Humphrey visual field findings in hydroxychloroquine toxicity.

PURPOSE: To analyze Humphrey visual field (HVF) findings in hydroxychloroquine (HCQ) retinal toxicity. METHODS: HVF tests were interpreted retrospectively in this observational case series of 15 patients with HCQ toxicity. Patients seen at Lahey Clinic were identified by diagnosis coding search. Patients with age-related macular degeneration or glaucoma with visual field loss were excluded. HVFs done before the diagnosis were analyzed to see if earlier diagnosis could have been possible. RESULTS: A total of 66 HVFs were reviewed and categorized. Some abnormalities were subtle. Paracentral defects were seen on 10-2 tests whereas 24-2 tests, due to their compressed scale, showed central changes. The abnormalities were often more obvious on pattern deviation rather than the gray scale. Of those patients with prior HVFs available for review, 50% showed HVF abnormalities typical of HCQ toxicity present several months or years before diagnosis. HVF changes preceded fundus changes in nine patients. CONCLUSION: HVF abnormalities indicating HCQ toxicity vary depending on the specific HVF test performed. Clinicians need to be aware of the subtle nature of HVF changes in early toxicity.

Durability of Field Resistance to Black Pod Disease of Cacao in Papua New Guinea.

Black pod disease of cacao, caused by various species of Phytophthora, is one of the most serious causes of cacao yield losses worldwide. In Papua New Guinea, such losses on local smallholdings are estimated at more than 40% of annual production. Genetic improvement of cacao resistance is the most promising way of reducing the impact of these pathogens. Field infection of 25 selected Trinitario × Upper Amazonian hybrid progenies in a factorial design (5 by 5) was monitored for five consecutive years at the Cocoa and Coconut Research Institute in Papua New Guinea. The resistance durability of the various hybrids was analyzed using a factorial split-plot model with years as the main factor. The reaction of the hybrid progenies remained stable and similar throughout the 5 years. Similarly, the general combining ability ranking of the parents was also the same for each year. Moreover, data accumulated over several years provided a clearer distinction between the parents. The analyses clearly showed female inheritance under field conditions, and the progenies from what are believed to be resistant females showed good resistance.

Localization of the ribosomal protection protein Tet(O) on the ribosome and the mechanism of tetracycline resistance.

Tet(O) belongs to a class of ribosomal protection proteins that mediate tetracycline resistance. It is a G protein that shows significant sequence similarity to elongation factor EF-G. Here we present a cryo-electron microscopic reconstruction, at 16 A resolution, of its complex with the E. coli 70S ribosome. Tet(O) was bound in the presence of a noncleavable GTP analog to programmed ribosomal complexes carrying fMet-tRNA in the P site. Tet(O) is directly visible as a mass close to the A-site region, similar in shape and binding position to EF-G. However, there are important differences. One of them is the different location of the tip of domain IV, which in the Tet(O) case, does not overlap with the ribosomal A site but is directly adjacent to the primary tetracycline binding site. Our findings give insights into the mechanism of tetracycline resistance.

Brain-derived neurotrophic factor administration after traumatic brain injury in the rat does not protect against behavioral or histological deficits.

Brain-derived neurotrophic factor has been shown to be neuroprotective in models of excitotoxicity, axotomy and cerebral ischemia. The present study evaluated the therapeutic potential of brain-derived neurotrophic factor following traumatic brain injury in the rat. Male Sprague-Dawley rats (N=99) were anesthetized and subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.8 atm) or sham injury. Four hours after injury, the animals were reanesthetized, an indwelling, intraparenchymal cannula was implanted, and infusion of brain-derived neurotrophic factor or phosphate-buffered saline vehicle was initiated from a mini-osmotic pump and continued for two weeks. In Study 1 (N=48), vehicle or 12 microg/day of brain-derived neurotrophic factor was infused into the dorsal hippocampus. In Study 2 (N=51), vehicle or brain-derived neurotrophic factor at a high (12 microg/day) or low dose (1.2 microg/day) was infused into the injured parietal cortex. All animals were evaluated for neurological motor function at two days, one week and two weeks post-injury. Cognitive function (learning and memory) was assessed at two weeks post-injury using a Morris Water Maze. At two weeks post-injury, neuronal loss in the hippocampal CA3 and dentate hilus and in the injured cortex was evaluated. In Study 2, neuronal loss was also quantified in the thalamic medial geniculate nucleus. All of the above outcome measures demonstrated significant deleterious effects of brain injury (P<0.05 compared to sham). However, post-traumatic brain-derived neurotrophic factor infusion did not significantly affect neuromotor function, learning, memory or neuronal loss in the hippocampus, cortex or thalamus when compared to vehicle infusion in brain-injured animals, regardless of the infusion site or infusion dose (P>0.05 for each). In contrast to previous studies of axotomy, ischemia and excitotoxicity, our data indicate that brain-derived neurotrophic factor is not protective against behavioral or histological deficits caused by experimental traumatic brain injury using the delayed, post-traumatic infusion protocol examined in these studies.

Interdigitation of nitric oxide synthase-, tyrosine hydroxylase-, and serotonin-containing neurons in and around the laterodorsal and pedunculopontine tegmental nuclei of the guinea pig.

The topography of neurons containing nitric oxide synthase (NOS) and monoamines was investigated in the guinea pig mesopontine tegmentum. NOS-containing neurons were identified with NADPH-diaphorase (NADPH-d) histochemistry, and monoamine-containing neurons were identified with tyrosine hydroxylase (TH) and serotonin (5-HT) immunocytochemistry. The distribution of NADPH-d positive cells was centered on the laterodorsal tegmental (LDT) and pedunculopontine tegmental (PPT) nuclei. Diaphorase-containing cells had a mean soma diameter of 23.0 +/- 4.1 microns (n = 160) and were distributed inhomogeneously, with numerous cells found within densely packed clusters. A nearest-neighbor analysis revealed that these cells were closely spaced, with up to 20% within one cell diameter and more than 50% within two cell diameters of a neighboring NADPH-d cell. Within the LDT and PPT, NADPH-d positive cells were mixed with smaller, diaphorase-negative cells (diam: 12.8 +/- 3.3 microns; n = 182; P << 0.01). TH-containing cells were not organized into a compact LC as in rat and their distribution more closely resembled that observed in cat. On average, TH-containing cells (diam: 21.2 +/- 4.8 microns; n = 160) were smaller than NADPH-d cells (P < 0.01). 5-HT-containing cells were mainly located in the raphe nuclei, as in other species. 5-HT-containing cells (diam: 18.2 +/- 4.4 microns; n = 161) were smaller on average than both the NADPH-d (P < 0.01) and TH-containing cells (P < 0.01). An analysis of the overlap in soma distributions revealed that TH-containing cells were largely interdigitated with NADPH-d containing cells. As much as 78% of the area occupied by the NADPH-d cells of LDT was contained within the area occupied by TH cells. Substantial numbers of TH and 5-HT immunoreactive processes were seen in both LDT and PPT. Varicose 5-HT and TH-containing fibers, as well as thicker, possibly dendritic processes containing TH were often seen in close apposition to NADPH-d containing somata and proximal dendrites. These results support the hypothesis that NADPH-d cells of both the PPT and LDT receive input from TH and 5-HT cells. Moreover, the clustered substructure of LDT and PPT and the extensive overlap of NADPH-d and TH-containing somata raise the possibility that the membrane permeable messenger nitric oxide plays a role in modulating TH-containing somata and their processes as well as 5-HT-containing processes in the LDT and PPT.

Estradiol target neurons in the hypothalamic arcuate nucleus and lateral ventromedial nucleus of young adult, reproductively senescent, and monosodium glutamate-lesioned female golden hamsters.

Histoautoradiographic methods were used to assess estrogen target neurons in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus, lateral portion (LVM), comparing young adult and aged female golden hamsters. A subgroup of young adult females had ARC lesions induced by monosodium glutamate at neonatal day 8. All were ovariectomized to remove endogenous estrogens. Controls were given nonradioactive estradiol. After 3H-estradiol (3H-E2) was injected intravenously, hypothalami were removed, frozen, and processed for histoautoradiography. In the ARC and LVM the ratio of 3H-E2 labelled neurons to total neurons counted was significantly lower in the older animals. Young females with ARC lesions had very few 3H-E2 labelled neurons remaining in the ARC but had a normal complement in the LVM. Although 3H-E2 labelled ARC neurons were notably decreased in old females, those ARC neurons that were labelled in the old had virtually the same frequency distribution of the labelling index as in the young, suggesting no change in the average estrogen uptake per target cell.

The numbers of neurons in the hypothalamic nuclei of young and reproductively senescent female golden hamsters.

The numbers of neurons in nine different hypothalamic nuclei were counted in every eighth section of serially-cut hypothalami in young (4 to 6 months) and reproductively senescent (15 to 18 months) female hamsters. There were no morphological differences discernible at the light microscopic level in the hypothalami of the aged hamster. There did not appear to be any significant differences in the lateral or rostral-caudal extent of these nuclei nor in neuron counts in old versus young animals. These results are discussed in light of species differences and possible functional alterations.

Uterine progesterone receptors in the aged golden hamster.

Uterine capacity to form cytoplasmic progesterone receptor was compared in ovariectomized golden hamsters at three months and 15-17 months of age. A dose-response test with 17beta-estradiol(E2) showed that the uterine content of progesterone receptor (pmole/uterus) was equal in young and old at all dose levels. However, heavier old uteri had less receptor per gm tissue. Old and young hamsters were mated, ovariectomized on day 7 post coitum and after two weeks, all were given the same dose of E2. Endometrium was separated from myometrium before analysis of progesterone receptor. Myometrium was analyzed for both estrogen and progesterone receptors. Myometrium of both groups had comparable levels of both receptors. The mean concentration of progresterone receptor (pmole/gm tissue) was higher in old endometrium. Some old animals with liver, kidney and adrenal disease had more endometrial reaction after E2 treatment. A few with low endometrial receptor levels had normal livers but at least one sterile uterine horn. There was, however, no general decline with age in intrinsic uterine capacity to form progesterone receptors.