Comparing the unified protocol for transdiagnostic treatment of emotional disorders to prolonged exposure for the treatment of PTSD: Design of a non-inferiority randomized controlled trial.

Background: Prolonged Exposure (PE), a trauma-focused therapy, is one of the most efficacious treatments available for PTSD. However, many people with PTSD do not lose their diagnosis following delivery of PE. The Unified Protocol (UP) for Transdiagnostic Treatment of Emotional Disorders is a non-trauma focused treatment that may offer an alternative treatment for PTSD. Methods: This paper describes the study protocol for IMPACT, an assessor-blinded randomized controlled trial that examines the non-inferiority of UP relative to PE for participants who meet DSM-5 criteria for current PTSD. One hundred and twenty adult participants with PTSD will be randomized to receive either 10 × 90-min sessions of UP or PE with a trained provider. The primary outcome is severity of PTSD symptoms assessed by the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) at post-treatment. Discussion: While evidence-based treatments are available for PTSD, high levels of treatment dropout and non-response require new approaches to be tested. The UP is based on emotion regulation theory and is effective in treating anxiety and depressive disorders, however, there has been limited application to PTSD. This is the first rigorous study comparing UP to PE in a non-inferiority randomized controlled trial and may help improve clinical outcomes for those with PTSD. Trial registration: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, Trial ID (ACTRN12619000543189).

High Velocity Gunshot Fractures of Humerus: Results of Primary Plate Osteosynthesis.

BACKGROUND: High velocity gunshot fractures usually seen in conflict zones, often mandate external fixation due to delayed presentation and associated contamination. In the presented observational study, we managed high velocity gunshot fractures of humerus with adequate debridement and primary plate osteosynthesis under controlled conditions with gratifying results. MATERIAL AND METHODS: Eighteen consecutive cases of fracture of the humerus secondary to high velocity gunshot wounds with ages ranging from 28 to 45 years reporting within 6 h of the initial injury formed our study group. Immediate debridement, lavage and primary plate osteosynthesis was carried out following hemodynamic stabilisation and intravenous antibiotics. All the cases were followed up at 2, 4, 6 months, 1 year and then annual follow-up including telephonic follow-up for six patients. RESULTS: Fifteen cases of Gustillo Anderson type III A, two of type III B and one of type III C were managed with primary plate osteosynthesis. Brachial artery injury was addressed immediately, however injured radial nerve ends were tagged. Five cases showed delayed/non-union and were managed with decortication and autologous bone grafting. Two cases of deep infection could be managed with implant retention till union. The implants were removed following fracture consolidation. All the fractures united and no patient was left with sequelae of chronic infection. CONCLUSION: Timely presentation of high velocity gunshot fractures of humerus teamed up with adequate debridement, soft tissue management and primary plate osteosynthesis can offer satisfactory outcomes. Associated vascular injury needs immediate attention. Nerve injuries can be addressed in a staged procedure. Our results have been satisfactory and add to the scant literature available on the subject, however further studies are warranted.

Role of myosin phosphatase isoforms in cGMP-mediated smooth muscle relaxation.

In vitro experiments showing the activation of the myosin phosphatase via heterophilic leucine zipper interactions between its targeting subunit (MYPT1) and cGMP-dependent protein kinase I suggested a pathway for smooth muscle relaxation (Surks, H. K., Mochizuki, N., Kasai, Y., Georgescu, S. P., Tang, K. M., Ito, M., Lincoln, T. M., and Mendelsohn, M. E. (1999) Science 286, 1583-1587). The relationship between MYPT1 isoform expression and smooth muscle responses to cGMP signaling in vivo has not been explored. MYPT1 isoforms that contain or lack a C-terminal leucine zipper are generated in birds and mammals by cassette-type alternative splicing of a 31-nucleotide exon. The avian and mammalian C-terminal isoforms are highly conserved and expressed in a tissue-specific fashion. In the mature chicken the tonic contracting aorta and phasic contracting gizzard exclusively express the leucine zipper positive and negative MYPT1 isoforms, respectively. Expression of the MYPT1 isoforms is also developmentally regulated in the gizzard, which switches from leucine zipper positive to negative isoforms around the time of hatching. This switch coincides with the development in the gizzard of a cGMP-resistant phenotype, i.e. inability to dephosphorylate myosin and relax in response to 8-bromo-cGMP after calcium activation. Furthermore, association of cGMP-dependent protein kinase I with MYPT1 is detected by immunoprecipitation only in the tissue that expresses the leucine zipper positive isoform of MYPT1. These results suggest that the regulated splicing of MYPT1 is an important determinant of smooth muscle phenotypic diversity and the variability in the response of smooth muscles to the calcium desensitizing effect of cGMP signaling.

A novel extractionless hplc fluorescence method for the determination of glyburide in the human plasma: application to a bioequivalence study.

PURPOSE: To develop a simple, sensitive and rapid HPLC fluorescence method with single step sample preparation for the determination of glyburide in the human plasma. METHODS: Glyburide and ketoconazole (internal standard) were extracted from the 0.5 mL plasma by addition of 0.5 mL acetonitrile and 50 microL CuSO(4) solution (5% w/v in water). The separation was achieved on the Kingsorb 3 microm, C8 reverse phase column at ambient temperature with a mobile phase consisted of 45% buffer solution (0.05 M NH(4)H(2)P(4)), 40% acetonitrile and 15% methanol adjusted to pH 5.7 by diluted ammonia solution. A fluorescence detector was set at 235 nm excitation wavelength and 354 nm emission wavelengths to monitor eluted components. RESULTS: The internal standard and glyburide eluted at about 6.7 and 9.6 min, respectively at the flow rate of 1 mL/min. The regression equation was established for every calibration curves (5 ng/mL to 400 ng/mL), which resulted in the correlation coefficient of 0.99 or greater. The absolute recovery ranged from 94.32 to 98.12% and the relative recovery ranged from 91.12 to 97.15%. The intraday coefficient of variation (CV) ranged from of 6.52 to 12.35% and interday varied from 6.21 to 16.07%. The limit of quantitation (LOQ) of glyburide was set to five ng/mL. CONCLUSION: This simple, rapid and sensitive method is suitable for pharmacokinetic, bioavailability and biequivalence studies.

Persistent hyperinsulinemic hypoglycemia of infancy.

OBJECTIVE: To study the nature and clinical course of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) due to nesidioblastosis. DESIGN: Clinical, laboratory and therapeutic evaluation of infants with this disorder and study the outcome. SETTING: Hospital born neonates and infants referred from other hospitals. SUBJECTS: Thirteen infants from 9 families inclusive of four pairs of siblings referred within few hours of birth to 3 months of age, for seizures. Mean birth weight was 3.68 +/- 0.45 kg. Consanguinity documented in one sporadic and one familial case. METHODS: Clinical and laboratory evaluation by standard biochemical and radioimmunoassay techniques. RESULTS: The mean serum insulin level of 24.2 +/- 12.5 mIU/ml was in the normal range but inappropriately high for the corresponding hypoglycemic blood sugar (23.1 +/- 9.1 mg/dl) value, with an I/G ratio of 1.36 +/- 0.97; as in hyperinsulinemia (normal < 0.4). Investigations excluded other causes of persistent hypoglycemia. A trial of i.v./oral glucose, frequent carbohydrate rich feeds in all, oral diazoxide (10 to 20 mg/kg) in 9/13 cases along with subcutaneous octreotide (20 micrograms/kg QID) in one helped, but pancreatic resection (85 to 90%) was opted for in two (1 familial, 1 sporadic). Six infants including one with pancreatic resection succumbed to hypoglycemia (n = 1) or fulminating infection (n = 3) or brain damage. Of the seven survivors, one familial case with pancreatic resection is brain damaged, and of the six on diazoxide therapy, one is slightly subnormal while one sporadic and three familial cases have done well. One infant was lost to follow up. Diazoxide could be withdrawn in two subjects (1 familial, 1 sporadic) by 8 years of age signifying maturation of islet cell function. CONCLUSION: PHHI appropriately known as 'Islet cell dysmaturation syndrome' is a complex disorder posing problems in diagnosis and therapy. The high familial incidence (77%), with intrafamilial variation in the severity, insulin levels in the normal range but in appropriately high for the blood glucose levels, normal C-peptide levels, with normal I/G ratio (< 0.4) in 4/13 are some of the notable features of this study. Severe recurrent infections in nearly 30%, is an unusual feature in this series and needs an indepth study. The mortality (46%) and morbidity (43%) in survivors is high and calls for greater awareness, early diagnosis and genetic counselling, as this disorder may be familial.

Selected pharmacodynamic and biochemical properties of selenonium choline.

1. Five minutes after intravenous administration of 50 mg/kg of the novel choline analogue selenonium choline [(CH3)2Se + CH2CH2OH, SeCh], only 8% of the administered dose was accounted for in blood, brain, liver, heart, and kidney tissues. 2. SeCh was acetylated in vivo to acetylselenonium choline (ASeCh) in all of the tissues examined. 3. During postmortem incubation, brain concentrations of SeCh and ASeCh increased to 535% and to 425%, respectively. 4. K(m) and Vmax values for the phosphorylation of SeCh by choline kinase were higher and lower, respectively, compared to the phosphorylation of choline. 5. Acetylation of SeCh was described with K(m) and Vmax values that were both higher than the values for Ch. 6. The data suggest that SeCh is phosphorylated and incorporated into various lipids in brain tissue, and is acetylated to ASeCh by both nonneural and neural tissues.

Hemoglobin S/hemoglobin Osler: a case with 3 beta globin chains. DNA sequence (AAT) proves that Hb Osler is beta 145 Tyr-->Asn.

A 13-year-old African-American female with erythrocytosis and three different beta globins on electrophoresis beta A, beta S, and beta Osler, raised the possibility that one chromosome 11 might contain a duplicated beta globin gene, since there are normally only 2 beta globin genes. DNA sequence analysis showed GTG at codon 6 in exon 1, corresponding to Hb S and AAT at codon 145 in exon 3, indicating a substitution of Asn for Tyr. Thus, Hb Osler undergoes spontaneous post-translational deamidation, beta 145 Asn-->beta 145 Asp. Unmodified Hb Osler (Asn) co-migrates with Hb A on electrophoresis and co-elutes with Hb A on HPLC; therefore it has not been identified previously. All previous studies have incorrectly identified the mutation as being beta 145 (HC 2) Tyr-->Asp.

Muscarinic and nicotinic activities of the novel acetylcholine analog acetylselenonium choline.

The present paper further characterizes the cholinergic properties of acetylselenonium choline (ASeCh, (CH3)2Se+CH2CH2OCOCH3). The data demonstrate that ASeCh possesses muscarinic receptor agonist properties as evidenced by vasodepressor and smooth muscle contractile activities which are enhanced by physostigmine and antagonized by atropine. ASeCh also possessed nicotinic agonist activity on frog rectus abdominis tissue which was potentiated by physostigmine, and blocked by d-tubocurarine. The relative potencies of ASeCh ranged from approximately 1% to approximately 6% of the potency of acetylcholine in the three types of preparations examined.