Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine transporters

Our structure-activity relationship (SAR) study on piperidine analogues for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, structurally constrained versions of flexible piperidine analogues, with preferential affinity for the dopamine transporter (DAT). In our attempt to further rigidify this structure to study influence of rigidity on binding and in vivo activity, we have developed a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. All synthesized derivatives were tested for their affinity at the DAT, serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [(3)H]WIN 35, 428, [(3)H]citalopram, and [(3)H]nisoxetine, respectively. Selected compounds were also tested for their ability to inhibit uptake of [(3)H]DA. The SAR study led to the discovery of a potent lead compound (-)-S,S-10c which exhibited high affinity and selectivity for the DAT (IC(50) = 22.5 nM; SERT/DAT = 384 and NET/DAT > 444). It is interesting to note that both (-)-10c and the lead compound from the 3,6-disubstituted series (-)-2 exhibited highest activity in their (S,S) isomer indicating similar requirement of regiospecificity for maximum interaction. Overall, our current SAR results corresponded well with the results from less constrained 3,6-disubstituted versions of these molecules albeit the former class exhibited more stringent requirement in molecular structure for activity. However, the potent compounds in the current series exhibited greater selectivity for the DAT compared to their corresponding lesser constrained 3,6-disubstituted versions indicating an effect of rigidity in selective interaction with the transporter proteins. In an effort to elucidate the bioactive conformational structure of the lead molecules in the current and the 3,6-disubstituted series, a preliminary molecular modeling study was carried out where the most rigid derivative (-)-10c was used as a template structure. Compounds (-)-2 and (-)-10c exhibited stimulant activity in locomotor tests in mice in which (-)-2 exhibited a slower onset and longer duration of action compared to (-)-10c. Both compounds occasioned complete cocaine-like responding in mice trained to discriminate 10 mg/kg ip cocaine from vehicle.     

MR imaging in toxoplasmosis encephalitis after bone marrow transplantation: paucity of enhancement despite fulminant disease

We present a patient who underwent bone marrow transplantation (BMT) after developing chronic myelocytic leukemia. Four months after BMT, he became comatose and died. MR imaging revealed multifocal brain lesions that were progressive but produced no edema. Postcontrast studies revealed that most of the lesions were nonenhancing. There was only discrete, irregular leptomeningeal enhancement with possible minimal enhancement of the cortex and subcortical white matter. Autopsy showed overwhelming toxoplasmosis encephalitis. This case illustrates that toxoplasmosis lesions may lack obvious contrast enhancement in the brain of the immunocompromised patients, despite severe involvement. Recognition of this unusual MR imaging manifestation of toxoplasmosis should lead to earlier diagnosis and treatment.     

Unmasking of ocular bobbing associated with jaw movement following inferior rectus surgery

MG phenomenon refers to involuntary lid movements associated with jaw movements. We report a case unilateral vertical movement of the globe in a case of monocular elevation deficit. The above mentioned movement may be an unreported variant of oculo-trigemial synkinesis.     

Resident glaucoma surgical training in United States residency programs

PURPOSE: To determine current trends in resident glaucoma surgical training throughout the United States. METHODS: A comprehensive survey was sent to the residency director of all 121 ACGME-accredited ophthalmology training programs in the United States. RESULTS: The mean and median number of glaucoma procedures a resident will complete by the end of their training is 8.6 and 8 respectively for trabeculectomy, 5.3 and 4 for combined trabeculectomy/phacoemulsification, and 3.6 and 2 for tube-shunts. One percent of residents will gain experience as primary surgeon on trabeculectomies during their first year, 32% during their second year, and 67% during their third year. Seventy-five percent of residents are taught more than one trabeculectomy technique by more than one staff surgeon. Eighty-four percent of residents are taught glaucoma surgery almost exclusively by fellowship-trained glaucoma surgeons. Eighty-two percent of residents use antimetabolites (mitomycin C or 5-FU) as an adjunct to trabeculectomy most or all of the time. More than 96% of resident tube-shunt procedures use Ahmed, Baerveldt, or Molteno devices. Eighty percent of residents do not perform any pediatric glaucoma surgeries. Sixty-two percent of residents rotate out of their main facility to perform glaucoma surgery. CONCLUSIONS: Residents are being exposed to glaucoma surgery early in their residency training. Most are performing a variety of different procedures and techniques, and are taught by fellowship-trained surgeons. Residents gain very little exposure to pediatric glaucoma surgery. All programs reported compliance with minimum RRC requirements for glaucoma filtering surgery.     

Immunoreactive estrogen receptor in breast tumor and adjacent tissue: association with clinicopathological characteristics in Indian population

BACKGROUND AND OBJECTIVES: Estrogen receptor (ER) status serves as an important prognostic marker in the management of breast cancer. The level of ER in breast tumor is different in different racial and ethnic groups. In the present study, we have compared the ER levels in breast tumor and adjacent normal tissue in Indian sub-population. METHODS: Immunoreactive ER was measured by enzyme immunoassay in breast tumors (ERt) and adjacent area (ERa) derived from 45 breast cancer patients from North India. Clinical parameters like age, menopausal status, tumor stage, recurrence and treatment status were recorded. RESULTS: A significant positive correlation was observed between the levels of ERt and ERa (r = 0.386, P = 0.009). While the ERt levels increased with advancing age (P = 0.087), the ERa levels did not change in different age groups. The ERt levels negatively correlated with tumor stage and recurrence (r = -0.263, P = 0.110 and r = -0.202, P = 0.189). A significant negative correlation was also observed between the ERa levels and tumor recurrence (r = -0.337, P = 0.025). Further, the ERt positivity was higher than the ERa positivity. The clinical characteristics like age, tumor stage, metastasis, recurrence, and treatment status did not correlate with ERt and ERa positivity. CONCLUSIONS: The present study shows that the levels of ERt and ERa positively correlate and both ERt and ERa show negative correlation with tumor recurrence.     

Reactive EEG patterns in pediatric coma

This study was designed to determine whether the observed reactive electroencephalographic patterns in comatose children were associated with a better outcome. All electroencephalograms performed in comatose children aged 2 months to 18 years during the period 1996-2003 were retrospectively analyzed and classified according to modified Young's classification. Reactivity to painful/auditory stimuli and passive eye closure (at least two modalities) was checked in all electroencephalograms. The clinical outcome at 1 year or during the last clinic/inpatient follow-up was scored according to the Pediatric Cerebral and Overall Performance Category Scale. Outcomes were then compared using Fisher exact test and the Mann-Whitney test. Thirty-three patients had electroencephalography within 72 hours after the onset of coma. Fourteen of 33 electroencephalograms revealed reactive patterns. Outcome was unfavorable in 4 (28.6%) of these patients. Three children had no residual neurologic impairment. Among the 19 children with nonreactive electroencephalogram, 13 (65%) had unfavorable outcome, which included 10 deaths. All the survivors had residual neurologic impairment. Outcome was better in children with reactive electroencephalographic patterns (Fisher exact test; P = 0.023). Comatose children with reactive electroencephalographic patterns have better clinical outcome in terms of morbidity and mortality. A careful assessment of electroencephalographic reactive patterns in all comatose children is required for better understanding of the clinical outcome.