Structural analysis of potential barriers to bulk-flow exchanges between uvea and sclera in eyes of Macaque monkeys

Summary The uveal tract of the eyes of monkeys was examined by electron microscopy using both thin sections and freeze-fracture replicas. The ultrastructural features of the lamina fusca in the monkey resembled those previously described for rabbit. The lamina fusca was composed of numerous interleaved processes of fibroblastic and pigmented cells and contained tight junctions between fibroblastic cell processes that were predominantly discontinuous, as well as numerous fenestrations through the attenuated cell processes. There was no regional compaction of cellular processes traversing the entire uvea at the level of the ora serrata as reported previously in hamster eyes.     

An enigmatic hypoplastic defect of the deciduous canine

A roughly circular hypoplastic defect restricted to the labial enamel surface of the deciduous canine is described. This pathology is quite common in available samples of Upper Paleolithic and Neolithic children and a cadaver sample of recent Calcuttans, affecting 44% to 70% of individuals. It is rare in a Neanderthal sample and in children from a clinical practice in Vancouver. The lesion occurs twice as commonly in the lower jaw. The defect appears to commence at or after birth owing to localized pressure on thin or nonexistent alveolar bone overlying the bulging crypt of the deciduous canine. Population differences in the incidence of the pathology probably reflect innate and acquired variation in hard and soft tissue thicknesses in this region.     

Immunotherapy of bovine ocular squamous cell carcinoma by repeated intralesional injections of live bacillus Calmette-Guérin (BCG) or BCG cell walls

Summary Thirty cows of the Dutch Friesian and the Maas-Rijn-Ijssel breed with histologically confirmed ocular squamous cell carcinoma were treated by repeated intralesional injection of live bacillus Calmette-Guérin (BCG) (n = 14) or a BCG cell-wall vaccine (n = 16). Complete regression of the primary tumour was observed in 64% and 57% of the animals respectively. In the 2-year follow-up period there was no recurrence of primary tumours. This sharply contrasts with the recurrence frequency (40%–50%) after complete remission induced by a single intralesional injection with BCG, observed in an earlier study. In 1 animal a new primary tumour developed. At necropsy metastases were present in 33% of the treated animals: in 3 of 17 animals that showed complete regression of the primary tumour and in 7 of 13 animals with partial regression or progressive disease. This did not differ significantly from results obtained after a single treatment (27%). Delayed-type hypersensitivity toM. bovis purified protein derivative (PPD) was more persistent in animals showing regression of the primary tumour than in non-responding animals. Of the animals with a positive PPD response 6 months after treatment, 79% showed tumour regression. Regression was observed in only 28% of the animals not responding to PPD after the same period of time. In conclusion: (a) recurrence of the primary tumour was not observed after repeated BCG treatment; (b) the frequency of metastases was not decreased compared to results obtained with a single treatment; (c) regression was correlated with a positive delayed-type hypersensitivity reaction to PPD (P <0.05) 6 months after treatment; (d) no significant differences were observed when the clinical results of treatment with live BCG and the BCG cell wall vaccine were compared.     

The influence of different flow velocities on tumor cell survival in micropore filters

Earlier studies have shown a lower degree of lodgement and early survival of tumor cells in muscle than in liver after infusion via the femoral artery and portal vein, respectively. A possible explanation to this difference might be that the tumor cells are mechanically destroyed, and thus die more rapidly in muscle because they enter this capillary network at a much higher flow velocity. In the present study, the effect on early tumor cell (rat fibrosarcoma) survival of a high and a low flow velocity/deformation rate was evaluated in micropore (5 μm) filters, using isotope (Cr⁵¹) technique. These experiments were combined with scanning electron microscopic (SEM) analyses. The filter experiments showed no significant differences in the rate of cell death in the filters between tumor cells subjected to high or low deformation rates, and there were no qualitative differences in tumor cell appearance in the SEM study. It is, therefore, concluded that the difference in tumor cell lodgement and survival between muscle and liver is not primarily caused by differences in the rate of cell deformation upon entry of the organ capillary network.     

Chroman amide and nicotinyl amide derivatives: Inhibition of lipid peroxidation and protection against head trauma

A series of chroman amide and nicotinyl amide derivatives was designed and synthesized for the treatment of traumatic and ischemic CNS injury. Five compounds were significantly more potent inhibitors of lipid peroxidation in vitro than the reference antioxidant, trolox (p < 0.01). Quantitative structure activity studies demonstrated that the inhibitory action was related to the ability to donate electrons, charge on hydroxy group and E_LUMO, to scavenging radicals and to the lipophilicity log P, which determines penetration of membrane lipids. ESR study indicated the ability of 12 to scavenge the hydroxyl radicals. The most promising compound, [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2yl)carbonyl]-3′-(aminoethyl) indole (12), inhibited ex vivo lipid peroxidation in a head injury model and showed potent in vivo neuroprotective efficacy. Improvement of neurological recovery within 1 h of injury (grip test score) by as much as 200% was observed together with significant anti-anoxia activity. Compound 12 was a potent antagonist of methamphetamine-induced hypermotility resulting from dopamine release in the mouse brain. These results support the importance of cerebroprotective radical-scavenging agents for the treatment of traumatic injury and anoxia as well as provide additional evidence for the role of oxygen radicals and dopamine in brain damage.     

SLEEP-WAKE SCHEDULE DISORDER DISABILITY: A LIFELONG UNTREATABLE PATHOLOGY OF THE CIRCADIAN TIME STRUCTURE

Certain sleep-wake schedule disorders (SWSDs) cannot be successfully managed clinically using conventional methods of sleep therapy. We describe two cases of SWSD, the first following head trauma and the second originating during childhood, that had been misdiagnosed by physicians for many years. After conventional treatment for SWSD with light therapy and melatonin failed to bring about substantial improvement, it was determined that they were suffering from an incurable disability. Hence, we propose new medical terminology for such cases—SWSD disability. SWSD disability is an untreatable pathology of the circadian time structure. Patients suffering from SWSD disability should be encouraged to accept the fact that they suffer from a permanent disability, and that their quality of life can only be improved if they are willing to undergo rehabilitation. It is imperative that physicians recognize the medical condition of SWSD disability in their patients and bring it to the notice of the public institutions responsible for vocational and social rehabilitation. (Chronobiology International, 18(6), 1019–1027, 2001)     

Activation of ER stress signalling increases mortality after a major trauma

The endoplasmic reticulum (ER) adapts to stress by activating a signalling cascade known as the ER stress response. While ER stress signalling is a central component of the cellular defence against environmental insult, persistent activation is thought to contribute to the progression of various metabolic complications via loss of protein function and cell death. Despite its importance however, whether and how ER stress impacts morbidity and mortality in conditions of hypermetabolism remain unclear. In this study, we discovered that chronic ER stress response plays a role in mediating adverse outcomes that occur after major trauma. Using a murine model of thermal injury, we show that induction of ER stress with Tunicamycin not only increased mortality but also resulted in hepatic damage and hepatic steatosis. Importantly, post‐burn treatment with chaperone ER stress inhibitors attenuated hepatic ER stress and improved organ function following injury. Our study identifies ER stress as a potential hub of the signalling network affecting multiple aspects of metabolism after major trauma and as a novel potential molecular target to improve the clinical outcomes of severely burned patients.     

The preventive and therapeutic effects of molecular hydrogen in ocular diseases and injuries where oxidative stress is involved

Oxidative stress initiates, accompanies and contributes to the development of several human diseases and injuries, including ocular diseases. Reactive oxygen species (ROS) can generate oxidative stress via excessive ROS production and/or decreased physiologically occurring antioxidants. To replace these weakened antioxidants, substances with effective antioxidant properties are needed in order to suppress oxidative stress and enable healing. Molecular hydrogen (H₂) is very suitable for this purpose due to its unique properties. H₂ is the only antioxidant that crosses the blood–brain and blood-ocular barriers. It quickly penetrates through tissue due to its small molecular size and effectively removes ROS, mainly hydroxyl radicals and peroxynitrite. Apart from its antioxidant effects, H₂ also displays anti-inflammatory, antiapoptotic, cytoprotective and mitohormetic properties. A significant advantage of H₂ is its nontoxicity, even when applied at high concentrations. In this review, we present the results of studies utilising H₂ in the treatment of ocular diseases involving oxidative stress. These results, obtained in experimental animals as well as in human clinical studies, show that the suppression of oxidative stress by H₂ treatment leads to the prevention or improvement of ocular diseases. In severe degenerative diseases, H₂ slows disease progression.     

Interpersonal violence in prehistoric San Pedro de Atacama, Chile: behavioral implications of environmental stress

The prehistoric population of San Pedro de Atacama lived through periods marked by prosperity and interregional interaction, as well as times of severe drought, social stress, and widespread poverty. A sample of 682 crania was analyzed for evidence of cranial trauma in order to assess changing patterns of interpersonal violence during the occupation of the oasis. It was hypothesized that the level of traumatic injuries in this population would parallel some of the changes seen in the archaeological record. Low fracture rates would be expected in periods of affluence and environmental stability, while periods characterized by environmental extremes and state collapse would yield elevated rates of aggression. This analysis found that rates of trauma escalated from 5.1% (5/99) in the earliest period, to 10.9% (10/92) in the Middle Horizon (AD 600-950). Although it may reflect problems related to increasing population density in the oasis, this increase is surprising, given that the early period witnessed the shift to permanent settlements, and the middle period was one of prosperity and plentiful resource availability. Trauma rates peaked at 35.6% (16/45) in an early Late Intermediate period (AD 950-1400) cemetery, with other Late Intermediate cemeteries demonstrating similarly high rates of traumatic injury. The elevated trauma rates during this period correlate with major droughts, the concentration of settlements on the oasis' east side, fortified structures, and material poverty, all reflected in the archaeological record. As the Late Intermediate waned and environmental conditions improved, trauma concomitantly decreased (7.0%), and remained low throughout the Inka occupation (AD 1400-1532). This indicates that while the Atacama was not peaceful, violence became commonplace only during periods of great social change and resource stress.     

Bidirectional synaptic mechanisms of ocular dominance plasticity in visual cortex

As in other mammals with binocular vision, monocular lid suture in mice induces bidirectional plasticity: rapid weakening of responses evoked through the deprived eye followed by delayed strengthening of responses through the open eye. It has been proposed that these bidirectional changes occur through three distinct processes: first, deprived-eye responses rapidly weaken through homosynaptic long-term depression (LTD); second, as the period of deprivation progresses, the modification threshold determining the boundary between synaptic depression and synaptic potentiation becomes lower, favouring potentiation; and third, facilitated by the decreased modification threshold, open-eye responses are strengthened via homosynaptic long-term potentiation (LTP). Of these processes, deprived-eye depression has received the greatest attention, and although several alternative hypotheses are also supported by current research, evidence suggests that alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor endocytosis through LTD is a key mechanism. The change in modification threshold appears to occur partly through changes in N-methyl-D-aspartate (NMDA) receptor subunit composition, with decreases in the ratio of NR2A to NR2B facilitating potentiation. Although limited research has directly addressed the question of open-eye potentiation, several studies suggest that LTP could account for observed changes in vivo. This review will discuss evidence supporting this three-stage model, along with outstanding issues in the field.