Radiation dose of cone beam CT combined with shape sensing robotic assisted bronchoscopy for the evaluation of pulmonary lesions: an observational single center study.

Background: Shape sensing robotic-assisted bronchoscopy (ssRAB) combined with radial endobronchial ultrasound (r-EBUS) and cone beam computed tomography (CBCT) is a newer diagnostic modality for the evaluation of pulmonary lesions. There is limited data describing the radiation dose of CBCT combined with ssRAB. The purpose of this study was to describe the technical factors associated with the use of CBCT combined with ssRAB to biopsy pulmonary lesions. Methods: We conducted a single center, prospective observational study of patients undergoing ssRAB combined with fixed CBCT for the pulmonary lesion biopsy. We report our patient demographics, and pulmonary lesion and procedure characteristics. Results: A total of 241 ssRAB procedures were performed to biopsy 269 pulmonary lesions. The mean lesion size was measured in the following dimensions: anteroposterior (18.0±8.8 mm), transverse (17.2±10.5 mm), and craniocaudal (17.7±10.2 mm). A mean of 1.5±0.7 (median: 1, range: 1-4) CBCT spins were performed. The mean total fluoroscopy time (FT) was 5.6±2.9 minutes. The mean radiation dose of cumulative air kerma (CAK) was 63.5±46.7 mGy and the mean cumulative dose area product (DAP) was 22.6±16.0 Gy·cm2. Diagnostic yield calculated based on results at index bronchoscopy was 85.9%. There was a low rate of complications with 8 pneumothoraces (3.3%), 5 (2.1%) of which required chest tube placement. Conclusions: We describe the use of ssRAB combined with CBCT to biopsy pulmonary lesions as a safe diagnostic modality with relatively low radiation dose that is potentially comparable to other image guided sampling modalities. Bronchoscopists should be cognizant of the radiation use during the procedure for both patient and staff safety.

Pulmonary Cryptococcosis.

Pulmonary cryptococcosis describes an invasive lung mycosis caused by Cryptococcus neoformans or Cryptococcus gattii complex. It is often a high-consequence disease in both immunocompromised and immunocompetent populations, and may be misdiagnosed as pulmonary malignancy, leading to a delay in therapy. Epidemiology follows that of cryptococcal meningoencephalitis, with C. gattii infection more common in certain geographic regions. Diagnostic tools include histopathology, microscopy and culture, and the detection of cryptococcal polysaccharide antigen or Cryptococcus-derived nucleic acids. All patients with lung cryptococcosis should have a lumbar puncture and cerebral imaging to exclude central nervous system disease. Radiology is key, both as an adjunct to laboratory testing and as the initial means of detection in asymptomatic patients or those with non-specific symptoms. Pulmonary cryptococcomas (single or multiple) may also be associated with disseminated disease and/or cryptococcal meningitis, requiring prolonged treatment regimens. Optimal management for severe disease requires extended induction (amphotericin B and flucytosine) and consolidation therapy (fluconazole) with close clinical monitoring. Susceptibility testing is of value for epidemiology and in regions where relatively high minimum inhibitory concentrations to azoles (particularly fluconazole) have been noted. Novel diagnostic tools and therapeutic agents promise to improve the detection and treatment of cryptococcosis, particularly in low-income settings where the disease burden is high.

Shape-Sensing Robotic-Assisted Bronchoscopy with Concurrent use of Radial Endobronchial Ultrasound and Cone Beam Computed Tomography in the Evaluation of Pulmonary Lesions.

PURPOSE: Lung nodules are a common radiographic finding. Non-surgical biopsy is recommended in patients with moderate or high pretest probability for malignancy. Shape-sensing robotic-assisted bronchoscopy (ssRAB) combined with radial endobronchial ultrasound (r-EBUS) and cone beam computed tomography (CBCT) is a new approach to sample pulmonary lesions. Limited data are available regarding the diagnostic accuracy of combined ssRAB with r-EBUS and CBCT. METHODS: We conducted a retrospective analysis of the first 200 biopsy procedures of 209 lung lesions using ssRAB, r-EBUS, and CBCT at UT Southwestern Medical Center in Dallas, Texas. Outcomes were based on pathology interpretations of samples taken during ssRAB, clinical and radiographic follow-up, and/or additional sampling. RESULTS: The mean largest lesion dimension was 22.6 ± 13.3 mm with a median of 19 mm (range 7 to 73 mm). The prevalence of malignancy in our data was 64.1%. The diagnostic accuracy of ssRAB combined with advanced imaging was 91.4% (CI 86.7-94.8%). Sensitivity was 87.3% (CI 80.5-92.4%) with a specificity of 98.7% (CI 92.8-100%). The negative and positive predictive values were 81.3% and 99.2%. The rate of non-diagnostic sampling was 11% (23/209 samples). The only complication was pneumothorax in 1% (2/200 procedures), with 0.5% requiring a chest tube. CONCLUSION: Our results of the combined use of ssRAB with r-EBUS and CBCT to sample pulmonary lesions suggest a high diagnostic accuracy for malignant lesions with reasonably high sensitivity and negative predictive values. The procedure is safe with a low rate of complications.

A platform for oncogenomic reporting and interpretation.

Manual interpretation of variants remains rate limiting in precision oncology. The increasing scale and complexity of molecular data generated from comprehensive sequencing of cancer samples requires advanced interpretative platforms as precision oncology expands beyond individual patients to entire populations. To address this unmet need, we introduce a Platform for Oncogenomic Reporting and Interpretation (PORI), comprising an analytic framework that facilitates the interpretation and reporting of somatic variants in cancer. PORI integrates reporting and graph knowledge base tools combined with support for manual curation at the reporting stage. PORI represents an open-source platform alternative to commercial reporting solutions suitable for comprehensive genomic data sets in precision oncology. We demonstrate the utility of PORI by matching 9,961 pan-cancer genome atlas tumours to the graph knowledge base, calculating therapeutically informative alterations, and making available reports describing select individual samples.

Pulmonary embolism as the presenting symptom and a confounder in ACTH-secreting bronchial carcinoid

Summary: Ectopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing's syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome. Learning Points: In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated. Patients with Cushing's syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism. Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome. Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors. A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing's disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.

Selectivity Enhancement by Using Double-Layer MOX-Based Gas Sensors Prepared by Flame Spray Pyrolysis (FSP).

Here we present a novel concept for the selective recognition of different target gases with a multilayer semiconducting metal oxide (SMOX)-based sensor device. Direct current (DC) electrical resistance measurements were performed during exposure to CO and ethanol as single gases and mixtures of highly porous metal oxide double- and single-layer sensors obtained by flame spray pyrolysis. The results show that the calculated resistance ratios of the single- and double-layer sensors are a good indicator for the presence of specific gases in the atmosphere, and can constitute some building blocks for the development of chemical logic devices. Due to the inherent lack of selectivity of SMOX-based gas sensors, such devices could be especially relevant for domestic applications.

Simultaneous laparoscopic paraesophageal hernia repair and sleeve gastrectomy in the morbidly obese.

BACKGROUND: Morbid obesity is associated with increased rates of hiatal and paraesophageal hernias. Although laparoscopic sleeve gastrectomy is gaining popularity as the procedure of choice for morbid obesity, there is little data regarding the management of paraesophageal hernias found intraoperatively. The aim of this study was to evaluate the feasibility and benefits of a combined sleeve gastrectomy and paraesophageal hernia repair in morbidly obese patients. METHODS: From May 2011 to February 2013, 23 patients underwent laparoscopic sleeve gastrectomy combined with the repair of a paraesophageal hernia. Only 4 patients had a large hiatal hernia documented preoperatively on esophagogastroduodenoscopy (EGD). The body mass index (BMI), operative time, length of stay, and complications were evaluated. RESULTS: The average operative time was 165 minutes (115-240 minutes) and length of stay was 2.83 days (2-6 days). All patients were female except for one, with an average age of 53.4 years and a BMI of 41.9 kg/m(2). There were no complications during the procedures. Mean follow-up was 6.16 months (1-19 months), and mean excess weight loss was 39%. The average cost of admission for a combined procedure ($10,056), was slightly higher than a laparoscopic sleeve gastrectomy ($8905) or laparoscopic paraesophageal hernia repair ($8954) done separately. CONCLUSIONS: Laparoscopic sleeve gastrectomy combined with a paraesophageal hernia repair is well-tolerated and feasible in morbidly obese patients. Surgeons should be aware that preoperative EGD is not effective at diagnosing large hiatal or paraesophageal hernias. Surgeons with the skill set to repair paraesophageal hernias should do a combined procedure because it is well-tolerated, feasible, and can reduce the cost of multiple hospital admissions.

Endoscopic submucosal dissection training with ex vivo human gastric remnants.

BACKGROUND: Endoscopic submucosal dissection (ESD) offers en bloc resection of early cancer or precancerous lesions, potentially saving patients from major organ resection, such as gastrectomy, colectomy, and esophagectomy. Japan now leads the world in ESD due to its high rate of gastric cancer. Western countries, with their lower gastric cancer rates, do not get as much experience with the technique. Training in ESD utilizing both in vivo and ex vivo porcine stomach has been shown to decrease rates of perforation and operative time. Both models can be prohibitively expensive or not generally available to the majority of endoscopists on a regular basis. This study describes the framework for using human gastric remnants from sleeve gastrectomy patients for ESD training. METHODS: Patients undergoing sleeve gastrectomy for morbid obesity were consented for use of their gastric specimen before surgery. The specimen was weighed and measured by the pathologist and then used for ESD training. The specimen was mounted to a 15-mm laparoscopic port and secured using a pursestring suture. ESD was then performed through this port. RESULTS: We were able to successfully use this model to resect multiple marked out lesions in an en bloc fashion. Training using this model has improved our dissection times from approximately 2 h to 30 min for a 2-cm simulated lesion. CONCLUSIONS: ESD requires the endoscopist to perform a surgical dissection. Until now, development of these skills required intensive training on porcine models that are not widely available. We were able to create a method using the excised portion from sleeve gastrectomy patients, providing a more accessible and cost-effective model for ESD training and potentially other endoscopic therapeutic modalities.

Cathepsin S is activated during colitis and causes visceral hyperalgesia by a PAR2-dependent mechanism in mice.

BACKGROUND & AIMS: Although proteases control inflammation and pain, the identity, cellular origin, mechanism of action, and causative role of proteases that are activated during disease are not defined. We investigated the activation and function of cysteine cathepsins (Cat) in colitis. METHODS: Because protease activity, rather than expression, is regulated, we treated mice with fluorescent activity-based probes that covalently modify activated cathepsins. Activated proteases were localized by tomographic imaging of intact mice and confocal imaging of tissues, and were identified by electrophoresis and immunoprecipitation. We examined the effects of activated cathepsins on excitability of colonic nociceptors and on colonic pain, and determined their role in colonic inflammatory pain by gene deletion. RESULTS: Tomography and magnetic resonance imaging localized activated cathepsins to the inflamed colon of piroxicam-treated il10(-/-) mice. Confocal imaging detected activated cathepsins in colonic macrophages and spinal neurons and microglial cells of mice with colitis. Gel electrophoresis and immunoprecipitation identified activated Cat-B, Cat-L, and Cat-S in colon and spinal cord, and Cat-S was preferentially secreted into the colonic lumen. Intraluminal Cat-S amplified visceromotor responses to colorectal distension and induced hyperexcitability of colonic nociceptors, which required expression of protease-activated receptor-2. Cat-S deletion attenuated colonic inflammatory pain induced with trinitrobenzene sulfonic acid. CONCLUSIONS: Activity-based probes enable noninvasive detection, cellular localization, and proteomic identification of proteases activated during colitis and are potential diagnostic tools for detection of predictive disease biomarkers. Macrophage cathepsins are activated during colitis, and Cat-S activates nociceptors to induce visceral pain via protease-activated receptor-2. Cat-S mediates colitis pain and is a potential therapeutic target.

Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress.

Prochelators are agents that have little affinity for metal ions until they undergo a chemical conversion. Three new aryl boronate prochelators are presented that are responsive to hydrogen peroxide to provide hexadentate ligands for chelating metal ions. TRENBSIM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)-2-aminoethyl]amine), TRENBSAM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-2-aminoethyl]amine), and TB (tris[(2-boronic acid-benzyl)2-aminoethyl]amine) convert to TRENSIM (tris[(salicylideneamino)ethyl]amine), TRENSAM (tris[(2-hydroxybenzoyl)-2-aminoethyl]amine), and TS (tris[2-hydroxybenzyl)2-aminoethyl]amine), respectively. The prochelators were characterized by (11)B NMR, and the structures of TRENBSAM, TRENBSIM, and the Fe(III) complex of TS were determined by X-ray crystallography. Of the three prochelator/chelator pairs, TB/TS was identified as the most promising for biological applications, as they prevent iron and copper-induced hydroxyl radical generation in an in vitro assay. TB has negligible interactions with metal ions, whereas TS has apparent binding constants (log K') at pH 7.4 of 15.87 for Cu(II), 9.67 Zn(II) and 14.42 for Fe(III). Up to 1 mMTB was nontoxic to retinal pigment epithelial cells, whereas 10 µM TS induced cell death. TS protected cells against H(2)O(2)-induced death, but only within a 1-10 µM range. TB, on the other hand, had a much broader window of protection, suggesting that it may be a useful agent for preventing metal-promoted oxidative damage.

Selective activation of p53-mediated tumour suppression in high-grade tumours.

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

Clevidipine for the treatment of severe hypertension in adults.

BACKGROUND: Intravenous antihypertensive agents are used when immediate control of blood pressure (BP) is required, including during the perioperative cardiac surgery period. Controlling postoperative BP is challenging because of the need to adequately reduce BP while maintaining appropriate end-organ perfusion. Clevidipine is an intravenous, ultra-short-acting, third-generation dihydropyridine calcium channel antagonist with selectivity for arteriolar vasodilatation. It is approved by the US Food and Drug Administration for the treatment of severe hypertension. OBJECTIVE: This paper reviews the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of clevidipine. METHODS: To minimize selection bias, each author conducted an independent search for English-language publications indexed on MEDLINE and International Pharmaceutical Abstracts through January 2010 using the term clevidipine. All identified prospective, randomized and nonrandomized Phase III trials were included in the review. RESULTS: Seven Phase III trials were identified in which clevidipine was compared with baseline, placebo, or other intravenous antihypertensive agents in the settings of severe hypertension (1 study), preoperative cardiac surgery (1), perioperative cardiac surgery (1), and postoperative cardiac surgery (4). In a multicenter, randomized, double-blind, placebo-controlled study of the efficacy of clevidipine in treating preoperative hypertension, the mean reduction from baseline in mean arterial pressure was 31.2% with clevidipine and 11.2% with placebo (P < 0.001). In a randomized, open-label, prospective study involving separate comparisons of clevidipine with nitroglycerin, sodium nitroprusside, and nicardipine, the median total AUC for digression in systolic BP from the predetermined target range differed significantly between clevidipine and nitroglycerin (4.14 vs 8.87 mm Hg . min/h; respectively, P < 0.001) and between clevidipine and sodium nitroprusside (4.37 vs 10.5 mm Hg . min/h; P = 0.003), but not between clevidipine and nicardipine (1.76 and 1.69 mm Hg . min/h). Another study found no significant difference in efficacy in controlling BP during the 3-hour study period between clevidipine and sodium nitroprusside (AUC for mean [SD] arterial pressure, 106 [25] and 101 [28] mm Hg . min/h, respectively). Adverse events in these studies included atrial fibrillation (13.0%-36.1% clevidipine vs 12.0% placebo), nausea (5.0%-21.0% vs 12.0%, respectively), fever (19.0% vs 13.7%), insomnia (12.0% vs 6.1%), and acute renal failure (9.0% vs 2.0%). In the studies reviewed, only 1 case of chest discomfort in the setting of severe hypertension was considered a serious adverse event related to clevidipine therapy. CONCLUSION: In the Phase III trials reviewed, clevidipine was effective in controlling BP in the settings of perioperative cardiac surgery and severe hypertension and was associated with minimal adverse effects.

Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although (111)In-labeled capropmab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties. METHODS: N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-(18)F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions. RESULTS: Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC(50)], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (>6-fold) in kidney activity was seen in mice injected with (2). CONCLUSION: (18)F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors.

Sitagliptin: a novel agent for the management of type 2 diabetes mellitus.

PURPOSE: The pharmacologic, pharmacokinetic, safety, clinical efficacy, and role of sitagliptin in the management of type 2 diabetes mellitus are reviewed. SUMMARY: Sitagliptin is a dipeptidyl-peptidase IV (DPP4) inhibitor that increases insulin release and decreases glucagon levels by preventing the activation of incretin hormones--glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The clinical trials reviewed provide evidence that sitagliptin, either alone or in combination with metformin or thiazolidinediones, is effective in reducing glycosylated hemoglobin (HbA(1c)), fasting plasma glucose, and two-hour postprandial glucose levels in patients with type 2 diabetes. Specifically, sitagliptin has a role in patients who have been compliant with their oral hypoglycemic agents but unable to attain target HbA(1c) values with monotherapy and lifestyle modifications. Sitagliptin is generally well tolerated, with the frequency of adverse events being similar to placebo and a low frequency of hypoglycemia. Sitagliptin does not appear to alter the pharmacokinetics of metformin, rosiglitazone, glyburide, simvastatin, warfarin, or oral contraceptives. The addition of sitagliptin to a patient's oral antidiabetic regimen would necessitate close monitoring for adverse events and possible drug interactions. The sitagliptin dosage recommended by the manufacturer is 100 mg once daily as monotherapy or in combination with metformin or a thiazolidinedione. No formal pharmacoeconomic evaluations of sitagliptin therapy have been conducted. CONCLUSION: Sitagliptin, a DPP4 inhibitor, offers a novel treatment option for patients with type 2 diabetes mellitus.

Counterions influence reactivity of metal ions with cysteinyldopa model compounds.

Cysteinyldopas are naturally occurring conjugates of cysteine and dopa (3,4-dihydroxy-l-phenylalanine) that are precursors to red pheomelanin pigments. Metal ions are known to influence pheomelanogenesis in vitro and may be regulatory factors in vivo. Cydo (3-[(2-amino-ethyl)sulfanyl]-4,6-di-tert-butylbenzene-1,2-diol) and CarboxyCydo (2-amino-3-(4,6-di-tert-butyl-2,3-dihydroxyphenylsulfanyl)-propionic acid) are model compounds of cysteinyldopa that retain its metal-binding functionalities but cannot polymerize due to the presence of blocking tert-butyl groups. Cydo reacts readily with zinc(II) acetate or nickel(II) acetate to form a cyclized 1,4-benzothiazine (zine) intermediate that undergoes ring contraction to form benzothiazole (zole) unless it is stabilized by coordination to a metal ion. The crystal structure of [Ni(zine)2] is reported. The acetate counteranion is required for the zinc-promoted reactivity, as neither zinc(II) sulfate nor zinc(II) chloride alone promotes the transformation. The counterion is less important for redox-active copper and iron, which both readily promote the oxidation of Cydo to zine and zole species; Cu(II) complexes of both zine and zole have been characterized by X-ray crystallography. In the case of CarboxyCydo, a 3-carboxy-1,4-benzothiazine intermediate decarboxylates to form [Cu(zine)2] under basic conditions, but in the absence of base forms a mixture of products that includes the carboxylated dimer 2,2'-bibenzothiazine (bi-zine). These products are consistent with species implicated in the pheomelanogenesis biosynthetic pathway and emphasize how metal ions, their counteranions, and reaction conditions can alter pheomelanin product distribution.

Adjunctive therapy with pramlintide in patients with type 1 or type 2 diabetes mellitus.

Uncontrolled diabetes mellitus is associated with both microvascular and macrovascular complications. Despite an array of treatment options available, achievement of euglycemia in most patients with diabetes is still lacking. Pramlintide acetate, a synthetic analog of the human hormone amylin and belonging to a new class of agents, was approved in March 2005 as adjunctive treatment in patients with type 1 or 2 diabetes mellitus. To evaluate the data available on the efficacy and safety of pramlintide, we conducted a search of MEDLINE (January 1966-May 2006) and International Pharmaceutical Abstracts (January 1970-May 2006). Bibliographies of clinical trials were reviewed for additional references. The literature reviewed demonstrated that pramlintide is effective in reducing levels of glycosylated hemoglobin and potentially preventing weight gain. The most commonly reported adverse effects associated with pramlintide were nausea, anorexia, and hypoglycemia. These adverse effects occurred more often during the initiation of therapy and were usually mild to moderate in nature. Whether this therapy is a cost-effective option for patients with type 1 or type 2 diabetes mellitus is yet to be determined.

A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation.

The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution.