Activation of PKC induces rapid morphological plasticity in dendrites of hippocampal neurons via Rac and Rho-dependent mechanisms

Activation of protein kinase C (PKC) produced a novel and rapid formation of lamellae over large surfaces of dendrites in cultured hippocampal neurons. This action was dendrite-specific, involved a postsynaptic locus of activation of PKC and required actin polymerization, but not activation of Erk. Over-expression of active Rho-A GTPase converted a mature, highly branched and spiny neuron into a primitive, non-branching, aspiny neuron. Overexpression of active Rac1 caused massive lamellae formation in the transfected neurons. These morphologically aberrant neurons retained synaptic connectivity with adjacent, normal neurons, as well as the ability to form lamellae in response to PKC. On the other hand, transfection with a dominant negative Rac-N17 or a toxin C3, Rho-A-inactivating plasmid blocked lamellae formation by PKC, but did not prevent PKC-induced plasticity of synaptic currents. These data indicate that PKC activates two independent molecular pathways, one of which involves Rac1 and Rho-A, to produce massive actin-based structural plasticity in dendrites and spines.     

Contribution of synaptic depression to phase maintenance in a model rhythmic network

In many rhythmic neuronal networks that operate in a wide range of frequencies, the time of neuronal firing relative to the cycle period (the phase) is invariant. This invariance suggests that when frequency changes, firing time is precisely adjusted either by intrinsic or synaptic mechanisms. We study the maintenance of phase in a computational model in which an oscillator neuron (O) inhibits a follower neuron (F) by comparing the dependency of phase on cycle period in two cases: when the inhibitory synapse is depressing and when it is nondepressing. Of the numerous ways of changing the cycle period, we focus on three cases where either the duration of the active state, the inactive state, or the duty cycle of neuron O remains constant. In each case, we measure the phase at which neuron F fires with respect to the onset of firing in neuron O. With a nondepressing synapse, this phase is generally a monotonic function of cycle period except in a small parameter range in the case of the constant inactive duration. In contrast, with a depressing synapse, there is always a parameter regime in which phase is a cubic function of cycle period: it decreases at short cycle periods, increases in an intermediate range, and decreases at long cycle periods. This complex shape for the phase-period relationship arises because of the interaction between synaptic dynamics and intrinsic properties of the postsynaptic neuron. By choosing appropriate parameters, the cubic shape of the phase-period curve results in a small variation in phase for a large interval of periods. Consequently, we find that although a depressing synapse does not produce perfect phase maintenance, in most cases it is superior to a nondepressing synapse in promoting a constant phase difference.     

Fetal urinoma as a sign of a dysplastic kidney

We describe a female neonate in whom a urinoma was first diagnosed at 20 weeks of gestation without any evidence of underlying urinary tract obstruction. The urinoma became apparent following the performance of a "bloody tap" amniocentesis. Sequential ultrasonography, both fetal and up to 3 months after birth, showed eventual resorption of the urinoma in parallel with the development of a shrunken, non-functioning kidney. Except for the onset of high-renin hypertension, which spontaneously remitted at 1 year of age, the baby's postnatal course was uneventful. Renal function was normal. The presence of a fetal urinoma as a sign of a dysplastic kidney is discussed.     

Impact of subsidizing effective anti-osteoporosis drugs on compliance with management guidelines in patients following low-impact fractures

Early in 2000, proven-effective antiresorptive drugs (alendronate and raloxifene) were included in the national "health basket" in Israel. We carried out the present study to evaluate the effect of subsidizing antiosteoporosis drugs on the use of antiosteoporosis drugs in patients following low-impact fractures. The rates of dispensation of antiosteoporosis drugs, in the hospital and in the community, before and after an incident of a newly diagnosed low-impact fracture, respectively, were evaluated during January and February 1998 and 1999 ("pre-basket") and the corresponding months of 2000 and 2001 ("post-basket"). The study was carried out in a 950-bed teaching hospital, the only one serving the area, and the largest health maintenance organization in the area. Hospital charts of women and men age 50 years and older with new fractures following low- or moderate-impact trauma treated in the emergency room, or admitted to the orthopedic surgery and rehabilitation departments, were reviewed. A centralized pharmacy computerized database was used to follow antiosteoporosis drug dispensation in the community. A significant, approximately two-fold, increase in the baseline (before fracture) rate of osteoporosis drug dispensation was observed between the pre- and post-basket periods. The rate of patients treated after a fracture incident also increased significantly, 1.6 fold, in the post-basket period; however, even in the post-basket period, two-thirds of the patients remained untreated following a fracture incident, and most of those treated received only calcium and vitamin D; only 17% received potent antiosteoporosis drugs. In a multivariate analysis, female gender, hospitalization, having the incident of fracture in the post-basket period, and above all being treated for osteoporosis before the fracture incident, had the greatest effect on the likelihood of being treated following a low-impact fracture incident. The increase in the pooled use of antiosteoporosis drugs and/or calcium/vitamin D supplements was continuous, and subsidizing created no step-up effect, besides a transient increase in the use of potent antiosteoporosis drugs in the first year following the health-basket amendment. We conclude that while subsidizing may have a significant, positive effect on antiosteoporosis drug utilization, other factors may be even more important. There is an ongoing need to find ways to encourage the use of effective pharmacological interventions for primary and secondary prevention of osteoporotic fractures.     

Replacing the Amsler grid: a new method for monitoring patients with age-related macular degeneration

PURPOSE: To investigate a method that uses hyperacuity, the Macular Computerized Psychophysical Test (MCPT), to evaluate the central macular visual field in patients with age-related macular degeneration (AMD). DESIGN: Prospective case-control study of a diagnostic test. PARTICIPANTS AND CONTROLS: One hundred eight eyes of 108 Patients with AMD and 51 eyes of 51 age-matched patients with no retinal disease. Patients with AMD included 32 (30%) patients with choroidal neovascularization (CNV), 23 (21%) with geographic atrophy (GA), 35 (32%) with AMD with high-risk characteristics (HRC), and 18 (17%) with early AMD with non-HRC. TESTING: Each subject underwent the MCPT, in which a virtual line composed of dots (white dots on a black background, maximal contrast) is flashed across different macular loci to a perifoveal radius of 7 degrees. Patients' responses were recorded and automatically analyzed using a specific algorithm developed before the onset of the study. All patients also underwent a supervised Amsler grid examination on the encounter before or after the MCPT in random order. MAIN OUTCOME MEASURES: Distortion, scotoma, or blurring perceived by the patient after a swift change of fixation was considered positive on the MCPT. Any perception of distortion, scotoma, or blurring was considered positive on the Amsler grid. RESULTS: Of the 32 patients with CNV, 30 (94%) were found positive on the MCPT and 11 (34%) were found positive on the Amsler grid. Of the 23 GA patients, 21 (91%) were found positive on the MCPT and 7 (30%) were found positive on the Amsler grid. Of the 35 HRC patients, 28 (80%) were found positive on the MCPT and 3 (9%) were found positive on the Amsler grid, and of the 18 early AMD with non-HRC patients, 8 (44%) were found positive on the MCPT and 3 (17%) were found positive on the Amsler grid. Of the 51 controls, 3 (6%) were positive on the MCPT and 1 (2%) was positive on the Amsler grid. CONCLUSIONS: The MCPT was superior to the Amsler grid in detecting AMD-related lesions in this cohort. Studies are underway to determine whether the MCPT is feasible for home monitoring to provide early detection of progression to CNV.     

Contact lenses for the treatment of pediatric cataracts

OBJECTIVE: To evaluate the experiences, attitudes, and perceptions of the caregivers of children with cataracts who were visually rehabilitated with contact lenses. PARTICIPANTS: One hundred twenty-three caregivers of children <8.1 years old treated for unilateral and bilateral cataracts at one pediatric hospital. DESIGN: Survey by questionnaire. INTERVENTION: Primary caregivers were asked to complete an anonymous questionnaire. MAIN OUTCOME MEASURES: Caregiver responses to questions assessing background and demographic and clinical information, as well as perceptions, attitudes, levels of compliance, and anxiety with respect to treatment, were reviewed. Caregivers were also asked to choose between aphakic rehabilitation with contact lenses, aphakic glasses, or intraocular lenses, given various hypothetical scenarios differing in regard to their final visual prognosis, risks of treatment complications, and cost. RESULTS: The response rate was 82.9%. Absolute average stress levels for contact lens use were 1.36 +/- 1.79 and 0.79 +/- 1.48 (scale, 0-5) for insertion and removal, respectively, compared with 4.03 +/- 1.64 and 2.40 +/- 1.92 for cataract surgery and patching therapy, respectively. Although average paired initial resistance to treatment (RT) levels for contact lens insertion and removal on a scale of 0 to 3 were high (2.09 +/- 1.15) and moderate (1.63 +/- 1.20), respectively, final RT levels were significantly lower (1.09 +/- 1.14 and 0.66 +/- 1.07, respectively; P < 0.0001). The vast majority of caregivers chose contact lens use in hypothetical scenarios that depicted realistic expectations for other forms of aphakic rehabilitation. CONCLUSIONS: In our study, contact lenses seemed to be well tolerated by most patients, as assessed by caregivers. Although initial resistance to contact lens use is high, this decreases with time. Relative to other events in the treatment of pediatric cataracts, contact lens use is not a major stressor for most caregivers and patients. This study supports the notion that contact lenses should continue to receive serious consideration as a treatment option for pediatric cataracts.     

Successful resuscitation after ropivacaine-induced ventricular fibrillation

Human data about resuscitation after cardiac arrest from ropivacaine are limited. We present a case of successful cardiopulmonary resuscitation after accidental ropivacaine-induced ventricular fibrillation. A 76-yr-old female patient presented for foot osteotomy. A femoral block was performed using a nerve stimulator, a short bevel needle and 20 mL of 1.5% mepivacaine with 1:400,000 epinephrine. The patient remained relaxed and conversant. Five minutes later, an anterior sciatic block was done with 0.5% ropivacaine with 1:400,000 epinephrine for prolonged analgesia. Despite a negative aspiration and incremental injection, the patient developed a tonic-clonic seizure, then gradual widening of the QRS complex, and subsequently ventricular fibrillation. The patient was resuscitated with chest compressions and airway support prior to pharmacologic treatment of defibrillation. Total venous ropivacaine concentration 5 min after the last injection was 3.2 mg/L, free ropivacaine was 0.5 mg/L, and total mepivacaine was 0.22 mg/L. The patient was admitted to the hospital and discharged the next morning without complications. This case demonstrates that techniques used to detect intravascular injection may reduce but not eliminate catastrophic events. Consequently, regional anesthesia using large amounts of local anesthetic should be done in locations with resuscitation equipment and by individuals trained to recognize these complications and begin early treatment.     

Prognostic assessment of gastrointestinal stromal tumor

The term "gastrointestinal stromal tumor" (GIST) has been applied to a collection of distinctive mesenchymal tumors occurring within the human gastrointestinal tract. As new drug therapy becomes available, data regarding the natural history of these unusual tumors are necessary to provide selection factors for treatment. Ninety-eight patients had light microscopy compatible with GIST at a single institution from 1989 to 2000. After immunostaining with c-kit and histopathologic review, 69 were judged to be GIST. All prognostic indicators were determined for gastric GIST, intestinal GIST, and all locations combined. The location of the GIST did not have a significant impact on survival. Clinically, tumor size, peritoneal cancer index, and completeness of cytoreduction had a significant impact on prognosis for GIST at all locations. Pathologically, cytologic atypia, necrosis, invasion and number of mitoses were significant prognostic indicators for GIST. Criteria to separate three pathologic groups of GIST according to the tumor size and the mitotic count were useful to evaluate the tumor behavior; in the borderline pathologic group invasion and cytologic atypia were statistically significant prognostic criteria. The cell phenotypes, as determined by immunostains, correlated with the prognosis of gastric GIST but not intestinal GIST. A correlation between the immunostain Ki-67 but not CD-34 or desmin and the prognosis was observed. It is possible to select clinical and pathologic parameters of GIST that impact on prognosis. Invasion and necrosis help to determine the prognosis with borderline tumors. The immunostain Ki-67 correlated with the prognosis and may be helpful to assess prognosis when dealing with small biopsy specimens.