibrium probabilities revealing, no perceptible inbreeding, greater genetic diversity and characteristic population structure being preserved in the three studied cattle populations. The phylogenetic tree constructed based on the frequencies of BoLA-DRB3.2 alleles observed in 10 Bos indicus and Bos taurus cattle breeds revealed distinct clustering of specific Bos indicus cattle breeds, along with unique genetic differentiation observed among them. The results of this study demonstrated that the BoLA-DRB3.2 is a highly polymorphic locus, with significant breed-specific genetic diversities being present amongst the three studied cattle breeds. The population genetics and phylogenetic analysis have revealed pivotal information about the population structure and importance of the presently studied three Bos indicus cattle breeds as unique animal genetic resources, which have to be conserved for maintaining native cattle genetic diversity.

Indian Space Research Organization and telemedicine in India.

Telemedicine in India is spearheaded by the Indian Space Research Organization (ISRO) and has matured beyond technology demonstration to enter an operational phase in its history. This article attempts to bring out the evolution and development of telemedicine in India: the genesis, the approach followed, the stakeholders involved, and the results so far, with an outline for the future. ISRO has coupled its prowess in satellite communication technology with medical science and information technology to project specialty healthcare to the doorsteps of the rural, remote, and distant populace across the country. Having set the telemedicine program as a model for benefiting society with advances in modern technology, India is advancing to international dimensions the proven domestic program to people in other parts of the globe. More specifically, the article attempts to bring out the role played by ISRO, its vision, goals, and partners in the program along with the technology and observed impact.

Correlation between simultaneous PSA and serum testosterone concentrations among eugonadal, untreated hypogonadal and hypogonadal men receiving testosterone replacement therapy.

The primary objective of this study was to correlate simultaneous measures of prostate-specific antigen (PSA) and serum testosterone among large samples of eugonadal, untreated hypogonadal and hypogonadal men treated with testosterone replacement therapy (TRT). From 2001 to 2007, laboratory records were reviewed to identify men who underwent simultaneous measurement of PSA and serum testosterone levels. The data were stratified based on three groups of men: group 1 consisted of eugonadal men (T>300 ng per 100 ml) evaluated for BPH, reproductive failure or sexual dysfunction; group 2 consisted of untreated hypogonadal men (T<300 ng per 100 ml); and group 3 comprised symptomatic hypogonadal men receiving TRT. Correlations were found between PSA (total and free fractions) and total serum testosterone levels among the three groups. Group 1: eugonadal men (n=385 patients), mean PSA and serum testosterone were 1.60 ng ml(-1) and 484 ng 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=-0.01, P=0.8). Group 2: untreated hypogonadal men (n=229 patients), mean PSA and serum testosterone were 1.49 ng ml(-1) and 269 ng per 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=0.03, P=0.6). Group 3: hypogonadal men on TRT (n=229 patients and 994 individual samples analyzed) mean PSA and serum testosterone were 1.50 ng ml(-1) and 555 ng per 100 ml, respectively. There was no significant correlation between PSA and serum testosterone levels (r=-0.005, P=0.9). Mean total serum testosterone levels were increased significantly (P<0.001) following treatment. Mean PSA levels did not increase in a statistically or clinically significant manner following TRT (mean PSA increase from baseline 0.05 ng ml(-1), P=0.6). In conclusion, TRT does not appear to significantly influence serum PSA expression and no significant correlation was identified between PSA and serum testosterone among eugonadal, untreated hypogonadal and hypogonadal men receiving TRT.

Percutaneous treatment of calculi in reconstructed bladder.

PURPOSE: To report our results with percutaneous removal of calculi from reconstructed bladders. PATIENTS AND METHODS: Twelve patients with reconstructed bladders who underwent endoscopic cystolithotomy were identified from our departmental database, and retrospective review of case notes and imaging was performed. RESULTS: Access was gained via an ultrasound-guided new tract in 9 patients (75%). An old suprapubic tract site was used in two patients, and the Mitrofanoff stoma was the route of access in one patient. The procedure was successful, with stone clearance achieved in all 12 cases. No major complications were observed. At a median follow up of 24 months, stone recurrence was observed in 5 patients (42%), 4 of whom underwent repeat procedures. Follow-up showed no change in continence in the patient with a Mitroffanoff stoma. CONCLUSION: Percutaneous cystolithotomy is a safe and effective minimally invasive option for removal of stones in a reconstructed bladder. We recommend endoscopic removal as the treatment of choice in these patients.

Is there a simpler method for predicting lower pole stone clearance after shockwave lithotripsy than measuring infundibulopelvic angle?

BACKGROUND AND PURPOSE: Several anatomic factors influence the clearance of lower pole stones treated with shockwave lithotripsy (SWL). One of these is the infundibulopelvic angle, but its measurement is complex. METHODS: We proposed a more simple measure of caliceal dependence, the caliceal pelvic height (CPH), which we defined as the distance between a horizontal line from the lowermost point of the calix containing the stone to the highest point of the lower lip of the renal pelvis. RESULTS: In 62 patients who had SWL for solitary lower pole stones, a CPH < 15 mm was associated with a stone clearance rate of 92%, whereas with a CPH > or = 15 mm, the clearance rate was only 52% (p < 0.05). A majority (74%) of the patients with an infundibular width of > or = 5 mm were rendered stone free compared with 40% of those with a width of < 5 mm (p < 0.05). CONCLUSION: Measurement of the CPH, in conjunction with other anatomic factors, may more accurately predict the outcome of SWL in patients with lower pole stones.

Androgen receptor mutations in prostate cancer.

We analyzed the frequency and relevance of mutations in the coding region of the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of patients affected by stage B disease [15 nonmicrodissected (group 1A) and 84 microdissected (group 1B)] and from the metastatic deposits of individuals with stage D1 disease [8 nonmicrodissected (group 2A) and 30 microdissected (group 2B)] who had not undergone androgen ablation therapy. The study was conducted by PCR-single strand conformational polymorphism (SSCP) analysis of exons 2-8 in the four groups and direct sequence analysis of exon 1 in group 1B. As positive and negative controls, we used genomic DNA extracted from genital skin fibroblasts of patients affected by various forms of androgen resistance with known mutations in the AR. To control for genetic instability, PCR-SSCP analysis of exon 2 of the human progesterone receptor was carried out on each specimen. The overall number of mutations detected was 11 (8%). No mutations were detected in any of the 99 patients with stage B disease. Eleven mutations were detected in exons 2-8 in 8 of the 38 patients with stage D1 disease (all in group 2B). Simultaneous analysis of exon 2 of the progesterone receptor was carried out, and no SSCP changes were identified. These data suggest that AR mutations are rare and presumably do not play a role in the initial phase of prostatic carcinogenesis. The presence of a significant number of AR mutations in metastatic disease indicates that mutations of this molecule may play a role in the most advanced phases of the natural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype.

Primary in situ extracorporeal shock wave lithotripsy in the management of ureteric calculi: results with a third-generation lithotripter.

OBJECTIVE: To review the results of primary in situ extracorporeal shock wave lithotripsy (ESWL) for the treatment of ureteric stones using a third-generation lithotripter, the Dornier MFL 5000 (Dornier Medizentechnic, Germany). PATIENTS AND METHODS: The study comprised a retrospective review of treatment outcome in 180 patients with 196 stones who were treated with primary in situ ESWL, assessing the success of this approach and establishing reasons for failure. RESULTS: At the 3-month follow-up, 88% of patients were stone-free; 21 patients failed ESWL and were treated by ureteroscopic stone extraction with no complications. Stone-free rates were 90% for upper ureteric, 89% for middle-third and 86% for lower-third calculi. Twenty-one patients required auxiliary procedures in the form of JJ stenting or nephrostomy. Failure of ESWL was associated with stone size (>1.3 cm) but not location or inadequate treatment. CONCLUSION: Where prompt access to ESWL is available, primary in situ ESWL remains an effective form of treatment for all ureteric calculi, although stone-free rates are lower for larger stones.

Intravenous urography in urinary tract surveillance in carcinoma of the bladder.

AIMS: The need for intravenous urography (IVU) in upper tract surveillance for primary transitional cell carcinoma (TCC) of the bladder is contentious. We reviewed our intensive screening policy in the follow-up of these patients to ascertain if such a policy is required and if specific groups could be identified to rationalise this protocol. METHODS: Review of the clinical and radiological data on 174 patients with a diagnosis of primary TCC of the bladder attending a teaching hospital urology department. RESULTS: Eight upper tract 'lesions' were identified: six TCC and two false-positive examinations using IVU. No link was demonstrable between upper tract recurrence and tumour stage, grade or multiplicity at diagnosis. All had recurrent bladder tumour but four of the six upper tract tumours occurred at 72 months or later. Twenty-nine patients over the study period developed either a dilated pelvi-calyceal system or a non-functioning kidney detected on IVU. CONCLUSIONS: Upper tract TCC can present late and patients with early bladder recurrence and those who do not show a reduction in bladder tumour number at follow-up cystoscopy are most at risk. IVU can probably be safely abandoned in those without local recurrence at 24 months. IVU is sensitive but not specific for upper tract tumour but also yields other relevant clinical information concerning the renal tract. Screening for upper tract metachronous disease should therefore be confined to those with recurrent transitional cell carcinoma of the bladder.

Analysis of the mesotelencephalic dopamine system by quantitative-trait locus introgression.

One of the significant factors that affect brain dopamine function is the activity of tyrosine hydroxylase (TH), the first and rate-limiting enzyme in catecholamine biosynthesis. For the analysis of the genetically determined role of dopamine function and TH in behavior and in the regulatory mechanisms of the mesotelencephalic dopamine system we devised a novel genetic strategy (Vadasz; Mouse Genome 88:16-18; 1990). We hypothesized that phenotypic introgression and recombinant fixation could ensure the transfer of Quantitative Trait Loci (QTL) from one strain onto the genetic background of another strain, and new, genetically very similar quasi-congenic strains could be created that would carry individual QTLs, or QTLs in various combinations. Here we summarize the construction of the first set of QTL Introgression strains, and present evidence that QTLs that are responsible for the continuous variation of mesencephalic tyrosine hydroxylase activity (TH/MES), have been transferred onto the C57BL/6By (B6) strain background from BALB/cJ (C) and CXBI (I) donor strains with high and low TH/MES, respectively. The QTL transfer was carried out in two directions by repeated backcross-intercross cycles with concomitant selection for the extreme high and low expressions of TH/MES in replicates, resulting in four QTL Introgression lines. Analysis of regional brain TH activities in the course of the QTL introgression indicated that (a) TH activity in B6.I lines showed quite limited heritability, (b) TH/MES was not highly correlated with striatal TH, and (c) the control of hypothalamic and olfactory tubercle TH activities was largely independent from that of TH/MES. Examination of the open-field (OF) behavior data demonstrated that TH activity did not correlate significantly with OF behavior. After 5 backcross-intercross cycles, TH/MES in each replicate line was still significantly different from that of the B6 background strain. A genomewide scanning of microsatellite markers in the QTL introgression lines demonstrated that about 96% of the markers were of background (B6) type. These results indicate the successful transfer of TH/MES QTLs. After the QTL transfer phase of the experiment altogether more than 100 new RQI strains were initiated in the QTL Introgression lines by strict brother x sister mating. After fixing the introgressed QTLs, ten of the inbred RQI strains were tested for TH/MES. The results showed that in one of the new RQI strains TH/MES was restored to a level that is characteristic to the C donor strain, while TH/MES values in some other strains were between those of the background and donor strains, confirming our hypothesis that phenotypic introgression and recombinant fixation can ensure a virtually complete transfer of QTLs. We conclude from this study that complex, continuously distributed neural traits can successfully be subjected to QTL introgression, and the results raise the possibility that the RQI method can be efficiently applied for gene mapping of complex neural and behavioral traits even if their phenotypic expression is sensitive to confounding developmental and environmental variations, genetic interactions, and genotype-environment interactions.