700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial.

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy.

BACKGROUND: Adjuvant treatment of hormone receptor-positive breast cancer in postmenopausal women with aromatase inhibitors may be associated with increased bone loss. PATIENTS AND METHODS: Two hundred patients were randomised to receive exemestane or tamoxifen as adjuvant treatment of hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6 and 12 months treatment. RESULTS: One hundred and sixty-one patients were assessable. Tamoxifen treatment resulted in a 0.5% increase from baseline in BMD at the spine, which was maintained at 12 months. Exemestane-treated patients experienced a 2.6% decrease from baseline in BMD at the spine at 6 months and a further 0.2% decrease at 12 months. There were significant differences in the changes in BMD between tamoxifen and exemestane at 6 and 12 months (P = 0.0026 and P = 0.0008, respectively). The mean changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen at 6 and 12 months (P = 0.0009 and P = 0.04, respectively). There was no difference between tamoxifen and exemestane in mean changes in BMD from baseline at the femoral neck. CONCLUSIONS: Exemestane treatment resulted in an increase in bone loss at 6 months; bone loss stabilised after 6- to 12-month treatment.

The generalized pattern of neuropsychological deficits in outpatients with chronic schizophrenia with heterogeneous Wisconsin Card Sorting Test results.

Forty schizophrenic outpatients and 40 normal subjects were assessed using extensive clinical (eg, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms) and neuropsychological (extended Halstead-Reitan Battery) measures. The schizophrenic patients had multiple neuropsychological deficits on tests of complex conceptual reasoning, psychomotor speed, new learning and incidental memory, and both motor and sensory-perceptual abilities. Neuropsychological impairment correlated more strongly with negative than positive symptoms. Overall, the schizophrenic outpatients showed relatively modest increases in the number of perseverative responses on the Wisconsin Card Sorting Test of abstraction flexibility. A subgroup of these schizophrenic patients seemed to be particularly impaired on the Wisconsin Card Sorting Test. This pattern of results, in conjunction with previous studies, supports the idea that, while some schizophrenic patients may have fixed, frontally based dysfunctions, these dysfunctions may be most prominent, and even fixed, in deteriorated, kraepelinian patients. These data provide evidence for diffuse and far-reaching deficits in a majority of outpatients with chronic schizophrenia.

Stability and course of neuropsychological deficits in schizophrenia.

BACKGROUND: Neuropsychological deficits in schizophrenia appear to predate clinical symptoms of the disease and become more pronounced at illness onset, but controversy exists about whether and when further neuropsychological progression may occur. OBJECTIVE: To identify and characterize any subset of patients who evidenced progressive neuropsychological impairment, we compared the longitudinal stability of neuropsychological functioning in schizophrenic outpatients and normal comparison subjects. METHODS: One hundred forty-two schizophrenic outpatients and 206 normal comparison subjects were given annually scheduled comprehensive neuropsychological evaluations during an average of 3 years (range, 6 months to 10 years). Clinically and demographically defined subgroups were compared, and test-retest norms were used to identify individual patients who showed unusual worsening over time. RESULTS: The schizophrenic group was neuropsychologically more impaired than the normal comparison subjects but showed comparable test-retest reliability and comparable neuropsychological stability over both short (mean, 1.6 years) and long (mean, 5 years) follow-up periods. No significant differences in neuropsychological change were found between schizophrenic subgroups defined by current age, age at onset of illness, baseline level of neuropsychological impairment, improvement or worsening of clinical symptoms, and occurrence of incident tardive dyskinesia. Norms for change also failed to show neuropsychological progression in individuals with schizophrenia. CONCLUSIONS: Neuropsychological impairment in ambulatory persons with schizophrenia appears to remain stable, regardless of baseline characteristics and changes in clinical state. Our results may not be generalizable to the minority of institutionalized poor-outcome patients.

Neuropsychological deficits in schizophrenics. Relationship to age, chronicity, and dementia.

BACKGROUND: We sought to determine whether neuropsychological impairment in schizophrenia is related to current age, age at onset, or duration of illness, and whether the pattern of such impairment can be distinguished from that caused by progressive dementias of Alzheimer's type. We administered a comprehensive neuropsychological test battery to a normal control group (n = 38), a group of ambulatory patients with Alzheimer's disease (n = 42), and three ambulatory schizophrenic groups: early onset-young (n = 85), early onset-old (n = 35), and late onset (n = 22). Tests were grouped and analyzed according to eight major ability areas, and published procedures were used to remove the expected effects of normal aging. RESULTS: The three schizophrenic groups were found to be neuropsychologically similar to one another and different from normal controls and patients with Alzheimer's disease. There were no significant differences among the schizophrenic groups in level or pattern of neuropsychological functioning. Patients with Alzheimer's disease demonstrated less efficient learning and particularly more rapid forgetting than did the other groups. CONCLUSIONS: These findings suggest that neuropsychological impairment in schizophrenia is unrelated to current age, age at onset, or duration of illness. The study further suggests that the encephalopathy associated with schizophrenia is essentially nonprogressive and produces a pattern of deficits that is different from that seen in progressive cortical dementias.

Past substance abuse and clinical course of schizophrenia.

To evaluate the effects of previous alcohol and drug use on the course and symptoms of schizophrenia, the authors compared 34 patients with schizophrenia who had histories of substance abuse with 17 patients with schizophrenia who were lifelong abstainers. Surprisingly, they did not find that individuals with past histories of abuse were more impaired or had more symptoms.

Clinical and neuropsychological characteristics of patients with late-onset schizophrenia.

OBJECTIVE: The goal was to compare clinical and neuropsychological characteristics of patients with late-onset schizophrenia, a poorly studied and controversial entity, with those of patients with early-onset schizophrenia and normal subjects. METHOD: The authors evaluated 25 patients who met DSM-III-R criteria as well as their own research criteria for late-onset schizophrenia (i.e., schizophrenia with onset after age 45) and compared them with 39 patients with early-onset schizophrenia and 35 normal subjects in this nonepidemiologic study. RESULTS: Patients with late-onset schizophrenia were similar to patients with early-onset schizophrenia and different from normal subjects on most clinical and neuropsychological variables assessed, such as psychopathology, family history, childhood social adjustment, and overall pattern of neuropsychological impairment. Compared with the early-onset group, the group with late-onset schizophrenia had a higher percentage of patients who were ever married, a better work history, and a greater frequency of paranoid subtype. CONCLUSIONS: These results support the diagnostic validity of schizophrenia with onset after the age of 45 years.

Depressive symptoms in schizophrenia.

OBJECTIVE: The authors assessed the presence and severity of depressive symptoms, as well as their associations with other clinical measures, in a group of mid- to late-life patients with schizophrenia who were not in a major depressive episode or diagnosed with schizoaffective disorder. METHOD: Sixty outpatients with schizophrenia between the ages of 45 and 79 years and 60 normal comparison subjects without major neuropsychiatric disorders, proportionally matched for age and gender, were studied. Depressive symptoms were rated primarily with the Hamilton Depression Rating Scale. Standardized instruments were also used to measure global psychopathology, positive and negative symptoms, abnormalities of movement, and global cognitive status. RESULTS: Depressive symptoms were more frequent and more severe in schizophrenic patients than in normal comparison subjects; 20% of the women with schizophrenia had a Hamilton depression scale score of 17 or more. Severity of depressive symptoms correlated with that of positive symptoms but not with age, gender, negative symptoms, extrapyramidal symptoms, or neuroleptic dose. CONCLUSIONS: Depressive symptoms are common in older patients with schizophrenia. They may be an independent, core component of the disorder or, alternatively, may be a by-product of severe psychotic symptoms.

Metabolic production of a blue-green fluorophor in lenses of dark-adapted mice and its increase with age.

A blue-green fluorophor (496 nm emission/406.7 nm excitation) occurs in the mouse lens; its increase with age is more pronounced in the nucleus than in the cortex. The level of fluorophor and its rate of production are the same for animals reared in the dark as for animals reared in the light. Thus, the fluorophor is not generated by a photochemical reaction but is a purely metabolic product.

Fluorescence/Raman intensity ratio for monitoring the pathologic state of human lens.

The authors have put quantitation of human lens fluorescence on a rational basis by using the accompanying Raman signal from lens protein as a normalization factor. The intensity ratio, Fluorescence/Raman (F/R), may be used to compare lenses of different ages when the exciting wavelength is long enough to give a measurable Raman signal. In younger lenses excited at 457.9 or 514.5 nm, the F/R shows a log increase with age. Older lenses, above 60 years of age, excited at 647.1 nm give a steeply rising sigmoid curve. In developing this procedure, the authors found that for each lens there is a characteristic wavelength that is called the critical wavelength (lambda critical). At wavelengths longer than lambda critical the Raman signal appears in the absence of a broad fluorescence peak; at shorter wavelengths the fluorescence intensity increases enough to overwhelm the Raman signal. For normal lenses, clear and not heavily pigmented, the lambda critical is age dependent, giving a curve that is a flattened sigmoid approximating a straight line.

Fluorophors and chromophors from rat lens crystallins in UV with hydroxykynurenine.

Isolated alpha-, beta-, and gamma-crystallins from young rat lenses were incubated in solution for 16 hr with 3-hydroxykynurenine under ultraviolet (366 nm) light. Controls included: incubation without light, without kynurenine, and with 2-mercaptoethanol. These procedures generated several chromophors (with absorption maxima or shoulders at 340, 370, and 470 nm) and fluorophors (with excitation/emission at 407/515, 458/550, 515/555, 647/664, and 647/740 nm). The formation of these pigments was inhibited by 2-mercaptoethanol. The findings are discussed in relation to the chromophors and fluorophors found in aged and brunescent human lenses.

Tryptophan Raman/457.9-nm-excited fluorescence of intact guinea pig lenses in aging and ultraviolet light.

Normal age-matched guinea pig lenses were compared with those exposed to (1) long-term ultraviolet (UV) light (9 months, 353-nm peak) in vivo, and (2) short-term UV light (3.5 hr, 325 nm) in vitro from a helium-cadmium laser. Tryptophan Raman and 457.9-nm-excited fluorescence profiles along the visual axis (VA) were obtained by taking 21 (for tryptophan) or 11 (for fluorescence) successive spectra for each intact lens using the Raman optical dissection technique. To indicate the extent of UV exposure, fluorescence spectra were obtained along the VA (excitation/emission = 457.9/497 nm); these spectra indicated that the major alteration by UV was in the nucleus with the least in the posterior cortex. Normal aging lenses had no apparent change in the tryptophan profile between 3 days and 12 months. The UV-irradiated lenses also showed no appreciable difference from the normal aging patterns. These results indicate that there is no detectable tryptophan photolysis in the intact guinea pig lens by longwave UV light.

A Raman study of disulfide and sulfhydryl in the Emory mouse cataract.

Emory mice (EM) are genetically predisposed to late-onset cataract formation. Our early work has shown UV-exposure slightly enhanced the expected 2 SH----SS conversion of normal mouse lenses only in the cortical regions. There was essentially no difference in the disulfide profiles of the nuclear region between UV-exposed and control lenses. Since the first noticeable change in the Emory mouse is a hazy nucleus when a lens is examined in vitro, we wondered if cataractogenesis in this model is different from the UV-produced cataract. This question was answered by comparing the visual axis profiles for SH and SS in early EM cataracts and in clear lenses from age-matched controls. The sulfhydryl profiles show that the SH level of 8.5-month-old EM lenses is essentially the same as that of the controls. Likewise, the disulfide profiles show no significant difference. The results clearly demonstrate that EM lenses do not undergo accelerated disulfide production. Therefore for the EM lens, the early stage of cataract formation must involve factors other than just accelerated oxidation of protein SH or glutathione SH. Invest Ophthalmol Vis Sci 29:823-826, 1988

Red fluorescence in older and brunescent human lenses.

Brunescent lenses and normal human lenses more than 70 years old exhibit red fluorescence due to a fluorophor with emission maximum at 672 nm under excitation by the 647.1 nm line of krypton ion laser. The properties and mode of occurrence of this fluorophor suggest that its formation is highly pertinent to senile nuclear pathology.

Proteases in the Emory mouse cataract.

Exopeptidases identified as dipeptidyl peptidase III and leucine aminopeptidase, and an endopeptidase, prolyl endopeptidase, were found in the Emory Mouse cataract and the Cataract Resistant mouse lens extracts. The specific activity measured on Arg-Arg-2-NNap for DPP III and the hydrolysis of Boc-Arg-Pro-2-NNap for prolyl endopeptidase were higher in the Emory Mouse cataractous lens extract. A relatively high rate of hydrolysis of the beta-naphthylamide of leucine aminopeptidase was present in both mouse categories; however, the Cataract Resistant mouse lens had approximately double the protease activity of the Emory Mouse cataract.

Command hallucinations in outpatients with schizophrenia.

BACKGROUND: The presence of command hallucinations in individuals with schizophrenia may result in an increase in clinical monitoring to reduce the perceived risk of violent behavior. However, the issue of whether command hallucinations hold any clinical relevance in relatively stable outpatient samples has not been established. METHOD: The clinical and research records of individuals with schizophrenia who participated in outpatient research protocols at the University of California, San Diego were reviewed for the presence of command hallucinations. Information on clinical characteristics was collected in a detailed chart review from 106 patient records. RESULTS: Command hallucinations were reported by one half of all patients with auditory hallucinations, and these hallucinations often were violent in content. Yet, in over a third of the patients, these hallucinations had not been documented in their clinical charts, but instead were uncovered during a secondary source review. Patients with command hallucinations generally did not differ on prognostic or clinical course variables. However, the 2 patients who committed suicide during the study were patients with command hallucinations. CONCLUSION: Although command hallucinations may be more frequent than clinicians generally note, in most cases they have minimal influence on the outcome of schizophrenia. However, in outpatients with schizophrenia who have a history of suicide attempts, suicidal command hallucinations should be taken seriously.

Depression in the context of human immunodeficiency virus infection: implications for treatment.

A chart review of 90 male outpatients was conducted to document the type of depressive symptomatology associated with HIV infection and to review the nature of antidepressant treatment provided in two university-affiliated outpatient settings. Forty-five individuals who tested positive for HIV infection and who were treated with antidepressant medications were compared with a like number of individuals who had no known risk factors as determined by chart review for HIV infection. Although depressive symptoms were generally similar among the two groups, HIV-positive individuals reported greater decreases in sleep and appetite than the HIV-negative comparison group. Overall, imipramine and fluoxetine earned the most favorable efficacy ratings while producing minimal side effect ratings in both HIV-positive and HIV-negative patients. Among the HIV-positive patients, the asymptomatic group had a better response to treatment with antidepressant medications than either the ARC or AIDS patient groups.

Is it possible to be schizophrenic yet neuropsychologically normal?

This study identified and characterized a group of schizophrenic patients without neuropsychological (NP) impairment. A comprehensive NP battery was administered to 171 schizophrenic outpatients and 63 normal comparison participants. Each participant's NP status was classified through blind clinical ratings by 2 experienced neuropsychologists; 27% of the schizophrenics were classified as NP normal. The NP-normal and NP-impaired schizophrenics were similar in terms of most demographic, psychiatric, and functional characteristics, except that NP-normal patients had less negative and extrapyramidal symptoms, were on less anticholinergic medication, socialized more frequently, and were less likely to have had a recent psychiatric hospitalization. The existence of NP-normal schizophrenics suggests that the pathophysiology underlying the cognitive deficits often associated with schizophrenia may be distinct from that causing some of its core psychiatric features.

Alterations in fiber cell membranes of Emory mouse cataract: a morphologic study.

Morphologic alterations in cortical fiber cell membranes of the developing Emory mouse cataract were studied with scanning, transmission and freeze-fracture electron microscopy. Scanning electron microscopy revealed the extensive formation of prominent ridges on the surfaces of normal-appearing fibers, greatly enlarged degenerating fibers and globular structures in the relatively superficial cortical regions of the cataractous lenses where such a surface pattern was not found in the normal controls. Transmission electron microscopy showed undulating 13 nm pentalamellar structures, which were thinner than 17 nm heptalamellar (or pentalamellar) structures of gap junctions, were distributed within the cell membranes having ridge patterns. Some globular structures were encircled by repeated undulating 13 nm pentalamellar structures and multilamallar membranes. Freeze-fracture studies demonstrated that 13 nm pentalamellar structures consisted of square crystalline arrays of 6 nm intramembrane particles whereas 17 nm heptalamellar profiles showed randomly-packed 9 nm intramembrane particles of typical lens fiber gap junctions. It is suggested that the extensive formation of ridges in the relatively superficial cortical regions of the Emory mouse lenses may be associated with a degenerative process of lens fiber cell membranes during cataractogenesis.