Gastrointestinal motility in the elderly]

The existence of specific, age-related changes in gastrointestinal motility with clinical significance is controversial. Beside the more infrequent primary motility disorders, secondary motility disturbances associated with collagen vascular diseases, endocrinopathies, and neuromuscular diseases are prominent in the older and often multimorbid patients. Especially in geriatric patients, motility associated symptoms are undesired side-effects of drug therapy. The pathophysiology, clinical syndromes, and therapeutic principles of motility disorders in the elderly are discussed. The major symptoms of esophageal dysfunction are dysphagia, chest pain, heartburn, and regurgitation. Oropharyngeal dysphagia, mostly caused by cerebrovascular accidents and other neurologic disorders, leads to disturbances in food intake, and is often complicated by broncho-pulmonary infections arising from recurrent aspiration of food or saliva. Gastrointestinal reflux disease and spastic motility disorders of the esophagus are regarded as possible causes of angina-like chest pain after exclusion of cardiac diseases. Motility disturbances of the stomach and small bowel are often related to systemic disease (i.e., diabetes mellitus, chronic intestinal pseudo-obstruction) of drug side-effects. Mental and physical decline, reduced fluid intake, and constipating drugs are the most relevant factors for idiopathic constipation in the elderly. Fecal incontinence means a great psychological strain for older patients and leads to social isolation.     

Annular pancreas--a congenital abnormality of the pancreas

Our case report on a 26-year-old male suffering from epigastric pain for several years should emphasize the fact, that even a rare congenital malformation like the annular pancreas must seriously discussed as a reason for the so called unspecific abdominal pain. Embryological development, age of manifestation, symptoms and therapeutic concepts are described. The importance of endoscopic methods such as gastroduodenal endoscopy and endoscopic retrograde cholangiopancreatography (ERCP) for a more precise and frequent diagnosis will be strengthened and the influence on the prevalence will be discussed.     

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. Using this platform, we revealed a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation (reduced neurite outgrowth and fewer synapses) in 3D layered hydrogels. Thus, this 3D system expands the range of neural phenotypes that can be studied in vitro to include those influenced by physical and mechanical stimuli or requiring specific arrangements of multiple cell types.Neuronal migration and maturation is a key step in brain development. Defects in this process have been implicated in many disorders, including autism (1) and schizophrenia (2). Thoroughly understanding how neural progenitor cell (NPC) migration is affected in neurodevelopmental disorders requires a means of dissecting the process using cells with genetic alterations matching those in patients. Existing in vitro assays of migration generally involve measurement of cell movement across a scratch or gap or through a membrane toward a chemoattractant in 2D culture systems. Although widely used, such assays may not accurately reveal in vivo differences, as neuronal migration is tightly regulated by physical and chemical cues in the extracellular matrix (ECM) that NPCs encounter as they migrate.In vitro 3D culture systems offer a solution to these limitations (3–7). Compared with 2D culture, a 3D arrangement allows neuronal cells to interact with many more cells (4); this similarity to the in vivo setting has been shown to lengthen viability, enhance survival, and allow formation of longer neurites and more dense networks in primary neurons in uniform matrices or aggregate culture (8, 9). Indeed, 3D culture systems have been used to study nerve regeneration, neuronal and glial development (10–12), and amyloid-β and tau pathology (13). Thus, measuring neuronal migration through a soft 3D matrix would continue this trend toward using 3D systems to study neuronal development and pathology.We sought to develop a 3D assay to examine potential migration and neuronal maturation defects in Rett syndrome (RTT), a genetic neurodevelopmental disorder that affects 1 in 10,000 children in the United States and is caused by mutations in the X-linked methyl-CpG-binding protein-2 (MECP2) gene (14). Studies using induced pluripotent stem cells (iPSCs) from RTT patients in traditional 2D adherent culture have revealed reduced neurite outgrowth and synapse number, as well as altered calcium transients and spontaneous postsynaptic currents (1). However, 2D migration assays seemed unlikely to reveal inherent defects in this developmental process, which could be affected because MeCP2 regulates multiple developmental related genes (15). Migration of RTT iPSC-derived NPCs has not previously been studied.Using a previously unidentified 3D tissue culture system that allows creation of layered architectures, we studied differences in migration of MeCP2-mutant iPSC-derived versus control iPSC-derived NPCs. This approach revealed a defect in migration of MeCP2-mutant iPSC-derived NPCs induced by either astrocytes or neurons. Further, this 3D system accelerated maturation of neurons from human iPSC-derived NPCs, yielding electrophysiologically active neurons within just 3 wk. With mature neurons derived from RTT patients and controls, we further confirmed defective neurite outgrowth and synaptogenesis in MeCP2-mutant neurons. Thus, this 3D system enables study of morphological features accessible in 2D system as well as previously unexamined phenotypes.     

Entrainment of reentrant tachycardia in a computer model

Capture of the cardiac rate by pacing followed by an immediate return to the original rate after pacing has been proposed as characteristic of reentrant rhythms. In this study, such entrainment has been demonstrated using computer-model simulations of propagated excitation and of reentry associated with structural and functional obstacles. With structural obstacles, the mechanism of entrainment was bidirectional propagation of paced excitation in reentry circuits, with collision of the reentrant and paced excitation in one direction and continued propagation of paced excitation in the other direction. The time of pacing onset, rate, and location all affected the QRS waveform during entrainment. With a particular time of onset and rate of pacing, the duration of time during which the QRS waveform underwent dynamic change was directly related to the distance between the pacing site and reentrant circuit. The location of reentry associated with functional obstacles moved so that the relationship between pacing-induced and reentrant excitation varied. In some cycles, pacing did not alter reentrant circuits, that is, entrainment did not occur, while other cycles were entrained, but by a different mechanism than that with structural obstacles. Leading circle reentry circuits, consisting of propagation away from and returning to reentry sites, did not have an excitable gap and paced excitation did not enter those circuits. Paced excitation did, however, enter the propagation paths between leading circle reentry circuits and modified the circuits by affecting the recovery of excitability.     

Results of a Double-Blind,Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

Context

Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

Relation of cardiac surface QRST distributions to ventricular fibrillation threshold in dogs

The relation between ventricular fibrillation threshold (VFT) and cardiac surface QRST area distributions was studied in eight pentobarbital-anesthetized dogs. Unipolar epicardial electrograms were recorded from 64 sites evenly distributed on the right and left ventricles. Localized areas of short repolarization properties were produced by directing five intensities of light onto the surface of the anterior right ventricle through apertures of three sizes. VFT, measured at the center of the lesion, decreased during warming and had a high negative correlation to the change (warming-control) in QRST area (delta QRST1) in the electrogram recorded from the center of the lesion. This correlation was independent of lesion size. For the six experiments, the correlation coefficients for 400-, 800-, and 1,600-mm2 lesions averaged -0.95, -0.94, and -0.96, respectively. The correlation between VFT and delta QRST1 without regard to lesion size averaged -0.88. VFT also had a negative correlation to root mean square (RMS)delta QRST because of warming. RMS delta QRST was calculated from the change in QRST areas (warming-control) in all 64 electrograms. The correlation between VFT and RMS delta QRST was dependent on lesion size. For all experiments, the correlation between VFT and RMS delta QRST averaged -0.97, -0.93, and -0.93 for 400-, 800-, and 1,600-mm2 lesions, respectively. The correlation between VFT and RMS delta QRST without regard to lesion size, however, was considerably lower, -0.59. The results of this study provide the first direct evidence that VFT is correlated with cardiac surface QRST area distributions.     

Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome

OBJECTIVE: To examine whether promoter polymorphisms associated with variation in interleukin-10 (IL-10) production are relevant to the development of rheumatoid arthritis (RA) or Felty's syndrome (FS). METHODS: DNA was obtained from 44 FS patients, 117 RA patients and 295 controls. The promoter region between -533 and - 1120 was amplified by polymerase chain reaction, and polymorphisms detected by restriction enzyme digest or sequence-specific oligonucleotide probing. RESULTS: We found no significant difference in allele or haplotype frequencies between the groups. CONCLUSION: There is no association between FS or RA and these recently identified IL-10 promoter polymorphisms. Other genetic or environmental factors could explain the alterations in IL-10 levels seen in these conditions.      

Determination of transmural location of onset of activation from cardiac surface electrograms

Methods of estimating depth of origin of ventricular activation from cardiac surface electrograms were evaluated in experiments on eight dogs. The ventricles were paced via multielectrode needle arrays placed transmurally in from four to six locations in the wall of the left ventricle. A multiplexed data-recording system was used to simultaneously record from 64 unipolar cardiac surface electrodes during pacing at each multielectrode needle site. The four indexes evaluated were the maximum and average gradients of activation isochrones around the site of earliest epicardial activation, the QRS area at the site of earliest epicardial activation, the interval between the QRS onset computed from all 64 epicardial surface electrograms, and the time of the minimum dV/dt in the electrogram displaying the earliest epicardial activation time (t(ee)-t(rmso) interval). Correlation coefficients between depth of stimulation and average and maximum gradients of isochrones, QRS area at the site of earliest epicardial activation, and t(ee)-t(rmso) interval were 0.985 or higher. These methods, particularly those involving gradients of isochrones, should be useful for evaluating electromaps of patients undergoing surgery for ablation of tachyarrhythmias.     

In vivo reliability of 3D cephalometric landmark determination on magnetic resonance imaging: a feasibility study

Clinical Oral Investigations - 3D cephalometric analysis performed on cone-beam or multi-slice computed tomography (CBCT, MSCT) has superior diagnostic value compared to 2D cephalometry based on...     

Purging of acute myeloid leukemic cells by ether lipids and hyperthermia

Ether lipids (EL) and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemic cells. In this study, the combined effects of EL (ET-18-OCH3, ET-16-NHCOCH3, or BM 41.440) and hyperthermia on the growth of hematopoietic progenitors, myeloid leukemic cell lines, and leukemic cells obtained from patients with acute myeloid leukemia (AML) were examined to determine if this combination resulted in a greater selective killing of leukemic cells than that achieved by either EL or heat alone. When the cells were treated simultaneously with EL (50 micrograms/mL) and hyperthermia (42 degrees C) for one hour, the killing of leukemic cell line cells was enhanced considerably. Among the three EL, however, the combination of ET-18-OCH3 and heat seemed to be the most cytotoxic to leukemic cell line cells with no effect on the growth of hematopoietic progenitors. An increase in the duration of treatment with ET-18-OCH3 to four hours with heat added during the last hour resulted in a further reduction of leukemic cell line cells while sparing 50% of hematopoietic progenitors after cryopreservation. The combined treatment with ET-18-OCH3 and heat also inhibited the growth of leukemic progenitors obtained from AML patients by 97% to 100%. These data indicate that the combined treatment with EL and hyperthermia might offer an efficient means to eliminate myeloid leukemic cells in vitro.