Acinar-islet cell carcinoma presenting as insulinoma

A case of acinar-islet cell carcinoma presenting as insulinoma is reported. The patient was a 28-year-old man who presented with two convulsive episodes. Fajans' index [immunoreactive insulin (IRI; μU/ml/ glucose mg/dl)] and Turner's [IRI (μU/ml) × 100/glucose (mg/dl)—30] index were high (2.8 and 308, respectively), as were serum proinsulin levels (550pg/ml). Abdominal computed tomography and angiography revealed a highly vascular tumor in the pancreatic tail and several similar tumors in the liver. Histologic features of a biopsy specimen from a hepatic tumor were those of a malignant pancreatic endocrine tumor. Insulin secretion by the liver metastases was confirmed by venous sampling after arterial stimulation with calcium. These findings led us to diagnose malignant insulinoma with liver metastases. Serum levels of α-fetoprotein and trypsin were markedly elevated, to 2234ng/ml (normal <10) and 22000ng/ml (normal<460) respectively, and these levels continued to rise with further growth of the liver metastases. Immunohistochemically, the metastatic liver tumor specimen was positive for α-fetoprotein, α1-antichymotrypsin, chromogranin A, and neuron-specific enolase. These findings of amphicrine features in the tumor were indicative of acinar-islet cell carcinoma that produced α-fetoprotein and trypsin in addition to insulin.     

TNF-alpha rapidly antagonizes the beta-adrenergic responses of the chloride current in guinea-pig ventricular myocytes.

The purpose of this study was to test the hypothesis that tumor necrosis factor-alpha (TNF-alpha) rapidly antagonizes the beta-adrenergic responses of the chloride current and to clarify the intracellular mechanisms responsible for the anti-adrenergic action. The whole-cell patch-clamp technique was used to monitor the anti-adrenergic effects of TNF-alpha on the cAMP-dependent chloride current (I(Cl)) recorded from isolated guinea-pig ventricular myocytes. Ramp pulses (+/-120 mV; dv/dt = +/-0.4 V/s) were applied from the holding potential of -40 mV. TNF-alpha rapidly (<15 min) inhibited the isoproterenol (Iso, 0.1 micromol/L)-induced I(Cl) in a concentration-dependent manner (30-1,000 U/ml, IC (50) = 144 U/ml, n=30). The inhibitory action of TNF-alpha was also observed when I(Cl) had been previously stimulated by 1 micromol/L forskolin (n=5). Prior exposure of myocytes to 5 microg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). However, when I(Cl) was induced by both 8-bromo-cAMP (100 micromol/L) and isobutylmethylxanthine (0.1 mmol/L), TNF-alpha (1,000 U/ml) failed to decrease I(Cl) amplitude (n=5). Prior exposure of myocytes to 5 mg/ml pertussis toxin (PTX) hardly affected the anti-adrenergic action of TNF-alpha (n=4). Furthermore, despite of the presence of nitro-L-arginine methyl ester (0.1 mmol/L), a nitric oxide synthase (NOS) inhibitor, TNF-alpha reversed the Iso-induced increase in I(Cl) (n=5). These results suggest that TNF-alpha rapidly antagonizes the beta-adrenergic responses of I(Cl) by reducing cAMP concentration. This anti-adrenergic action is mediated by neither the PTX-sensitive G proteins regulatory pathway nor constitutive NOS activation.     

Ghrelin regulates insulin release and glycemia: physiological role and therapeutic potential

Insulin release from pancreatic islet beta-cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, a novel acylated 28-amino acid peptide isolated from stomach, is the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in stomach. Ghrelin is a potent stimulator of GH release and feeding as well as exhibiting positive cardiovascular effects. In relation to the glucose metabolism, initial studies indicated that low plasma ghrelin levels are associated with elevated fasting insulin levels, insulin resistance, and obesity. It has recently been demonstrated that ghrelin suppresses glucose-induced insulin release via G alpha(i2) subtype of GTP-binding proteins and delayed outward K(+) (Kv) channels, representing a novel signaling mechanism, and that the ghrelin originating from islets regulates insulin release and thereby glycemia. Furthermore, elimination of ghrelin enhances insulin release to prevent or ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the physiological roles of ghrelin in regulating insulin release and glycemia, the insulinostatic mechanisms of ghrelin in islet beta-cells, and the potential of ghrelin-GHS-R system as the therapeutic target to treat type 2 diabetes.     

A mitochondrial superoxide theory for oxidative stress diseases and aging

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O₂^•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q₁₀) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.     

Cervical ossification of the posterior longitudinal ligament: Biomechanical analysis of the influence of static and dynamic factors

Objective

Cervical myelopathy due to ossification of the posterior longitudinal ligament (OPLL) is induced by static factors, dynamic factors, or a combination of both. We used a three-dimensional finite element method (3D-FEM) to analyze the stress distributions in the cervical spinal cord under static compression, dynamic compression, or a combination of both in the context of OPLL.

Methods

Experimental conditions were established for the 3D-FEM spinal cord, lamina, and hill-shaped OPLL. To simulate static compression of the spinal cord, anterior compression at 10, 20, and 30% of the anterior–posterior diameter of the spinal cord was applied by the OPLL. To simulate dynamic compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction. To simulate combined static and dynamic compression under 10 and 20% anterior static compression, the OPLL was rotated 5°, 10°, and 15° in the flexion direction.

Results

The stress distribution in the spinal cord increased following static and dynamic compression by cervical OPLL. However, the stress distribution did not increase throughout the entire spinal cord. For combined static and dynamic compression, the stress distribution increased as the static compression increased, even for a mild range of motion (ROM).

Conclusion

Symptoms may appear under static or dynamic compression only. However, under static compression, the stress distribution increases with the ROM of the responsible level and this makes it very likely that symptoms will worsen. We conclude that cervical OPLL myelopathy is induced by static factors, dynamic factors, and a combination of both.     

Late assessment of quality of life in patients with rectal carcinoma: comparison between sphincter preservation and definitive colostomy

Purpose

Patients with cancer of the lower and middle rectum who are candidates for curative surgery often have negative opinions on definitive colostomy. The purpose of this study is to compare the quality of life (QoL) of patients who undergo standard treatment for rectal cancer with sphincter preservation or definitive colostomy.

Methods

A total of 125 patients with adenocarcinoma of the lower or middle rectum who underwent radical surgery with curative intent with a follow-up ≥?1 year were recruited: 83 patients (group 1) were subjected to low anterior resection and low colorectal or coloanal anastomosis—thus preserving their sphincter—and 42 (group 2) were treated with abdominoperineal resection, followed by terminal definitive colostomy. QoL was assessed with the EORTC QLQ-C30 and QLQ-CR29 questionnaires.

Results

Health and global quality of life were similar between groups; however, patients who underwent definitive colostomy had higher scores on the emotional (p value?=?0.016) and cognitive function scales (p value?=?0.017). Patients with sphincter preservation presented with more symptoms that were related to stool frequency (p value <?0.001), intestinal constipation (p value?=?0.005), fecal incontinence (p value?=?0.001), buttock pain (p value?=?0.023), and nausea and vomiting (p value?=?0.036), whereas patients with permanent colostomy had higher scores for dysuria (p value?=?0.033).

Conclusion

Although global QoL scores did not differ between groups, patients who underwent definitive colostomy had significantly better functional and symptom scale scores, reflecting greater function with fewer symptoms.

     

Assessment of oxidative stress in the spontaneously hypertensive rat brain using electron spin resonance (ESR) imaging and in vivo L-Band ESR.

This study examined the blood brain barrier (BBB)-permeable nitroxyl compound, 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (MC-PROXYL), as a spin probe for the assessment of oxidative stress in the brain by electron spin resonance (ESR) imaging and in vivo L-band ESR. Preliminary comparisons were made by ESR imaging of MC-PROXYL in the isolated brains of normal Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke prone SHR (SHRSP). The decay of the ESR images of MC-PROXYL in the isolated brains was faster in SHR than in normal WKY, but was only moderate in SHRSP. In addition, the decay rate of MC-PROXYL in the heads of live rats, as measured noninvasively by L-band ESR, was faster in SHR than in WKY, and was slower in SHR than in SHRSP. Taken together, our data suggest that the oxidative stress of SHR is not as high as that in high oxidative stress animal models such as SHRSP. This is the first study to present reconstructed 3D images of the distribution of MC-PROXYL in the isolated SHR brain. The ESR technique employed herein appears to be a powerful tool for evaluating oxidative stress and for detecting the region of oxidative stress in the brain of SHR.     

A case of hypopituitarism due to inflammatory myofibroblastic tumor of the sella turnica

An 18-year-old man with 4-year history of central diabetes insipidus and partial pituitary dysfunction was admitted to our hospital because of headache and nasal discharge. Magnetic resonance imaging (MRI) revealed abnormal mass in the sella turnica invading into the cavernous sinus and sinus maxillaries along with thickened tentorium cerebelli. Histopathology of the mass in the sinus maxillaries revealed spindle-shaped cells arranged in a fascicular pattern with varied myxoid and collagenized regions with various inflammatory cells. Immunostaining revealed the spindle-shaped cells were positive for smooth muscle actin. These features were identical to those of inflammatory myofibroblastic tumor (IMT). He was diagnosed with IMT in the sella turnica and other regions. Corticosteroid therapy improved clinical symptoms and follow-up MRI revealed amelioration of the thickened tentorium cerebelli. However, the other lesions were unchanged and pituitary dysfunction did not improve. Although rare, IMT should be considered in the differential diagnosis of a sellar mass. Early treatment with corticosteroid therapy may reduce the risk of disease progression.     

Effects of flecainide on the electrophysiological properties of atrial vulnerability in humans.

The aims of this study were to evaluate the changes in the electrophysiological characteristics of the right atrium after the administration of flecainide and to clarify whether flecainide has a selective effect on human atrial tissue. Electrophysiological measurements were made in 38 patients, before and after intravenous administration of flecainide (2 mg/kg per 10 min). The effective refractory period of the right atrium (ERP-A), maximum conduction delay (Max.CD), repetitive atrial firing zone (RAFZ), fragmented atrial activity zone (FAAZ), and conduction delay zone (CDZ) were studied in the patients who were divided into 2 groups based on whether repetitive atrial firing (RAF) was induced in the baseline study. Flecainide significantly prolonged the ERP-A (202+/-22 to 238+/-33 ms, p<0.001) and shortened Max.CD (77+/-17 to 63+/-32 ms, p<0.05) in the patients with RAF, but not in those without RAF in the baseline study. After flecainide administration, there were significant reductions in the RAFZ (43+/-22 to 13+/-19 ms, p<0.0001), FAAZ (51+/-22 to 28+/-26 ms, p<0.001) and CDZ (70+/-21 to 48+/-30 ms, p<0.01) in the patients with RAF. However, atrial fibrillation (AF) was induced by stimulation after flecainide in 2 patients without RAF in the baseline study. There was a significant negative correlation between the ERP-A in the baseline study and the change in the ERP-A upon flecainide administration (r=0.45, p<0.01). Flecainide may preferentially activate the substrate for AF and RAF, but that action is mainly based on the electrophysiological characteristics found in the baseline study.