Symptomatic ��H�� Type Duplex Gallbladder

Gallbladder duplication with an incidence at autopsy of about 1 in 4000 is important in clinical practice, because it may cause some clinical, surgical, and diagnostic problems. Preoperative identification of this rare anomaly avoids biliary injuries and the other consequences of missed diagnosis. In this report, we present a case of ductular type duplex gallbladder diagnosed preoperatively by magnetic resonance cholangiopancreatography (MRCP) and ultrasound and managed successfully by laparoscopy.     

Type 2 diabetes: what therapeutic strategy?

GOAL OF TREATMENT: Prevention of diabetic micro and macroangiopathy is the goal of treatment in type 2 diabetes mellitus. A well-controlled glucose level is the key to prevention of microangiopathy; there is no threshold level. Antihypertensive treatment, with the goal of blood pressure below 130/80 mmHg is also beneficial in preventing aggravation of microangiopathy. For macroangiopathy, prevention is based in priority on treatment of other risk factors for cardiovascular disease; the threshold level for drug treatment and the therapeutic objective are those defined for secondary prevention in non-diabetic patients, i.e. blood pressure below 140/80 mmHg and LDL cholesterol under 1.30 g/l. The beneficial effect of lower glucose levels on preventing macrovascular risk was not formally demonstrated by the UKPDS, probably because the difference between the control and the treatment group HbA1c levels was minimal, 0.9 points. REVISITING STRATEGY: It is thus time to revisit the preventive strategy for type 2 diabetes mellitus, i.e. step-by-step increments, as currently proposed for worsening glucose levels. Metformine should be prescribed if the HbA1c is above normal in order to achieve the demonstrated benefit in prevention of microangiopathy and in the hope, motivated by pathophysiology data, of preventing insulin failure. Slow-release insulin at bedtime should be added to the oral hypoglycemiants if fasting glucose exceeds 1.60 or 1.80 g/l, even if the HbA1c remains below 8%. NEW HYPOGLYCEMIANTS: The role of these new agents in this more "aggressive" strategy remains to be defined. Glinides will have to demonstrate their superiority over sulfamides (fewer episodes of hypoglycemia with comparable efficacy) to justify their high cost. Glitazones will have to demonstrate a beneficial effect in second intention combination with metformine on cardiovascular morbidity mortality in type 2 diabetes patients with a metabolic insulin-resistance syndrome and visceral obesity. OBSERVANCE: Since patients with type 2 diabetes mellitus are often taking 3 to 6 tablets to control their glucose level, 3 to control blood pressure, plus another to lower the lipid level and finally one more for an antiplatelet effect reducing the number of tablets and patient education will most certainly help improve therapeutic observance.     

Can Phosphodiesterase Type 5 Inhibitors Cure Erectile Dysfunction?

INTRODUCTION AND OBJECTIVES: To systematically analyze and review the available evidence about the potential role of chronic administration of phosphodiesterase type 5 (PDE-5) inhibitors for the cure of erectile dysfunction (ED) based on clinical and basic science data. METHODS: Analysis of published full-length papers that were identified with Medline and Cancerlit from January 1993 to September 2005. Abstracts published in the journals European Urology, the Journal of Urology, the International Journal of Impotence Research, and the Journal of Sexual Medicine as official proceedings of internationally known scientific societies held in the same time period were also assessed. RESULTS: Chronic administration of PDE-5 inhibitors have reportedly been associated with increased persistent vascular and endothelial function--which represents a key factor in maintaining vascular tone and inducing vasodilation--by increasing the level of endothelial cGMP generated by activation of endothelial nitric oxide. Clinical studies have revealed a potential protective role of these compounds on endothelial function in short- and long-term assessments. Several studies based on animal models have provided direct experimental support for the role of PDE-5 inhibitors in improving the structure and function of the cavernosal tissue and have suggested potential molecular mechanisms involved. CONCLUSIONS: Although evidence increasingly supports the potential role of chronic administration of PDE-5 inhibitors for improving erectile function in patients affected by ED, long-term data are lacking. However, data available from animal models support the evidence of potential benefits induced on endothelial function by chronic exposure to PDE-5 inhibitors.     

Type 2 diabetes mellitus and Alzheimer’s disease

Epidemiological and biological evidences support a link between type 2 diabetes mellitus (DM2) and Alzheimer’s disease (AD). Persons with diabetes have a higher incidence of cognitive decline and an increased risk of developing all types of dementia. Cognitive deficits in persons with diabetes mainly affect the areas of psychomotor efficiency, attention, learning and memory, mental flexibility and speed, and executive function. The strong epidemiological association has suggested the existence of a physiopathological link. The determinants of the accelerated cognitive decline in DM2, however, are less clear. Increased cortical and subcortical atrophy have been evidenced after controlling for diabetic vascular disease and inadequate cerebral circulation. Most recent studies have focused on the role of insulin and insulin resistance as possible links between diabetes and AD. Disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD. Hyperglycemia itself is a risk factor for cognitive dysfunction and dementia. Hypoglycemia may also have deleterious effects on cognitive function. Recurrent symptomatic and asymptomatic hypoglycemic episodes have been suggested to cause sub-clinical brain damage, and permanent cognitive impairment. Future trials are required to clarify the mechanistic link, to address the question whether cognitive decline may be prevented by an adequate metabolic control, and to elucidate the role of drugs that may cause hypoglycemic episodes.     

Type IIc Sodium–Dependent Phosphate Transporter Regulates Calcium Metabolism

Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodium–dependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c^−/−) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D₃ levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D₃ in Npt2c^−/− mice compared with age-matched Npt2c^+/+ mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D–24-hydroxylase mRNA but no change in 1α-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c^−/− mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c^+/+, Npt2c^+/−, and Npt2c^−/− mice. In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis.Inorganic phosphate (Pi) is an essential nutrient in terms of both cellular metabolism and skeletal mineralization. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi needs. Up to 70% of filtered Pi is reabsorbed in the proximal tubule in which sodium (Na)-dependent Pi transport systems in the brush border membrane (BBM) mediated the rate-limiting step in the overall Pi reabsorptive process.^{1, 2} The type II Na/Pi co-transporter (Npt2a and Npt2c) is expressed in the BBM of the renal proximal tubular cells.^{2, 3} The type IIa Na/Pi co-transporters (Npt2a) play a major role in reabsorption (70 to 80%) in the kidney. Npt2a-knockout (KO) mice exhibit renal Pi wasting, loss of BBM Na/Pi co-transport, hypophosphatemia, and an appropriate adaptive increase in the serum concentration of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] with attendant hypercalcemia, hypercalciuria, and hypoparathyroidism but do not develop rickets.^{2, 4}Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria.⁵ Npt2a-KO mice display biochemical features similar to patients with HHRH; the bone phenotype is markedly different in the human and mouse disorders.^{2, 4} Jones et al.⁶ excluded mutations of the renal Na/Pi transporter NPT2 (human Npt2a) gene in affected members of the family that was originally described by Tieder and colleagues.⁷ More recently, linkage analyses have suggested that HHRH may arise from mutations in the NPT2c/SLC34A3 gene.⁸ That HHRH is caused by a loss-of-function mutation is compatible with HHRH phenotype and the prevailing view of renal phosphate regulation. These observations suggest that the Npt2c has an important role in renal Pi reabsorption and bone mineralization and that it may be a key determinant of plasma Pi concentrations in humans; however, it is not clear why loss of function of the less abundant and energetically less favorable electroneutral NaPi-IIc transporter causes rickets and osteomalacia in humans, whereas mutations in the more abundant electrogenic Npt2a elicits a mild skeletal phenotype that lacks the typical features of rickets and osteomalacia in mice. Thus, the goal of this study was to investigate the role of the Npt2c transporter in the overall maintenance of Pi homeostasis and bone mineralization by disrupting the murine Npt2c gene and analyzing the phenotypes.     

Are Type II (Branch Vessel) Endoleaks Really Benign?

The natural history and clinical significance of type II or branch vessel endoleaks following endovascular aortic aneurysm (AAA) repair remain unclear. Some investigators have suggested that these endoleaks have a benign course and outcome and that they can be safely observed. The purpose of this study was to document the natural history and outcome of all type II endoleaks that have occurred following endovascular AAA repair at our institution. A review of a prospectively compiled database of all endovascular AAA repairs performed at our institution was performed. From this review, we determined that type II endoleaks appear to have a relatively benign course, with a reasonable chance of spontaneously sealing within a 2-year period. No cases of rupture or aneurysm enlargement were documented in patients with open type II leaks. However, almost one-third of the patients did not manifest a type II leak until after their initial CT scan. The implications of such a "delayed" leak are unclear. Careful follow-up remains mandatory in patients with type II endoleaks to better define outcome.     

Type of Lateral Internal Sphincterotomy Incision: Parallel or Vertical?

Background  

The lateral internal sphincterotomy (LIS) technique is considered the optimal surgical treatment for chronic anal fissures (CAFs), although questions remain regarding the best technique. The present study investigated whether the type of anoderm incision (vertical or parallel to the anus) affects wound healing, wound-related complications, incontinence, and recurrence rates in CAF patients undergoing open LIS.     

Acute Type A Aortic Dissection—Diagnostic Aspects and Surgical Experience

Acute type A aortic dissection was surgically treated in 33 patients aged 20-65 years, all critically ill on admission to hospital. Transthoracic echocardiography revealed pericardiac tamponade in eight cases of extreme emergency, indicating surgery without need of additional imaging. Transesophageal echocardiography provided a definitive diagnosis in 16 cases, with excellent reliability and no false positive findings. Composite graft replacement with button technique was used in 24 patients and other methods of repair in nine. The perioperative mortality was 12% (4/33) and the late mortality 7% (2/29). The actuarial 5-year survival rate was 73%. No aortic root reoperation was required during follow-up for a mean of 4 years. Transesophageal echocardiography proved to be an accurate tool for speedy diagnosis of acute type A aortic dissection and open composite graft replacement with button technique highly satisfactory treatment, avoiding late aortic root problems.     

Why Does the Gastric Bypass Control Type 2 Diabetes Mellitus?

The remarkable control of diabetes by the gastric bypass remains to be explained. Although it may be totally due to the weight loss induced by the operation, it is likely that the detour of the hormonally active foregut plays a role as well. This keynote address explores the pathophysiology of non-insulin-dependent diabetes mellitus and reviews the data which support the thesis that the gastric antrum, duodenum, and proximal jejunum modulate glucose metabolism and insulin action.     

Insulin-Sensitizing Therapy Attenuates Type 2 Diabetes�CMediated Mammary Tumor Progression

OBJECTIVE

Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes–mediated mammary tumor progression.

RESEARCH DESIGN AND METHODS

We studied mammary tumor development in MKR^+/+ mice, a nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR^+/+ mice were either crossed with mice expressing the polyoma virus middle T oncogene specifically in the mammary gland or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR^+/+ or control mice harboring tumors were treated with CL-316243, a specific β₃-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells.

RESULTS

CL-316243 treatment significantly reduced the elevated insulin levels in MKR^+/+ mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of insulin and IGF-I receptors in transformed mammary tissue.

CONCLUSIONS

Insulin-sensitizing treatment is sufficient to abrogate type 2 diabetes–mediated mammary tumor progression. Therefore, early administration of insulin-sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.Type 2 diabetes has become a major public health problem worldwide and is associated with severe acute and chronic complications. Recently it has been shown that the disease increases breast cancer risk and mortality (1–4). In our previous studies, we have identified hyperinsulinemia as the predominant factor responsible for diabetes-mediated mammary tumor progression (5). Elevated insulin levels are observed mainly at early stages of the disease, where peripheral insulin resistance results in a compensatory increase in insulin secretion by the pancreatic β-cells to meet the higher insulin demand. Thus, before the onset of clinically overt type 2 diabetes, patients are often hyperinsulinemic but euglycemic, and hence unaware of their disease for many years. There is growing evidence that the risk for the development of breast cancer is substantially increased in patients with early stage type 2 diabetes (6,7).Pharmacological treatment of type 2 diabetes may have an impact on cancer risk and mortality. Early stage type 2 diabetes is treated by two main approaches: insulin secretagogues (e.g., sulfonylureas) stimulate insulin secretion from the pancreatic β-cells and thus increase insulin levels. Conversely, insulin-sensitizing agents (e.g., metformin and thiazolidinediones [TZDs]) improve insulin action in peripheral tissues and, as a consequence, reduce hyperinsulinemia. There is growing evidence that antidiabetic therapy elevating insulin levels increases cancer risk as well as cancer-related mortality (8,9), whereas insulin-sensitizing drugs may reduce cancer risk, morbidity, and mortality (8–14) in patients with type 2 diabetes. However, it is as yet unclear whether the antineoplastic effects of the two mainly used insulin-sensitizing agents (metformin and TZDs) are a result of their direct action on tumor cells (15–23) or an indirect effect via a reduction of insulin levels.Our study was aimed to explore whether lowering insulin levels in type 2 diabetes would mitigate mammary tumor progression, independent of any direct effect of the applied drug. To address this question, we used the insulin-sensitizing drug CL-316243 (24), a potent β₃-adrenergic receptor (β₃-AR) agonist with no known direct effects on breast cancer, in a nonobese mouse model of type 2 diabetes (MKR^+/+ mice). MKR^+/+ mice develop severe insulin resistance and hyperinsulinemia at an early age due to overexpression of muscle creatine kinase–driven dominant-negative IGF-I receptors (IGF-IRs), and subsequent abrogation of IGF-I and insulin signaling in skeletal muscle (25). Female MKR^+/+ mice develop only mild dysglycemia but display marked insulin resistance and hyperinsulinemia, similar to early stages of type 2 diabetes in humans (5). The nonobese hyperinsulinemic phenotype of these mice makes them an ideal model to specifically study the effect of insulin reduction on mammary tumor progression, independent of numerous confounding factors originating from obesity or overt type 2 diabetes (e.g., adipokines, proinflammatory cytokines, adipose tissue–derived sex steroids, hyperglycemia) (26). To initiate mammary tumors, we used three different approaches: polyoma virus middle T (PyVmT) transgenic mice (27) served as a model for early stages of cancer development. To study solid tumor formation, PyVmT- and Neu/ErbB2-expressing tumor cells (28,29) were used in syngeneic orthotopic cell injection experiments.Here we demonstrate that chronic CL-316243 treatment is capable of reducing insulin levels in female MKR^+/+ mice, leading to an abrogation of the accelerated mammary tumor progression in all three cancer models tested. Furthermore, we show that this effect is accompanied by a reduced activation of the insulin receptor (IR) and the IGF-IR in transformed mammary tissue. Our findings indicate that insulin-sensitizing therapy is sufficient to abrogate the tumor-promoting activity of early stage type 2 diabetes. Thus, we propose that early treatment of hyperinsulinemia might contribute to lower breast cancer risk, morbidity, and mortality in patients with type 2 diabetes.