Genetic ablation of the p66Shc adaptor protein reverses cognitive deficits and improves mitochondrial function in an APP transgenic mouse model of Alzheimer's disease.

The mammalian ShcA adaptor protein p66Shc is a key regulator of mitochondrial reactive oxygen species (ROS) production and has previously been shown to mediate amyloid ß (Aß)-peptide-induced cytotoxicity in vitro. Moreover, p66Shc is involved in mammalian longevity and lifespan determination as revealed in the p66Shc knockout mice, which are characterized by a 30% prolonged lifespan, lower ROS levels and protection from age-related impairment of physical and cognitive performance. In this study, we hypothesized a role for p66Shc in Aß-induced toxicity in vivo and investigated the effects of genetic p66Shc deletion in the PSAPP transgenic mice, an established Alzheimer's disease mouse model of ß-amyloidosis. p66Shc-ablated PSAPP mice were characterized by an improved survival and a complete rescue of Aß-induced cognitive deficits at the age of 15 months. Importantly, these beneficial effects on survival and cognitive performance were independent of Aß levels and amyloid plaque deposition, but were associated with improved brain mitochondrial respiration, a reversal of mitochondrial complex I dysfunction, restored adenosine triphosphate production and reduced ROS levels. The results of this study support a role for p66Shc in Aß-related mitochondrial dysfunction and oxidative damage in vivo, and suggest that p66Shc ablation may be a promising novel therapeutic strategy against Aß-induced toxicity and cognitive impairment.

Corticosteroids for the management of severe intracranial hypertension in meningoencephalitis caused by Cryptococcus gattii: A case report and review.

Immune reconstitution inflammatory syndrome in meningitis caused by Cryptococcus gattii in immunocompetent patients after initiation of antifungal therapy appears to be the result of paradoxical antifungal treatment-induced clinical deterioration due to improved local immune responses to cryptococcal organisms. Recent anecdotal reports have suggested a favorable clinical response to corticosteroids in select patients with C. gattii central nervous system (CNS) infections. In this report, we describe a 65-year-old patient with meningoencephalitis caused by C. gattii who developed persistent intracranial hypertension and was successfully managed with antifungal therapy, repeated lumbar puncture and corticosteroids. Our observations suggest a possible benefit of dexamethasone in the management of select cases of C. gattii CNS infection with intracranial hypertension. Further studies are necessary to evaluate the long-term use of steroids in select patients with C. gattii with intracranial hypertension.

Neonatal hyperviscosity: I. Incidence.

Capillary hematocrits were performed on 790 infants during the first four hours after birth. These infants were delivered between August 8 and December 7, 1974, at the University of Colorado Medical Center, which is at an altitude of 1,061 m above sea level. When the capillary hematocrit was 7% or greater, venous hematocrit and blood viscosity were determined. Capillary hematocrits obtained from warmed heels in the first hour after birth were spuriously high and not consistently related to venous hematocrit. Venous polycythemia, defined as a hematocrit of 65% or greater, occurred in 4% of the newborn population. Hyperviscosity (greater than 2 SD above the mean for newborns) occurred in 5% of the newborn infants. At a venous hematocrit of 65% or greater, hyperviscosity was predictable, but some infants with venous hematocrits between 60% and 64% also had hyperviscosity of the blood. The incidence of polycythemia and hyperviscosity was further related to birth weight and gestational age. The infants who were small for gestational age were at highest risk of polycythemia and hyperviscosity, followed by infants who were large for gestational age. However, the greatest number of infants with hyperviscosity were term appropriate for gestational age. Preterm infants with gestational ages of less than 34 weeks were not affected.

Neonatal hyperviscosity. II. Effect of partial plasma exchange transfusion.

To determine the effect of partial plasma exchange transfusion, 20 newborn infants with neonatal hyperviscosity were randomly assigned to observation or treatment with partial plasma exchange transfusion within the first eight hours after birth. They were studied for organ involvement by roentgenogram, blood count, coagulation studies, and neurologic behavior and were followed up using the Brazelton Neonatal Behavior Assessment scale at 8, 24, and 72 hours and 2 weeks of age; in addition, ten control infants without hyperviscosity of similar birth weights and gestational ages were also studied. Exchange transfusion improved blood viscosity but both hyperviscous groups showed a higher proportion of abnormal results than did the control subjects. Infants receiving exchange transfusions subsequently improved during the period from 8 hours to 2 to 3 weeks of age, until they were indistinguishable from the control subjects. Neurologic improvement in hyperviscous infants who had not received exchange transfusions were significantly slower during this period. At 8 months of age, abnormal neurologic and developmental findings were impressive in both groups; no significant differences in neurologic abnormalities were noted at that time. Developmental delays, tremors, spastic diplegia, and monoparesis were found in four of six untreated infants and five of ten infants who had received exchange transfusions. A fine tremor was present in one control child.

Kinetic nephelometric determination of transthyretin and retinol-binding protein in neonatal serum.

We have developed a kinetic immunonephelometric method for the determination of retinol-binding protein and modified the method of Jacob et al (Clin Chem 1983; 29: 564) for the determination of transthyretin (prealbumin) in neonatal serum specimens from small, premature infants. The methodologies allow detection of 17.5 mg/l transthyretin and 1.7 mg/l retinol-binding protein in 25 microliter of serum. Between-run precision studies using pooled neonatal serum gave CV values of 3% and 5-6% for transthyretin and retinol-binding protein, respectively. Results obtained for neonatal specimens using this method agreed well with those obtained for the same specimens using radial immunodiffusion. Mean (SD) serum concentrations for 39 neonatal specimens were 100.4 (46.6) and 26.3 (10.8) mg/l for transthyretin and retinol-binding protein, respectively.

Reversible somatosensory evoked potential changes with neodymium: yttrium-aluminum-garnet laser use.

Reversible prolongation and dissolution of the tibial somatosensory evoked potential (SEP) was observed with operative use of the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser during extirpation of a foramen magnum meningioma. Rapid normalization of the SEP followed irrigation with cool saline. The absence of postoperative dorsal column deficit suggests that heat-related physiological changes occurred before the point of irreversible tissue injury. Should intraoperative SEP monitoring prove a reliable index of tissue temperature, it could enable safer use of the Nd:YAG laser in the vicinity of the spinal cord and brain stem.

Surgical treatment of incidental intracranial aneurysms.

A 6-year retrospective analysis of incidental intracranial aneurysm surgery was conducted at 12 medical centers (1975-1981). The surgical facilities and techniques were comparable at the institutions surveyed. From a total of 1671 aneurysms operated upon, 119 in 107 patients were unruptured and were discovered incidentally. Among these 107 patients, there was no operative mortality. Operative morbidity occurred in 7 cases (6.5%). Surgical treatment of large aneurysms in less accessible locations incurred the greatest operative morbidity. Presenting symptoms of cerebral ischemia seemed to be associated with increased operative morbidity, whereas repair of aneurysms incidental to other ruptured aneurysms had a uniformly low morbidity. These surgical results compare favorably with the risks of hemorrhage from unruptured intracranial aneurysms as defined by recent reports. The low morbidity without mortality supports a recommendation for surgical management of incidental aneurysms in the anterior circulation at centers equipped for modern aneurysm surgery.

Experience with the neodymium:yttrium-aluminum-garnet laser in forty-two cases.

The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser has been utilized in the treatment of 42 cases during the past 2 years at two institutions. The laser was used under investigational permits from the Food and Drug Administration. It was found to be of particular value in the treatment of vascular intracranial tumors, especially meningiomas, and metastatic tumors of the spine. The ability of the laser to shrink and devascularize these tumors was efficacious as a surgical adjunct. Laser treatment of tumor attachments, especially those of meningiomas to the skull base, seemed to be effective in eradication of residual tumor. Long term benefits of such therapy, however, remain unproven. Because of the penetrating ability of the Nd:YAG laser beam, this device must be used with care by surgeons experienced in its use to prevent injury to adjacent structures.

Ocular motor dysfunction in total and hemicerebellectomized monkeys.

Studies of ocular motor function in monkeys undergoing either total or hemicerebellectomies has revealed the following abnormalities which can be attributed to cerebellar dysfunction: 1. Loss of smooth pursuit movements 2. Gaze-fixation nystagmus 3. Loss of inhibitory input on the vestibular apparatus reflected in a decreased latency and prolonged response to caloric stimuli. It is intimated that the role of the hemicerebellum deals with ipsilateral tone and its effect on eye movements.

Anterior cervical discectomy: is fusion necessary?

OBJECT: A prospective, randomized trial was performed to compare the efficacy of anterior cervical discectomy (ACD) with ACD and fusion (ACDF) for the treatment of cervical spondylosis in patients with neurological compromise. METHODS: Forty-four patients underwent ACD and 40 underwent ACDF. Operative time and length of hospital stay were shorter and there was less need for analgesia in the ACD group. It was found that whereas the incidence of fusion was greater in the ACDF group compared to the ACD group (97 compared with 70%, respectively; p<0.01), patient satisfaction and a return to preoperative activity level was similar between groups. CONCLUSIONS: Analysis of the results suggests that the addition of a fusion procedure may be unnecessary.

Rupture of previously documented small asymptomatic saccular intracranial aneurysms. Report of three cases.

In a recent study from the Mayo Clinic on the natural history of intact saccular intracranial aneurysms, none of the aneurysms smaller than 10 mm in diameter ruptured. It was concluded that these aneurysms carry a negligible risk for future hemorrhage and that surgery for their repair could not be recommended. These findings and recommendations have been the subject of much controversy. The authors report three patients with previously documented asymptomatic intact saccular intracranial aneurysms smaller than 5 mm in diameter that subsequently ruptured. In Case 1, a 70-year-old man bled from a 4-mm middle cerebral artery aneurysm that had been discovered incidentally 2 1/2 years previously during evaluation of cerebral ischemic symptoms. A 10-mm internal carotid artery aneurysm and a contralateral 4-mm middle cerebral artery aneurysm had not ruptured. Case 2 was that of a 66-year-old woman who bled from a 4-mm pericallosal aneurysm that had been present 9 1/2 years previously when she suffered subarachnoid hemorrhage (SAH) from a 7 x 9-mm posterior inferior cerebellar artery aneurysm. Although the pericallosal aneurysm had not enlarged in the intervening years, a daughter aneurysm had developed. The third patient was a 45-year-old woman who bled from a 4- to 5-mm posterior inferior cerebellar artery aneurysm that had measured approximately 2 mm on an angiogram obtained 4 years previously; at that time she had suffered SAH due to rupture of a 5 x 12-mm posterior communicating artery aneurysm. These cases show that small asymptomatic intact saccular intracranial aneurysms are not innocuous and that careful consideration must be given to their surgical repair and long-term follow-up study.

Atypical fibromuscular hyperplasia. Report of two cases.

Two cases of atypical fibromuscular hyperplasia of the internal carotid artery (ICA) are reported. These cases are unique because the changes involve the intima of the vessels without involvement of medial structures as seen in the more common form of fibromuscular hyperplasia. Case 1 is only the fourth report of a symptomatic fibromuscular stenosis at the origin of the ICA. Case 2 is the first report of fibromuscular hyperplasia involving the common carotid artery. Changes similar to those in Case 2 (an elongated area of tubular fibromuscular stenosis) have been reported in the ICA. These atypical or intimal forms of fibromuscular hyperplasia appear to be more common in males and blacks, and may be more often unilateral as well.

Cervical discectomy. A prospective analysis of three operative techniques.

BACKGROUND: Cervical disc herniation causing neurological compromise is a common affliction. Sophisticated surgical treatments have been developed throughout the twentieth century and are largely successful. Although each procedure has its supporters, it is still unclear if one surgical technique is superior. METHODS: A prospective trial was designed to evaluate the efficacy of three surgical procedures for the treatment of cervical radiculopathy caused by a unilateral acute herniated cervical disc. Patients were randomized to posterior cervical foraminotomy (FOR), and anterior cervical discectomy with (ACDF), and without (ACD) fusion. Perioperative data, office follow-up and long-term follow-up were used to compare the procedures. RESULTS: All of the procedures yielded excellent relief of symptoms and signs postoperatively and during follow-up. Operative time and hospital stay were slightly shorter for ACD compared with ACDF and FOR. Reoperations occurred in all groups but there was a trend for higher recurrence at the same level with FOR and recurrence at other levels with ACDF. CONCLUSION: All three of the procedures were successful for treatment of cervical radiculopathy caused by a herniated cervical disc. Although the numbers in this study were small, none of the procedures could be considered superior to the others. This study suggests that the selection of surgical procedure may reasonably be based on the preference of the surgeon and tailored to the individual patient.

Disseminated cutaneous protothecosis in an immunocompromised host: a case report and literature review.

Protothecosis is an infection caused by achloric algae of the genus Prototheca. These organisms have been isolated from water, sewage, soil, and the slime flux of trees, and are a known cause of disease in other mammals. Infection in humans occurs after traumatic inoculation, producing localized olecranon bursal or, rarely, systemic disease. Only two previous cases of disseminated cutaneous disease have been reported in patients with defective neutrophil function. We describe a rare case of widespread cutaneous dissemination occurring after an arthropod bite in an immunocompromised patient.

Surgical treatment of incidental intracranial aneurysms.

It is clear that more incidental aneurysms will be encountered in the future. Approximately 5% or more of the population harbors these lesions, and advancing technology can be expected to demonstrate them with increasing regularity. Multiple aneurysms will also be found in at least 18% of patients with subarachnoid hemorrhage due to aneurysms. The best estimates suggest a rate of hemorrhage approximating 1%/year for incidental aneurysms and a 0.4 to 0.65% annual mortality rate for these lesions. It has also been shown that even small aneurysms may enlarge and bleed unpredictably with the passage of time. Surgery for incidental aneurysms of the anterior circulation can be accomplished without mortality and with an operative morbidity of 6.5%. Higher morbidity occurs in surgery for aneurysms in more difficult locations as well as larger aneurysms. The increased risk of bleeding from larger aneurysms, however, may justify the increased morbidity of surgery for these lesions. Surgery for incidental aneurysms can be recommended in healthy individuals whose anesthetic risk is acceptable and for aneurysms less than 1.5 cm in diameter arising from the middle cerebral and posterior communicating arteries. Advancing age alone is not a contraindication for surgery, nor is size greater than 1.5 cm in diameter; however, the latter factor increases the operative risk. Operations to clip aneurysms of the carotid bifurcation, carotid-ophthalmic, and anterior communicating arteries may also be recommended, but these aneurysms are more difficult to approach and surgery carries a higher morbidity. Larger aneurysms, greater than 1.5 cm in diameter, in patients over 60 years of age, and in less accessible locations may not benefit from operation because surgical morbidity for these lesions is high and with advancing age the lifetime risk of rupture has decreased. For incidental aneurysms of the posterior circulation there are insufficient data to make a recommendation regarding surgery, although it is anticipated that the counsel for anterior circulation aneurysms will apply. If operative mortality and morbidity are to be maintained at acceptable levels, incidental aneurysm surgery should be the province of the accomplished aneurysm surgeon who has available to him the most modern techniques and equipment. With the clipping of incidental aneurysms, hopefully the number of patients suffering from subarachnoid hemorrhage with its high morbidity and mortality rates can be further reduced.

Head injury at the southeastern Georgia Regional Trauma Center: a three-year review.

The impact of head injury on our trauma center is significant because of the large number of cases with their heavy utilization of trauma center resources. Head injury also exerts a major influence on the Trauma Center in a rural area since it serves as a major provider of care for the head injured over a wide geographical area. Mortality rates seen in this population compare favorably with contemporary data from other studies using GCS and Head AIS as indicators of level of injury.

Early accumulation of intracellular fibrillar oligomers and late congophilic amyloid angiopathy in mice expressing the Osaka intra-Aß APP mutation.

Pathogenic amyloid-ß peptide precursor (APP) mutations clustered around position 693 of APP-position 22 of the Aß sequence--are commonly associated with congophilic amyloid angiopathy (CAA) and intracerebral hemorrhages. In contrast, the Osaka (E693Δ) intra-Aß APP mutation shows a recessive pattern of inheritance that leads to AD-like dementia despite low brain amyloid on in vivo positron emission tomography imaging. Here, we investigated the effects of the Osaka APP mutation on Aß accumulation and deposition in vivo using a newly generated APP transgenic mouse model (E22ΔAß) expressing the Osaka mutation together with the Swedish (K670N/M671L) double mutation. E22ΔAß mice exhibited reduced α-processing of APP and early accumulation of intraneuronal fibrillar Aß oligomers associated with cognitive deficits. In line with our in vitro findings that recombinant E22Δ-mutated Aß peptides form amyloid fibrils, aged E22ΔAß mice showed extracellular CAA deposits in leptomeningeal cerebellar and cortical vessels. In vitro results from thioflavin T aggregation assays with recombinant Aß peptides revealed a yet unknown antiamyloidogenic property of the E693Δ mutation in the heterozygous state and an inhibitory effect of E22Δ Aß42 on E22Δ Aß40 fibrillogenesis. Moreover, E22Δ Aß42 showed a unique aggregation kinetics lacking exponential fibril growth and poor seeding effects on wild-type Aß aggregation. These results provide a possible explanation for the recessive trait of inheritance of the Osaka APP mutation and the apparent lack of amyloid deposition in E693Δ mutation carriers.

Functional deficits and morphological changes in the neurogenic bladder match the severity of spinal cord compression.

UNLABELLED: Following spinal cord injury (SCI), loss of spinal and supraspinal control results in desynchronisation of detrusor vesicae (parasympathicus) and external urethral sphincter (sympathicus) activity. Despite recovery of lower urinary tract function being a high priority in patients with SCI, effective treatment options are unavailable largely because mechanisms are poorly understood. PURPOSE AND METHODS: We used a clinically relevant model of thoracic SCI compression injury in adult female Wistar rats and confirmed that lesion volumes following severe injuries were significantly greater compared to moderate injuries (p < 0.05). Between 1-9 weeks, we assessed recovery of bladder function as well as return of locomotor function using the Basso, Beattie and Bresnahan (BBB) score. Bladder morphometrics and overall intramural innervation patterns, as assessed with ß-III tubulin immunohistochemistry, were also examined. RESULTS: Despite variability, bladder function was significantly worse following severe compared to moderate compression injury (p < 0.05); furthermore, the degree of bladder and locomotor dysfunction were significantly correlated (r = 0.59; p < 0.05). In addition, at 9 weeks after SCI we saw significantly greater increases in bladder dry weight (p < 0.05) and wall thickness following severe compared to moderate injury as well as increases in intramural axon density (moderate: 3× normal values; severe 5×; both p < 0.05) that also correlated with injury severity (r = 0.89). CONCLUSION: The moderate and severe compression models show consistent and correlated deficits in bladder and locomotor function, as well as in gross anatomical and histopathological changes. Increased intramural innervation may contribute to neurogenic detrusor overactivity and suggests the use of therapeutic agents which block visceromotoric efferents.