Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase

N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.     

Gamma-knife radiosurgery for trigeminal neuralgia

Gamma knife was installed at the PD Hinduja National Hospital and Medical Research Centre, Mumbai, India, in January 1997. In the first year of gamma-knife radiosurgery to January 1998, we treated 110 patients, of whom six had medically refractory trigeminal neuralgia. Seven treatments were administered to this group of six patients (one had bilateral neuralgia). This report evaluates the effectiveness of radiosurgery treatment in these patients. The median age of the patients was 56 years and there were five males and one female. Following Leksell stereotactic frame fixation, a magnetic resonance imaging scan was done in all. The Leksell gamma plan was used for planning. A radiosurgery dose of 70-80 Gy was delivered to the trigeminal root entry zone, 2-4 mm anterior to the junction of the pons and trigeminal nerve with a single 4 mm collimator helmet. Complete pain relief was achieved in four patients. Two had partial relief. No patient developed any radiosurgery related morbidity during the follow-up period of 5-16 months. Radiosurgery seems to be an effective approach for medically or surgically refractory trigeminal neuralgia.     

Free thyroid transfer to anterolateral thigh for prevention of radiation induced hypothyroidism: An initial experience

Aim

Radiation induced hypothyroidism (RIHT) is one of the commonest late side effects of radiation therapy and is seen in more than half of patients and affects quality of life significantly. We report our initial experience on feasibility of free microvascular transfer of thyroid gland out of radiation field to prevent development of RIHT.

Sciatic nerve of normal and T200x5R Swiss white mice fails to support multiplication of intraneurally injected M. leprae

In a preliminary study we have shown that freshly harvested Mycobacterium leprae, when injected into the sciatic nerve in normal and immunosuppressed (TR) mice, induce massive but localized epithelioid and macrophage granuloma, respectively, in 3-4 weeks. In order to determine the fate of M. leprae injected intraneurally into normal and TR mice, in the present study we measured sequentially the viability, fold increase and clearance, if any, using semi-quantitative methods. The average M. leprae yield per nerve assessed at regular intervals, beginning at 24 hr and including 72 hr, 1 week, 2, 3, 4, 12, 24 and 48 weeks, showed neither a significant increase nor a decrease in either the normal or the TR mice. The viability of M. leprae, assessed using the standard mouse foot pad method, showed a significant decrease as compared to baseline growth effective at 24 hr and remained static until approximately 4 weeks. A further decline and total loss of viability was noted by 12 months. The results show that injection of M. leprae via the intraneural route in both normal and TR mice failed to sustain the viability and failed to support the multiplication of the organisms.     

Laparoscopic lateral pancreaticojejunostomy

BACKGROUND: Lateral pancreaticojejunostomy is considered as the standard surgery for chronic pancreatitis. Yet there are very few reports of this procedure being done laparoscopically. We present our experience with laparoscopic lateral pancreaticojejunostomy till date and describe our technique. MATERIAL AND METHOD: Since 1997, we have done 12 laparoscopic lateral pancreatojejunostomies. There were 9 females and 3 males and the average age was 29.3 years. The indication for surgery in all patients was intractable abdominal pain and significant weight loss. Additionally, two patients were also suffering from pancreatic ascites. RESULTS: The average diameter of the pancreatic duct was 14.7 mm. We used a four-port technique. All surgeries were completed without any conversion to open surgery. Post-operatively, there were no major morbidity and nil mortality. The average operating time was 172 minutes. Post-operative stay was short (average 5 days) and on median follow-up of 4.4 years, 83.3% patients had complete pain relief while 16.7% had partial relief. All patients had significant weight gain. CONCLUSIONS: Laparoscopic lateral pancreaticojejunostomy is safe, effective and feasible in experience hands. Mastery of intracorporeal knotting and suturing techniques is mandatory before embarking on this surgery.     

Does this patient have hearing impairment?

Akshay Bagai, MD; Paaladinesh Thavendiranathan, MD; Allan S. Detsky, MD, PhD

JAMA. 2006;295:416-428.

Context  Hearing impairment is prevalent among the elderly population but commonly underdiagnosed.

Objective  To review the accuracy and precision of bedside clinical maneuvers for diagnosing hearing impairment.

Data Sources  MEDLINE and EMBASE databases (1966 to April 2005) were searched for English-language articles related to screening for hearing impairment.

Study Selection  Original studies on the accuracy or precision of screening questions and tests were included. Articles that used unaccepted reference standards or contained insufficient data were excluded. Medical Subject Headings or keywords used in the search included hearing loss, hearing handicap, hearing tests, tuning fork, deafness, physical examination, sensitivity, specificity, audiometry, tuning fork tests, Rinne, Weber, audioscope, Hearing Handicap Inventory for the Elderly–Screening version, whispered voice test, sensorineural, and conductive.

Data Extraction  One author screened all potential articles and 2 authors independently abstracted data. Differences were resolved by consensus. Each included study (n = 24) was assigned a methodological grade.

Data Synthesis  A yes response when asking individuals whether they have hearing impairment has a summary likelihood ratio (LR) of 2.5 (95% confidence interval [CI], 1.7-3.6); a no response has an LR of 0.13 (95% CI, 0.09-0.19). A score of 8 or greater on the screening version of the Hearing Handicap Inventory for the Elderly (HHIE-S) has an LR of 3.8 (95% CI, 3.0-4.8); a score less than 8 has an LR of 0.38 (95% CI, 0.29-0.51). An abnormal Weber tuning fork test response has an LR of 1.6 (95% CI, 1.0-2.3); a normal response has an LR of 0.70 (95% CI, 0.48-1.0). An abnormal Rinne tuning fork test response has LRs ranging from 2.7 to 62; a normal response has LRs from 0.01 to 0.85. Inability to perceive a whispered voice has an LR of 6.1 (95% CI, 4.5-8.4); normal perception has an LR of 0.03 (95% CI, 0-0.24). Not passing the audioscope test has an LR of 2.4 (95% CI, 1.4-4.1); passing has an LR of 0.07 (95% CI, 0.03-0.17).

Conclusions  Elderly individuals who acknowledge they have hearing impairment require audiometry, while those who reply no should be screened with the whispered-voice test. Individuals who perceive the whispered voice require no further testing, while those unable to perceive the voice require audiometry. The Weber and Rinne tests should not be used for general screening.

     

In vivo confocal microscopic findings of interlamellar stromal keratopathy induced by elevated intraocular pressure

We report the confocal microscopic findings in a case of interlamellar stromal keratopathy induced by elevated intraocular pressure (IOP) after laser in situ keratomileusis (LASIK). In vivo confocal microscopy showed swollen and enlarged cellular structures and the presence of microlacunae separating the stromal collagen lamellae. Inflammatory mononuclear cells and granulocytes typically seen in patients with diffuse lamellar keratitis (DLK) were absent. Stopping the topical steroids with concurrent lowering of the IOP resulted in improvement in the uncorrected and best corrected visual acuities and was associated with resolution of the corneal findings. In vivo confocal microscopy is a useful tool to study interlamellar stromal keratopathy induced by elevated IOP after LASIK in humans and the response to treatment and to differentiate interlamellar stromal keratopathy from DLK.