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.

The effect of exemestane or tamoxifen on markers of bone turnover: results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Adjuvant treatment of breast cancer with aromatase inhibitors has been associated with increased bone loss. In this study, postmenopausal patients with oestrogen receptor positive breast cancer were randomised to exemestane for 5 years or tamoxifen for 2-2.5 years, followed by exemestane for 2-2.5 years. Levels of bone formation markers (bone specific alkaline phosphatase, amino terminal propeptide of type I procollagen, osteocalcin), and the bone resorption marker (carboxyterminal crosslinked telopeptide of type I collagen), were assessed at baseline and after 3, 6 and 12 months of treatment. Exemestane (n=78) resulted in increases from baseline in all bone turnover marker levels at all timepoints. In contrast, levels of all bone marker turnovers decreased with tamoxifen (n=83). Differences between tamoxifen and exemestane were statistically significant for all bone turnover markers at all timepoints. In conclusion, exemestane results in increases in markers of bone formation and resorption, while decreases are observed with tamoxifen.

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.

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.

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.

Psychiatric disorders in patients with fibromyalgia. A multicenter investigation.

The authors conducted an investigation in four tertiary-care centers to determine if psychiatric comorbidity and psychological variables were predictive of functional impairment in patients with fibromyalgia syndrome (FMS). Seventy-three individuals were administered the Structured Clinical Interview for DSM-III-R, the Rand 36-item Health Survey (SF-36), and multiple self-report measures. The patients with FMS were found to have a high lifetime and current prevalence of major depression and panic disorder. The most common disorders were major depression (lifetime [L] = 68%, current [C] = 22%); dysthymia (10% [C only]); panic disorder (L = 16%, C = 7%); and simple phobia (L = 16%, C = 12%). The self-report scales revealed significant elevations in depression, anxiety, neuroticism, and hypochondriasis. Functional impairment on all measures of the SF-36 was severe (e.g., physical functioning = 45.5 and role limitations due to physical problems = 20.0). Stepwise multiple-regression analysis revealed that current anxiety was the only variable that predicted a significant proportion of the variance (29%) in SF-36 physical functioning. Thus, in this multicenter study, the persons with FMS exhibited marked functional impairment, high levels of some lifetime and current psychiatric disorders, and significant current psychological distress. Current anxiety level appears to be an important correlate of functional impairment in individuals with FMS.

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.

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.

Gender differences in schizophrenia.

In an assessment of gender differences in schizophrenia, 85 outpatients (53 men and 32 women) with schizophrenia were evaluated for illness history, symptom severity, IQ, neurocognitive status, cerebral volume loss, and cortical asymmetry. Social functioning was assessed using marital status, independent living skills, and employment status. Significant gender differences were found, as women were on lower doses of neuroleptic medications and more frequently met criteria for paranoid and disorganized subtypes of schizophrenia than men. Women also were better educated and more often married, living independently, and employed. No gender differences were found in present age, symptom severity, neurocognitive functioning, or clinical magnetic resonance imaging scan readings. Our findings suggest that women may experience less of the adverse interpersonal psychosocial consequences of schizophrenia than men, even when symptom and neurocognitive status is equivalent between groups. However, more extensive investigations are warranted to better understand the role of pathophysiological or social mechanisms in gender differences.

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.

The nature of learning and memory impairments in schizophrenia.

The California Verbal Learning Test was used to characterize the learning and memory impairment in schizophrenia (SC) and to evaluate potential clinical and demographic factors associated with this impairment. SC patients (n = 175) performed worse than normal comparison (NC) subjects (n = 229) on all learning, recall, and recognition memory measures. The most important clinical correlates of these impairments were earlier age of onset, more negative symptoms, and greater anticholinergic medication dosage. SC patients showed a prominent retrieval deficit as indicated by disproportionate improvement when tested in a recognition, rather than a free recall, format. A residual impairment seen with recognition testing suggests a mild encoding deficit as well. In contrast, the relative absence of a storage deficit is suggested by the lack of rapid forgetting. Using a discriminant function analysis that differentiates cortical dementia [i.e., Alzheimer's disease (AD)], subcortical dementia [i.e., Huntington's disease (HD)], and normals, it was found that 50% of the SC patients were classified as having a subcortical memory profile and 35% were classified as having a normal profile, whereas only 15% were classified as having a cortical memory profile. Although these findings reflect the clinical heterogeneity often found in SC, results suggest that most SC patients demonstrate a pattern of learning and memory impairments that resembles the pattern seen in patients with primary subcortical (specifically striatal) pathology.

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.

Actin filament bundles are associated with fiber gap junctions in the primate lens.

A unique association between actin filament bundles and gap junctions in cortical fiber cells of human and monkey lenses was studied with thin-section electron microscopy and immunocytochemistry. Thin-section electron microscopy showed that distinct layers of filament bundles (approximately 55 nm thick) were consistently associated with fiber gap junctions (approximately 16 nm thick) from intermediate to deep cortical regions in both species studied. The filament bundle was composed of 6-8 nm microfilaments which lay along both cytoplasmic surfaces of the junction. Fluorescence microscopy revealed a patchy pattern of F-actin labeling along the fiber cell membranes in the intermediate and deep cortical regions of the lens. The size and distribution pattern of F-actin labeling appear to correlate well with those of filament bundles/gap junctions seen in thin-section electron microscopy. By immunoelectron microscopy, the anti-actin antibody was shown to be localized to filament bundles/gap junctions in the intermediate cortical fibers of human lens, indicating that filament bundles are F-actin in nature. The identical filament bundle/gap junction association was not found in other species examined, including rodent, bird and fish, by the same procedure, suggesting that an association between actin bundles and gap junctions has a special functional role in the primate lens. It is proposed that gap junction-associated actin bundles may provide added structural stability for the primate lens.

The altricial pigeon is born blind with a transient glycogen cataract.

The lens nucleus of altricial birds contains a large amount of glycogen. It is not known why glycogen in such concentration does not cause a trace of lens opalescence. Here we report that the altricial pigeon is born with a dense nuclear opacity; this opacity has practically disappeared by 4 weeks of age. Thin-section electron microscopy revealed that the opacity was specifically associated with an enormous number of large glycogen aggregates in nuclear fiber cells. These aggregates of various sizes (up to approximately 5 microns) were composed of smaller individual 35-nm beta glycogen particles. In contrast, glycogen aggregates were not seen in nuclear fiber cells of all transparent older lenses. The glycogen aggregates have gradually dissociated into a homogeneous distribution of individual beta particles in the entire cytoplasm of nuclear fibers which accompanies the development of lens transparency. This study suggests that an extensive accumulation of glycogen aggregates in the lens nucleus is the cause of light scattering and opacification. The transparency of the altricial pigeon lens during normal development is therefore regulated by two different forms of glycogen. Precocial birds such as chick have no lens glycogen, therefore never develop a glycogen cataract and have excellent visual acuity upon hatching.

Negative symptomatology in schizophrenic outpatients.

This study examines the prevalence of negative symptoms, and assesses the convergence of negative and depressive symptoms in 60 chronically ill schizophrenic outpatients. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms and the negative symptom cluster of the Brief Psychiatric Rating Scale (BPRS). Depressive symptoms were assessed with the depression subscale of the Brief Symptom Inventory and the depressive symptom cluster of the BPRS. A majority of patients in this group of relatively stable, schizophrenic outpatients demonstrated mild to moderate degrees of both negative and depressive symptoms. Correlations were not significant between negative symptom and depressive symptom measures, which suggests that the symptom constructs are relatively independent. Comparisons between a subgroup with prominent negative symptoms (N = 18) and a subgroup with minimal negative symptoms (N = 32) also revealed no significant group differences in variables that characterize clinical course (i.e., age of onset and frequency and duration of hospitalization) or in the severity of depressive symptoms. This lack of any significant differences on the clinical course variables may be partially explained by the heterogeneity of negative symptoms. The constellation of negative symptoms may differ not only in etiology but also in their temporal relationships to other aspects of the patient's clinical course. Longitudinal studies will be needed to track the long-term outcome of negative and depressive symptoms.

Nature and localization of avian lens glycogen by electron microscopy and Raman spectroscopy.

Electron microscopy confirms the presence of a high concentration of glycogen particles in the lens nuclear region of birds of flying habit such as the ring-neck dove and pigeon. This observation is consistent with Raman spectroscopy. The glycogen particles in the dove lens, which are approximately 35 nm in diameter, are classified as beta type particles. Although this type has been previously characterized by high rates of glycogen turnover in other tissues, its localization in the lens nucleus indicates that it may serve a structural function rather than as a storage depot of carbohydrate in the lens. In a comparative electron microscopy study, glycogen particles were not observed in the chicken lens.

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.

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.

Near-infrared Fourier transform Raman and conventional Raman studies of calf gamma-crystallins in the lyophilized state and in solution.

We present in this report a detailed structural study of calf gamma-crystallins both in the solid state and in solution by the newly developed technique of near-infrared (IR) Fourier transform (FT)-Raman spectroscopy as well as by the conventional Raman method. In comparison with conventional laser Raman spectroscopy, the near-IR FT-Raman approach exhibits several attractive features such as fluorescence rejection capability, frequency accuracy, and the FT's multiplex and throughput advantages. These distinct characteristics combined form the basis for the particular suitability of FT-Raman in crystallin structural analysis and elucidation. We have thus obtained evidence in support of the view that native calf gamma-II crystallin does not contain a disulfide bond either in the lyophilized state or in solution. In addition, conventional Raman spectra are examined for all four gamma-crystallin fractions. gamma-S, gamma-II, gamma-III, and gamma-IV, and the results indicate a high degree of structural similarities among them. It is also found that the sulfhydryl groups in all four gamma-crystallins are highly resistant to air oxidation and are capable of maintaining their reduced state during isolation in the absence of added reductants or such chelating agents as EDTA.