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Although gemcitabine is the cornerstone of care for pancreatic ductal adenocarcinoma (PDA), patients lack durable responses and relapse is inevitable. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. This study evaluated casein kinase 1 delta (CK1δ) as a potential therapeutic target for PDA and bladder cancer, in which CK1δ is frequently overexpressed. We assessed the antitumor effects of genetically silencing or pharmacologically inhibiting CK1δ using our in-house CK1δ small-molecule inhibitor SR-3029, either alone or in combination with gemcitabine, on the proliferation and survival of pancreatic and bladder cancer cell lines and orthotopic mouse models. Genetic studies confirmed that silencing CK1δ or treatment with SR-3029 induced a significant upregulation of deoxycytidine kinase (dCK), a rate-limiting enzyme in gemcitabine metabolite activation. The combination of SR-3029 with gemcitabine induced synergistic antiproliferative activity and enhanced apoptosis in both pancreatic and bladder cancer cells. Furthermore, in an orthotopic pancreatic tumor model, we observed improved efficacy with combination treatment concomitant with increased dCK expression. This study demonstrates that CK1δ plays a role in gemcitabine metabolism, and that the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic PDA as well as other cancers with upregulated CK1δ expression.

This 4-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study was designed to compare the efficacy and safety of etodolac and nabumetone in the treatment of patients with active osteoarthritis (OA) of the knee. Ninety-one patients received etodolac 400 mg twice daily, 89 received nabumetone 1500 mg once daily, and 90 received placebo. Both active treatments significantly improved the patients' condition relative to baseline (P < or = 0.001) at all evaluations during treatment and relative to placebo (P < or = 0.05) by visit 4. Improvement relative to placebo in investigator's global assessments was earlier in the etodolac group (ie, by visit 3) than in the nabumetone group. At visit 4, improvement in investigator's and patient's global assessment scores, and in the distribution of investigator's assessment scores, was significantly (P < or = 0.05) greater in the etodolac group than in the nabumetone group. Other than hypokalemia, which occurred only in three patients in the nabumetone group (P = 0.035), there were no significant differences among the groups in the frequency of study events or premature discontinuation from the study as a result of study events. Study events considered at least possibly treatment related were reported for 26 patients in the etodolac group (28.6%), 20 in the nabumetone group (22.5%), and 23 in the placebo group (25.6%). The most frequently reported symptoms for all groups were dyspepsia, nausea, and headache. Four patients treated with nabumetone (4.5%) had elevations in aspartate aminotransferase or alanine aminotransferase during treatment. The results of this study show that etodolac 400 mg twice daily is at least as effective as nabumetone 1500 mg once daily and is equally well tolerated in the treatment of patients with active OA of the knee; etodolac may have an earlier onset of action and/or a relatively greater efficacy in patient and investigator global assessments than nabumetone.

We analyzed the medical records of all live birth infants (LBs) born with major birth defects (MBDs) at King Fahd Hofuf Hospital (KFHH) during a three-year period. Our objectives were to determine defect prevalence rate, patterns, geographic differences, associated maternal and infant risk factors, and the contribution of the defects to mortality in our Neonatal Intensive Care Unit (NICU). Out of 30,159 infants born alive during the study period, 687 (2.27%) had one or more MBDs. Systems most commonly affected were the cardiac (20.8%), musculoskeletal (18.7%), and central nervous (18.3%) systems. We observed higher rates/1000 LBs of life-threatening CNS and cardiac defects and diaphragmatic hernia than rates reported from other countries. Rate of defects/1000 LBs increased from 0.79% in the birth-weight group/=4000 g to 15.2% in the birth-weight category1500 g. Fifty-six infants with MBDs were born to diabetic mothers; diabetes was the only identified maternal disease associated with birth defects. Diabetic mothers and those of infants with chromosomal anomalies had higher means of age and parity than the control mothers ( 33.5 yrs (SD 5.2), 31.4 yrs (7.5), and 8.8 (3.8), 7.39 (3.8), for age and parity of diabetic and chromosomal anomalies respectively vs. 26.8 yrs (6.4) and 5.2 (3.7) in the controls, P0.01). Out of the 687 infants, 254 (36.97%) died; and MBDs were the most common disease- specific cause of death in our NICU throughout the study period.

Shoulder dystotia is a rare but serious obstetric complication that can result in significant neonatal and maternal morbidity and in costly litigation. Conflict exists in the literature regarding definition, incidence, predictability and preventability, relationship to neonatal injury, and appropriate management models. Anticipatory clinical interventions for potential shoulder dystocia have included ultrasound assessment of macrosomia; elective induction of labor; elective caesarean section; altered place of birth; and generous episiotomy/episioproctotomy. The authors note that these interventions often conflict with client desires and nurse-midwifery philosophy of birth, generate significant risks and costs in themselves, and do not address the poor predictability of shoulder dystocia. In recent literature, the safety and efficacy of maternal position change maneuvers (such as McRoberts maneuver, hands-knees position, and squatting) have been presented as methods to resolve most cases of shoulder dystocia. Despite the success of these more benign, external maneuvers, the episiotomy mandate remains in nearly all obstetric and midwifery texts and handbooks (1–8) and journal references (9–19). A literature review of related professional disciplines was undertaken to study these conflicts and to identify support for applying a philosophy of minimal, appropriate intervention to the complex issue of shoulder dystocia.

G protein-coupled receptors (GPCR) are the major site of action for endogenous hormones and neurotransmitters. Early drug discovery efforts focused on determining whether ligands could engage G protein coupling and subsequently activate or inhibit cognate "second messengers." Gone are those simple days as we now realize that receptors can also couple βarrestins. As we delve into the complexity of ligand-directed signaling and receptosome scaffolds, we are faced with what may seem like endless possibilities triggered by receptor-ligand mediated events.

SYNOPSISDiagnostic communication between doctors and patients is thought to differ radically between Japan and Western countries. To understand diagnostic disclosure to psychiatric patients, a questionnaire with six case vignettes was sent to practising psychiatrists in Japan (N= 166) and North America (N= 112). While over 90% of both groups would inform patients with affective and anxiety disorders of their diagnoses, only 70% of North Americans and less than 30% of Japanese would similarly inform patients with schizophrenia or schizophreniform disorders. The Japanese preferred alternative was to give a vague alternative diagnosis such as neurasthenia. North Americans would discuss differential diagnoses with the patient instead. Nearly all in both groups would inform the family, but North Americans would do so only with patient consent. For disorders for which there are effective treatments, diagnostic disclosure is common to both cultures; when prognosis is uncertain or the diagnosis is feared, as in schizophrenia, culturally constructed views of patienthood govern disclosure practice.

Background Stimulation of β 1 - and β 2 -adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β 3 AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. Methods and Results To better understand the role of β 3 ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human β 3 AR (TGβ 3 mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous β 1 - and β 2 ARs, isoproterenol resulted in an increase in contractility in the TGβ 3 mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human β 3 AR agonist L-755,507 significantly increased contractility in the TGβ 3 mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGβ 3 mice was investigated in terms of β 3 AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGβ 3 mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [ 35 S]GTPγS loading and a 1.6-fold increase in adenylyl cyclase activity. Conclusions Cardiac overexpression of human β 3 ARs results in positive inotropy only on stimulation with a β 3 AR agonist. Overexpressed β 3 ARs couple to G s and activate adenylyl cyclase on agonist stimulation.

Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dtmax as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.

Two patients, a 43-year-old woman and a 62-year-old man, developed benign peripheral nerve sheath tumors (neurofibromas) of the lacrimal gland, in the former case of the deep orbital lobe, and in the latter of the palpebral lobe. A neurogenic tumor was not seriously considered clinically in either case, because of the paucity of previous reports on the occurrence of neural tumors in the lacrimal fossa region. Instead, in the first case a benign mixed tumor was considered the most likely clinical diagnosis, whereas in the second the coexistence of a swelling in the parotid gland raised the possibilities of a lymphoid tumor or a leukemia. Due to unusual light microscopic features, transmission electron microscopy was required to secure unequivocal diagnoses. In the orbital lobe tumor, an encapsulated spindle cell proliferation without nuclear palisading but with focal areas of myxoid change suggested either a cellular benign mixed tumor or a schwannoma. The palpebral lobe lesion displayed a myxoid spindle cell proliferation that had splayed apart the ducts and acinae of the lacrimal gland, to impart the overall appearance of a benign mixed tumor. The ducts, however, were multilaminar rather than possessing the usual double cellular layer seen in classical benign mixed tumors, and the glandular units contained zymogen granules, which are typically not seen in benign mixed tumors. Electron microscopy disclosed in both lesions the presence of interrupted basement membrane material partially surrounding the tumor cells, long spacing collagen (banded basement membrane material), and poorly developed desmosomes, features compatible with a neural tumor. Neither myofilaments, tonofilaments, nor ductal-type granules sometimes observed in benign mixed tumors were discovered. The tumor cells in these cases therefore failed to demonstrate clear-cut Schwann cell characteristics (eg, continuous basement membranes, pseudo-mesaxons, tangles of cell processes), and more closely resembled perineural cells that have been described in ultrastructural studies of peripheral nerve tumors including neurofibromas of other sites.

• A training program for researchers using standard clinical assessment procedures has been developed to enhance comparability of findings across studies through reducing critical sources of unreliability. The need for such a program is especially important in large multifacility collaborative studies in which the pooling of diagnostic and rating-scale data is planned. The program described here focuses on the Schedule for Affective Disorders and Schizophrenia and Research Diagnostic Criteria, two instruments widely used in clinical research. It consists of the following four phases of training: use of written case vignettes, videotaped interviews, in-person training interviews, and ongoing monitoring to maintain reliability. Checks on reliability are built into each successive phase of training. This program can serve as a model for training in the use of other standard interview assessment procedures requiring clinical judgment.

In this study we assess the reliability of rating past psychiatric symptoms and lifetime diagnoses in a currently ill population using the SADS and RDC. Five raters from different centers interviewed 25 subjects in a short-interval test-retest design. Subjects had a wide diversity of affective and non-affective diagnoses and high levels of manifest psychopathology. Our results demonstrate that it is possible for raters from different research centers to reliably rate lifetime diagnoses and previous symptoms. Two important exceptions to the high reliability are the lifetime diagnoses of hypomania and the recurrent unipolar subtype of major depressive disorder, and we alert clinicians and researchers to be cautious when diagnosing these conditions. We conclude that the next step in measuring reliability should be a long-interval test-retest design with separate interviews conducted at the later assessment, one by the original rater and the other by a blind rater.

Aldosterone is 1 of the various hormones with detrimental functions for the failing heart, whose circulating levels are elevated post-myocardial infarction (MI) and in patients with chronic heart failure (HF) [(1)][1]. We have recently discovered that angiotensin II, acting through its type 1