Dependence of insulin secretion from permeabilized pancreatic beta-cells on the activation of Ca(2+)/calmodulin-dependent protein kinase II. A re-evaluation of inhibitor studies

Previous studies utilizing inhibitors of the Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II) to address the role of this enzyme in insulin secretion have produced contradictory results. In the current study, these inconsistencies have been addressed by evaluating the effect of various CaM kinase II inhibitors to decrease Ca(2+)-induced insulin secretion from permeabilized beta-cells. KN-93 (2-[N-(2-hydroxyethyl)-N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlo rocinnamyl)-N-methylbenzylamine) markedly inhibited both CaM kinase II activation and insulin secretion in parallel in alpha-toxin-permeabilized beta-cells. These effects were specific since they were not mimicked by the inactive analog, KN-92 (2-[N-(4-methoxy-benzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methy lbenzylamine). In contrast, KN-62 (1-[N, O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine) , while reported to be similar to KN-93 with respect to mechanism of action, did not inhibit Ca(2+)-induced activation of CaM kinase II or insulin secretion in these cell preparations. All three agents suppressed Ca(2+) influx in intact beta-cells induced by depolarization in the presence of elevated extracellular potassium although to different extents. The synthetic peptide inhibitors of CaM kinase II, [Ala(286)]CaMK 281-302 and AIP (autocamtide-2-related inhibitory peptide), strongly inhibited Ca(2+)-induced insulin secretion from electropermeabilized islets, an effect that also correlated with an equivalent inhibition of CaM kinase II activation. This re-evaluation (i) explains a lack of effect of KN-62 on insulin secretion from permeabilized cells based on its inability to inhibit CaM kinase II activation in these preparations; (ii) has revealed that CaM inhibitors, either chemical or peptide in nature, that are capable of preventing enzyme activation uniformly suppress Ca(2+)-sensitive insulin secretion; and (iii) cautions the use of KN-62/93/92 as selective inhibitors of CaM kinase II in intact cell studies. These observations reinforce the suggestion that CaM kinase II plays an important role in insulin exocytosis in the beta-cell.     

Amitraz Poisoning

Amitraz is a formamidine insecticide and acaricide which acts on alpha 2-adrenergic receptors. There is little information available in the literature about the toxicity and treatment of poisoning by this compound. The authors report amitraz poisoning in a 13-y-old boy which was managed with supportive care with a good outcome.     

Microwave-irradiated synthesis and antimicrobial activity of 2-phenyl-7-substitutedalkyl/arylaminoquinoline-4-carboxylic acid derivatives

This report focuses on the synthesis of 2-phenyl-7-substitutedquinoline-4-carboxylic acid derivatives through both conventional and microwave-irradiated methods. Intermediate 7-chloro-2-phenyl-quinoline-4-carboxylic acid was synthesized by condensation and cyclization of benzaldehyde, pyruvic acid, and m-chloroaniline in the presence of absolute ethanol and further substituted with aromatic, aliphatic, and alicyclic amines to obtain the desired 2-phenyl-7-substitutedaryl/alkylamino-quinoline-4-carboxylic acid derivatives under the influence of microwave irradiation, with output power ranging from 160 to 480 W, yield ranging from 90% to 95%, and a shorter reaction time than with the conventional method. All the synthesized compounds were screened for in vitro antimicrobial activity against six gram-positive and four gram-negative organisms. All synthesized compounds are active against a broad spectrum of microorganisms, with prominent results for Streptococcus pyrogenes and Pseudomonas aeruginosa. Compounds 7c and 7h showed a minimum inhibitory concentration of less than 10 μg.     

Noninvasive mapping of human trigeminal brainstem pathways

The human trigeminal system mediates facial pain and somatosensory processing. The anatomic location of neuronal substrates and axonal pathways of the trigeminal system have previously been characterized with conventional in vitro methods. The present investigation implemented diffusion tensor imaging (DTI) and probabilistic tractography to first segment the peripheral trigeminal circuitry, trigeminal nerve branches (ophthalmic, maxillary, and mandibular nerves), ganglion, and nerve root. Subsequent segmentations involved the spinal trigeminal and trigeminal thalamic tracts, which respectively convey information to the spinal trigeminal nuclei and ventral thalamic regions. This latter procedure also identified 1) spinal thalamic (anterolateral [AL]) system pathways (propagating pain and temperature information from the body), 2) trigeminal lemniscus (TL; touch and face position), and 3) medial lemniscus (ML; touch and limb position). The anatomic location of the identified pain and somatosensory pathways compared well with previous functional findings in the human trigeminal system, as well as the tract position in human histological cross sections. Probabilistic tractography may be a useful method to further comprehend the functional and structural properties of trigeminal and other related systems. Application of DTI to map pain and somatosensory pathways in conjunction with a characterization of function properties of pain and somatosensory processing would further define the systematic changes that occur in trigeminal pathology. Magn Reson Med 60:1037–1046, 2008. © 2008 Wiley‐Liss, Inc.     

Project Muskan: Social responsibility of the plastic surgeon

Although exact statistics are not available, Indian plastic surgeons see around 7,00,000–8,00,000 burn admissions annually with around 10,00,000 cleft patients yet to be operated. In spite of this voluminous load, India does not have national health programs for the various deformities Indian plastic surgeons typically treat. As Plastic Surgeons, it is our social responsibility to treat these patients and bring ‘muskan’ (smile in Hindi) back into their lives. Project Muskan was initiated as an innovative model for targeting these patients and is probably one of its kind in the field of plastic surgery in our country. It is unique because it is a perfect collaboration of government institutions, a Non Government Organization (NGO), and cooperative sectors providing free health care at the doorstep. Identification of the patients was done with the help of the extensive milk dairy network in the state of Gujarat. Provision of transport and other facilities was done by the NGOs and quality health care provision was taken care of by the government hospital. Project Muskan started from a single village but now covers around 3000 villages and tribal areas of Gujarat. It is a system that can be easily reproducible in all hospitals and has reestablished the faith of the common man in government institutes.     

Intravascular Ultrasound to Assess Extracranial Vertebral Artery Restenosis: Case Report

We present a case report of a patient who developed restenosis 5 months after initial stent placement. computed tomography (CT) angiography revealed a 70% stenosis, while conventional angiography revealed a 40% stenosis. An intravascular ultrasound (IVUS) was used to assess the degree of narrowing along with the mechanism causing the stenosis. IVUS can be utilized to resolve discrepancies between imaging modalities for degree of stenosis and also aid in determining the mechanism of restenosis after stent placement in the extracranial vertebral arteries.