TGF-ß signaling is required for maintenance of retinal ganglion cell differentiation and survival.

PURPOSE: To determine the role of TGF-ß1 in the maintenance of retinal ganglion cell line (RGC-5) differentiation and integrity. METHODS: RGC-5 cells were differentiated in media conditioned by human non-pigmented ciliary epithelial cells (HNPE) for 4 days before treatment with TGF-ß1 for 24 h. Cells were examined for morphological changes and harvested for western blot and real-time PCR analysis. For study of apoptosis, differentiated RGC-5 cells were grown in serum-free medium for 24 h in the presence or absence of TGF-ß1 and collected for Annexin V/Propidium iodide FACs analysis. The role of MAPK pathways in TGF-ß1-dependent signaling was determined by treatment with specific inhibitors of ERK, JNK and p38. RESULTS: Differentiation of RGC-5 cells in HNPE-conditioned media (CM) increased the neural cell markers, Brn-3c, NF-160, Thy1.2, Tau and PGP9.5. Treatment with TGF-ß1 significantly increased the length of neurites extended by differentiated RGC-5s, concomitant with increased expression of NF-160 and PGP9.5, but not Brn-3c, Thy1.2 or Tau. TGF-ß1 also decreased RGC-5 cell apoptosis in serum-free medium. p38 phosphorylation, but not smad2/3, JNK or ERK phosphorylation, was increased in TGF-ß1 treated cells. Specific inhibition of p38 signaling reversed TGF-ß1 induced neurite growth. CONCLUSIONS: These findings demonstrate the induction of RGC-5 cell differentiation by HNPE-derived CM and illustrate a role for TGF-ß1 in maintaining RGC-5 cell survival and promoting neurite outgrowth through p38 MAPK.

Isolated pancreatic metastases from a bronchogenic small cell carcinoma.

We describe the case of a 60 year old female smoker who presented with a three month history of weight loss (14 Kg), generalized abdominal discomfort and malaise. Chest radiography demonstrated a mass projected inferior to the hilum of the right lung. Computed Tomography of thorax confirmed a lobulated lesion in the right infrahilar region and subsequent staging abdominal CT demonstrated a low density lesion in the neck of the pancreas. Percutaneous Ultrasound guided pancreatic biopsy was performed, histology of which demonstrated pancreatic tissue containing a highly necrotic small cell undifferentiated carcinoma consistent with metastatic small cell carcinoma of the bronchus.

Safety of mirtazapine in overdose.

INTRODUCTION: We report 6 confirmed cases of substantial overdose with mirtazapine, a new antidepressant compound, that occurred up to January 1997 in the United States during postmarketing surveillance or in the clinical trials. RESULTS: In 6 patients, the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, and there were no serious adverse effects of overdose. Two patients at special risk, a 90-year-old man and a 3-year-old child, took higher-than-usual doses without serious sequelae. The 4 patients who combined other central nervous system (CNS) depressants with mirtazapine appeared to experience more CNS depression. One patient who ingested 60 mg of alprazolam had clinically significant respiratory depression in the emergency room but recovered fully within 24 hours. CONCLUSION: After an overdose of substantial multiples of mirtazapine that exceed the maximum recommended daily dosage, the new antidepressant mirtazapine appears to be safe in a limited number of cases.

Neurological concepts in archaic Greece: what did Homer know?

There are few written records which tell us about Archaic Greek thought and certainly no medical writings. The earliest notions about neurologic matters can be found, however, in the Homeric epics. The attitudes and information which made up the culture of the Archaic Greeks were the starting point from which the later Greek medical literature grew. Although the Odyssey and Iliad are not medical texts, they contain many neurologic descriptions which can be analyzed to reveal the knowledge and concepts which were held by the people in Archaic Greece. By knowing the beginnings of the ancient medical traditions one is better equipped to understand the later works written specifically about medical matters.

Randomized trial of Cervene, a kappa receptor-selective opioid antagonist, in acute ischemic stroke.

The purpose of this randomized trial was to confirm drug safety and to obtain preliminary efficacy data on Cervene (nalmefene), an opioid antagonist with relative kappa receptor selectivity, for the treatment of acute ischemic stroke. Patients were treated for 24 hours with either intravenous Cervene (0.05 mg/kg as an initial infusion over 15 minutes and 0.01 mg/kg/h maintenance) or placebo within 6 hours of an ischemic stroke. Efficacy was assessed by comparing the change from baseline to day 7 in the National Institutes of Health stroke scale score (NIHSSS) and the Glasgow Outcome Scale and Barthel Index at 3 months. Forty-four evaluable patients were randomized (3:1) to Cervene (n = 34; treated at 5.0 +/- 0.9 hours after onset) and placebo (n = 10; treated at 4.6 +/- 1.5 hours). No deaths or serious adverse events reasonably attributable to Cervene have been reported. A "major improvement" (NHSSS > 4) was seen at day 7: placebo, 33% (three of nine patients) and Cervene, 66% (19 of 29 patients). Only patients with initial NIHSSS >/= 4 were considered evaluable for this primary endpoint. "Good recovery" at 3 months (Glasgow = 5) was as follows: placebo, 50% (5 of 10 patients) and Cervene, 73% (24 of 33 patients). The death rate at 3 months was placebo, 20% (2 of 10 patients) and Cervene, 9.1% (3 of 33 patients). One patient was lost to follow-up. In conclusion, results from this randomized trial suggest that Cervene is safe, tolerable, and may be beneficial in the treatment of acute stroke patients.

Two combined, multicenter double-blind studies of paroxetine and doxepin in geriatric patients with major depression.

Depressive illness among the elderly is an important public health concern. However, treatment of the elderly may be complicated by age-related changes in physiology, general medical status, and susceptibility to side effects. There is therefore a need for improved treatment modalities for depressed elderly patients. Paroxetine is an antidepressant that acts through selective inhibition of serotonin reuptake. It lacks the anticholinergic and cardiovascular side effects of most first- and second-generation antidepressants. The authors present the combined data from two similarly designed comparisons of paroxetine and doxepin in outpatients over 60 years of age with major depression. The results show that paroxetine was an effective as doxepin in alleviating depression as measured on the Hamilton Rating Scale for Depression (HAM-D) total score, the Montgomery and Asberg Depression Rating Scale (MADRS), and the Hopkins Symptom Checklist (SCL) depression factor score. Paroxetine was significantly superior to doxepin on the Clinical Global Impressions (CGI) scale for severity of illness, the HAM-D retardation factor, and the HAM-D depressed mood item. Doxepin produced significantly more anticholinergic effects, sedation, and confusion. Paroxetine was associated with more reports of nausea and headache. These results suggest that paroxetine may be a valuable tool for the treatment of major depression in the elderly.

Blocking the Ca(2+)-activated cytotoxic mechanisms of cholinergic neuronal death: a novel treatment strategy for Alzheimer's disease.

The major neuropathological finding in Alzheimer's disease (AD) is the death of cholinergic cell bodies originating in the nucleus basalis of Mynert. This paper will review the data suggesting that a pharmacologic strategy designed to slow the rate of cholinergic neuronal death (CND) should be of palliative value in the treatment of AD. Recent data on the biology of cell death (CD) show that there are two patterns of CD: necrosis and apoptosis or genetically controlled, programmed cell death. Regardless of whether cells die by necrosis or apoptosis, four Ca(2+)-activated cytotoxic mechanisms are triggered. Cytosolic free [Ca2+]i increases with aging. After 75 years, this rise may lead to the activation of a putative apoptotic gene in AD that results in CND. Since the increase in cytosolic [Ca2+]i may be mediated by the voltage operated L-type Ca2+ channel on the neuronal cell body, chronic treatment with an L-channel blocker, like nimodipine, might palliate the progression of and possibly prevent the majority of cases of AD.

Dementia in Parkinson's disease: the problem of clinicopathological correlation.

Four cases of Parkinson's disease with advanced dementia are described. Postmortem examination revealed cell loss in the substantia nigra, with Lewy bodies present, and loss of cells in the basal nucleus of Meynert. A few tangles were observed in the hippocampus, but no senile plaques or neurofibrillary tangles were found in the neocortex. The authors note that a dramatic dementia syndrome may occur with Parkinson's disease alone, without the associated cytoskeletal markers of Alzheimer's disease. Cases were characterized by disorientation, episodic confusion and hallucinations persisting off medication, disturbed behavior, and the absence of aphasia.

Decreased iodine-123 IMP caudate nucleus uptake in patients with Huntington's disease.

To determine whether I-123 isopropyl iodoamphetamine (IMP) uptake is reduced in the basal ganglia of patients with Huntington's disease compared with that in aged-matched normal and abnormal control subjects, a caudate ratio was defined that compared the average separation (in pixel units) between the midline and the left and right caudate heads to the width of the brain as measured on transaxial cross-sections of I-123 IMP SPECT brain images. For six patients with Huntington's disease, the average caudate ratio was 29.0% (SD +/- 2.7%), significantly higher than that for 12 normal volunteer subjects (average caudate ratio, 19.1% +/- 3.5%; p less than 0.001) and 13 patients with a variety of other neurologic disorders (average caudate ratio, 19.3 +/- 2.2%; p less than 0.001).

Neurologic examination of the elderly patient. Signs of normal aging.

Once the signs of normal aging are recognized, findings that indicate aging alone can be separated from those that clearly suggest a focal neurologic lesion. Using the patient's history and other data, the physician can relate the findings to the complaints. However, it behooves the physician to explain all the findings on the examination and not merely blame the aging process for every neurologic sign.

Cerebral perfusion imaging in Alzheimer's disease. Use of single photon emission computed tomography and iofetamine hydrochloride I 123.

We used single photon emission computed tomography (SPECT) to study 15 patients with Alzheimer's disease and nine controls. Iofetamine hydrochloride I 123 uptake data were recorded from the entire brain using a rotating gamma camera. Activity ratios were measured for the frontal, posterior parietal, posterior, medial, and lateral cortical temporal regions and striate cortex and were normalized by the activity in the cerebellum. Abnormalities in iofetamine hydrochloride I 123 activity were similar to the abnormalities in glucose metabolism observed with positron emission tomography. Cortical tracer activity was globally depressed in patients with Alzheimer's disease, with the greatest reduction in the posterior parietal cortex.

Persistent vegetative state. Extension of the syndrome to include chronic disorders.

Twenty-nine institutionalized patients had the vegetative state as a sequela of chronic progressive neurologic disorders. During three years, the state was persistent; none improved, ten died. Eight similar patients were reviewed retrospectively post mortem. Eight patients with severe dementia, while acutely ill or sedated, temporarily met the criteria for persistent vegetative state (PVS) but improved when the underlying condition was treated. Abnormalities on electroencephalography or computed tomographic scan are not specific for the PVS. Electroencephalograms were normal in three patients with PVS. The computed tomographic scans showed extensive destruction of the brain parenchyma but were not different from those of severely demented patients without the PVS. The PVS is a feature of the terminal phase of several progressive neurologic disorders. Patients should be treated without excessive intervention.

Physiologic analysis of the myoclonus of Alzheimer's disease.

Ten patients with clinically diagnosed Alzheimer's disease, including three cases of trisomy 21 (Down's syndrome), developed a chronic myoclonic disorder. The technique of jerk-locked averaging of EEG activity was used to analyze the myoclonus. Seven subjects demonstrated a focal, contralateral central, negative cerebral potential antecedent to the myoclonic jerks. This EEG event differs from that previously reported to be associated with the myoclonus of subacute spongiform encephalopathy (Creutzfeldt-Jakob disease).

Huntington's disease in monozygotic twins reared apart.

Monozygotic twins, identical by serological studies, with Huntington's disease are described who were raised in separate households from birth. Age at onset, landmarks of the disease, and behavioural abnormalities were strikingly similar. Previously reported twin studies in Huntington's disease are reviewed. Twin data support the hypothesis that age at onset and several other clinical features of the illness are substantially determined by genetic mechanisms.

Carbon monoxide poisoning with features of Gilles de la Tourette's syndrome.

A previously healthy 58-year-old man had severe carbon monoxide poisoning. Following a comatose state, tics of the head, coprolalia, fits of shouting, and abnormal vocal utterances developed. In addition to the signs of diffuse encephalopathy, he had some of the features associated with idiopathic Gilles de la Tourette's syndrome. The computed tomographic scan showed ventricular enlargement and low-density areas in the basal ganglia.

Malignant transformation in benign cerebellar astrocytoma. Case report.

The authors give follow-up information on Case 59 of Cushing's 1931 series of cerebellar astrocytomas. The patient died with a malignant cerebellar astrocytoma 48 years after partial removal of a previously benign astrocytoma at the same site. Including the present one, there have been only five reported cases in which this has occurred. Ordinarily, juvenile pilocytic astrocytomas are of extremely genign character, and it is well established that even with incomplete resections patients have survived for years without progression of the tumor. Not all of the cases so reported can be wholly accepted as respresenting malignant transformation of the tumor, but may instead be instances of recurrence of an inherently benign glioma since the presence of features such as endothelial hyperplasia or nuclear atypicality in a juvenile pilocytic astrocytoma does not warrant is being classified as malignant. Features truly suggestive of malignancy are hypercellularity, frequent mitoses, necrosis, and, in some instances, a diffusely infiltrative growth pattern; all of these features were found in the present case.

Thalamic hemorrhage: a computed tomographic-clinical correlation.

An analysis has been made of the clinical manifestations in 18 cases of hypertensive thalamic hemorrhage diagnosed by computed tomography (CT). CT scans permitted accurate determination of the site, size, and extension of the hemorrhages. A sensorimotor hemiplegia or hemiparesis was present in all cases. Diagnostic clinical features included limitation of vertical gaze, downward deviation of the eyes, and small unreactive or sluggish pupils. All hemorrhages larger than 3.3 cm in diameter were fatal.