Communication skills in nursing home residents with dementia : Results of a prospective intervention study over 21 months.

BACKGROUND: The dementia syndrome compromises effective communication and may thus lead to social isolation, psychological distress and decreased quality of life. It is therefore of importance to maintain communication capacity in dementia as long as possible. MATERIAL AND METHODS: A total of 24 professional caregivers from 8 nursing homes were assigned to train 254 of their respective colleagues using the train-the-trainer program MultiTANDEMplus. As in the 6 control nursing homes, severity of dementia, depressive symptoms and communication capacity were assessed in a total of 358 residents at baseline and 21 months later. Overall, 189 residents completed the study. RESULTS: Communication capacity declined in control home residents but remained stable in the intervention group although dementia severity increased in both groups. The intervention group exhibited significantly fewer depressive symptoms after the intervention than the control group. CONCLUSION: A standardized training of communication skills for professional caregivers can stabilize communication capacity and reduce depressive symptoms in nursing home residents. These effects are likely sustainable and could be demonstrated 21 months postintervention.

[COVID-19 in old age-The geriatric perspective]. / COVID-19 im Alter ­ Die geriatrische Perspektive.

Predominantly the older population is affected by a severe course of COVID-19. The mortality of hospitalized patients with COVID-19 above the age of 80 years is up to 54% in international studies. These observations indicate the necessity to highlight the geriatric perspective on this disease. The diagnostics and treatment of COVID-19 do not differ between younger and older patients but atypical symptoms should be expected more frequently in old age. Older subjects show an increased need for rehabilitation after COVID-19. Paradoxically, increasing rehabilitation demands go along with a reduced availability of geriatric rehabilitation options, the latter being a consequence of closure or downsizing of rehabilitation departments during the pandemic. In general, measures of isolation and quarantine should be diligently balanced as the health and emotional consequences of such measures may be severe in older persons. In light of the poor prognosis of older COVID-19 patients, advanced care planning becomes even more relevant. Caregivers and physicians should be encouraged to compose advanced care directives that also reflect the specific circumstances of COVID-19. Fortunately, current data suggest that the effectiveness of the vaccination with the mRNA-vaccines approved in Germany may be equally high in older compared to younger persons.

Train the trainer in dementia care. A program to foster communication skills in nursing home staff caring for dementia patients.

BACKGROUND: Improvement of communication skills in nursing home staff is key to provide better care for dementia patients and decrease occupational mental stress. OBJECTIVES: An innovative train-the-trainer program to improve and maintain professional caregivers' social competencies in nursing home dementia care is described. DESIGN AND METHODS: Over a period of 6 months, a group of 6 senior staff members were qualified as program trainers (multiplicators) for the TANDEM training program, which qualified them to design, deliver, and evaluate training sessions that foster specific social competencies in dementia care. In a subsequent intervention study with 116 geriatric caregivers in 14 nursing homes, training was provided either by multiplicators (intervention group) or directly by project coworkers (control group). RESULTS: Participants in both groups improved their dementia-specific communication skills. In a follow-up survey, the intervention group also reported lasting reductions in mental stressors at work (p < 0.05) and occupational mental stress (p < 0.01) compared with the control group. CONCLUSIONS: The qualification of staff members in German nursing homes to be multiplicators for the TANDEM train-the-trainer program for dementia-specific communication skills has a beneficial influence on social competencies, mental stressors at work, and occupational mental stress of staff who care for dementia patients and may contribute to a sustainable implementation of dementia-specific social competencies.

[Neurocognitive disorders in old age : Role of pharmacotherapy in prevention and treatment]. / Neurokognitive Störungen im Alter : Rolle der Pharmakotherapie bei Prävention und Behandlung.

Neurocognitive disorders (e.g. dementia, mild cognitive impairment and delirium) belong to the most frequently occurring problems in older patients. For most types of dementia as well as for mild cognitive impairment no causal pharmacotherapy is currently available. This also applies to delirium, which should be primarily treated through the identification and elimination of predisposing factors while cautiously using symptomatic therapy with psychotropic drugs. Despite intensive ongoing research efforts the search for disease-modifying drugs for the treatment of Alzheimer's dementia has not been successful. In the prevention and treatment of neurocognitive disorders, rational and evidence-based pharmacological interventions can nonetheless play an important role. Besides the limited benefits of symptomatic treatment with currently available anti-dementia drugs, this includes the strict management of medical risk factors as well as the avoidance of drugs with delirogenic and dementing side effects.

Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress.

BACKGROUND: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer's disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. OBJECTIVES: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. METHODS: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. RESULTS: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. CONCLUSIONS: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).

Environmental gradients structure Daphnia pulex × pulicaria clonal distribution.

The rarity of eukaryotic asexual reproduction is frequently attributed to the disadvantage of reduced genetic variation relative to sexual reproduction. However, parthenogenetic lineages that evolved repeatedly from sexual ancestors can generate regional pools of phenotypically diverse clones. Various theories to explain the maintenance of this genetic diversity as a result of environmental and spatial heterogeneity [frozen niche variation (FNV), general-purpose genotype] are conceptually similar to community ecological explanations for the maintenance of regional species diversity. We employed multivariate statistics common in community ecological research to study population genetic structure in the freshwater crustacean, Daphnia pulex × pulicaria. This parthenogenetic hybrid arose repeatedly from sexual ancestors. Daphnia pulex × pulicaria populations harboured substantial genetic variation among populations and the clonal composition at each pond corresponded to nutrient levels and invertebrate predator densities. The interclonal selection process described by the FNV hypothesis likely structured our D. pulex × pulicaria populations.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

[Development and evaluation of a training program for nursing home professionals to improve communication in dementia care]. / Evaluation eines Kommunikationstrainings für Altenpfleger in der stationären Betreuung demenzkranker Menschen (Tandem im Pflegeheim).

The purpose of this study was to develop and evaluate a skill training aimed at increasing the social competence of caregivers of nursing home residents suffering from dementia. Herewith, the professional burden and occupational stress of the caregivers should be reduced and the quality of life of dementia patients should be increased. The contents of the training focused on problems and strategies in the communication with dementia patients and the communication with colleagues. The effectiveness of the intervention was tested in a controlled training study using a multiple control group design and process measurement. The participants of the trainings were 53 nursing home professionals, who were in daily contact with residents suffering from dementia. The results of the study verify effects for all relevant variables. The "social competence" of the caregivers increased and their "work stress" decreased while the "quality of life of dementia patients" increased. Therefore it can be concluded that training the social competence of nursing home professionals is a method to indirectly reduce their work stress and support dementia patients. The results of research in this program underline very clearly that the developed training is an effective option to improve the situation of dementia care in nursing homes. To make the intervention widely applicable we are currently developing a "multiplier program" in a follow-up project.

Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and it affects more women than men. Mitochondrial dysfunction (MD) plays a key role in AD, and it is detectable at an early stage of the degenerative process in peripheral tissues, such as peripheral mononuclear blood cells (PBMCs). However, whether these changes are also reflected in cerebral energy metabolism and whether sex-specific differences in mitochondrial function occur are not clear. Therefore, we estimated the correlation between mitochondrial function in PBMCs and brain energy metabolites and examined sex-specific differences in healthy participants to elucidate these issues. METHODS: The current pilot study included 9 male and 15 female healthy adults (mean age 30.8 ± 7.1 years). Respiration and activity of mitochondrial respiratory complexes were measured using a Clarke-electrode (Oxygraph-2k system), and adenosine triphosphate (ATP) levels were determined using a bioluminescence-based assay in isolated PBMCs. Citrate synthase activity as a mitochondrial marker was measured using a photometric assay. Concentrations of brain energy metabolites were quantified in the same individuals using 1H-magnetic resonance spectroscopy (MRS). RESULTS: We detected sex-associated differences in mitochondrial function. Mitochondrial complexes I, I+II, and IV and uncoupled respiration and electron transport system (ETS) capacity in PBMCs isolated from blood samples of females were significantly (p < 0.05; p < 0.01) higher compared to males. ATP levels in the PBMCs of female participants were approximately 10% higher compared to males. Citrate synthase (CS) activity, a marker of mitochondrial content, was significantly (p < 0.05) higher in females compared to males. Sex-associated differences were also found for brain metabolites. The N-acetylaspartate (NAA) concentration was significantly higher in female participants compared to males in targeted regions. This difference was observed in white matter (WM) and an area with a high percentage (> 50%) of gray matter (GM) (p < 0.05; p < 0.01). The effect sizes indicated a strong influence of sex on these parameters. Sex-associated differences were found in PBMCs and brain, but the determined parameters were not significantly correlated. CONCLUSIONS: Our study revealed sex-associated differences in mitochondrial function in healthy participants. The underlying mechanisms must be elucidated in more detail, but our study suggests that mitochondrial function in PBMCs is a feasible surrogate marker to detect differences in mitochondrial function and energy metabolism in humans and it underscores the necessity of sex-specific approaches in therapies that target mitochondrial dysfunction.

Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer's disease.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative stress and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, a correct diagnosis in the early stage of AD is not only of importance considering that early drug treatment is more effective but also that the psychological burden of the patients and relatives could be decreased. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as biomarker for AD in a peripheral cell model, the lymphocytes.

Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial.

There is mounting evidence that aerobic exercise has a positive effect on cognitive functions in older adults. To date, little is known about the neurometabolic and molecular mechanisms underlying this positive effect. The present study used magnetic resonance spectroscopy and quantitative MRI to systematically explore the effects of physical activity on human brain metabolism and grey matter (GM) volume in healthy aging. This is a randomised controlled assessor-blinded two-armed trial (n=53) to explore exercise-induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age >65) were allocated to a 12-week individualised aerobic exercise programme intervention (n=29) or a 12-week waiting control group (n=24). The main outcomes were the change in cerebral metabolism and its association to brain-derived neurotrophic factor (BDNF) levels as well as changes in GM volume. We found that cerebral choline concentrations remained stable after 12 weeks of aerobic exercise in the intervention group, whereas they increased in the waiting control group. No effect of training was seen on cerebral N-acetyl-aspartate concentrations, nor on markers of neuronal energy reserve or BDNF levels. Further, we observed no change in cortical GM volume in response to aerobic exercise. The finding of stable choline concentrations in the intervention group over the 3 month period might indicate a neuroprotective effect of aerobic exercise. Choline might constitute a valid marker for an effect of aerobic exercise on cerebral metabolism in healthy aging.

Temporal horn index and volume of medial temporal lobe atrophy using a new semiautomated method for rapid and precise assessment.

BACKGROUND AND PURPOSE: Quantitative markers of Alzheimer disease (AD), particularly in the early stages, are needed for clinical assessment and monitoring. We have evaluated a novel method to segment and visualize the ventricular system and obtain volumetric measures thereof. The temporal horn volume (THV) and index in patients with mild cognitive impairment (MCI) and in those with AD were evaluated. METHODS: High-resolution T1-weighted volume imaging was performed in 52 subjects (21 patients with MCI, 10 with AD, and 21 healthy control subjects). An interactive watershed transformation and semiautomated histogram analysis were implemented to produce segmented THV and temporal horn indices (THI) (ratio of THV to lateral ventricular volume). RESULTS: Cerebral ventricular and temporal horn size could be semiautomatically quantified from all 52 datasets. The method was fast and rater-independent. Qualitative ventricular inspections using surface rendering shading could uncover atrophic process with enlargement of the whole and especially temporal horn volume. Both THV and THI of patients with AD were significantly larger than those of patients with MCI or control subjects (P < .005). There was no significant difference in THV and THI between patients with MCI or control subjects (P > .05). There was a significant correlation between the neuropsychologic performance and both THI and THV across groups (P < .01). CONCLUSION: THV and THI could be used as markers of AD in the clinical environment and are expected to be helpful in monitoring therapeutic intervention.

Genetic Variants of the FADS Gene Cluster Are Associated with Erythrocyte Membrane LC PUFA Levels in Patients with Mild Cognitive Impairment.

BACKGROUND: Long-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI). METHODS: The present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes). RESULTS: Minor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck's depression-inventory). DISCUSSION AND CONCLUSION: These findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

Improving the forecast for biodiversity under climate change.

New biological models are incorporating the realistic processes underlying biological responses to climate change and other human-caused disturbances. However, these more realistic models require detailed information, which is lacking for most species on Earth. Current monitoring efforts mainly document changes in biodiversity, rather than collecting the mechanistic data needed to predict future changes. We describe and prioritize the biological information needed to inform more realistic projections of species' responses to climate change. We also highlight how trait-based approaches and adaptive modeling can leverage sparse data to make broader predictions. We outline a global effort to collect the data necessary to better understand, anticipate, and reduce the damaging effects of climate change on biodiversity.

Targeting the cis-dimerization of LINGO-1 with low MW compounds affects its downstream signalling.

BACKGROUND AND PURPOSE: The transmembrane protein LINGO-1 is a negative regulator in the nervous system mainly affecting axonal regeneration, neuronal survival, oligodendrocyte differentiation and myelination. However, the molecular mechanisms regulating its functions are poorly understood. In the present study, we investigated the formation and the role of LINGO-1 cis-dimers in the regulation of its biological activity. EXPERIMENTAL APPROACH: LINGO-1 homodimers were identified in both HEK293 and SH-SY5Y cells using co-immunoprecipitation experiments and BRET saturation analysis. We performed a hypothesis-driven screen for identification of small-molecule protein-protein interaction modulators of LINGO-1 using a BRET-based assay, adapted for screening. The compound identified was further assessed for effects on LINGO-1 downstream signalling pathways using Western blotting analysis and AlphaScreen technology. KEY RESULTS: LINGO-1 was present as homodimers in primary neuronal cultures. LINGO-1 interacted homotypically in cis-orientation and LINGO-1 cis-dimers were formed early during LINGO-1 biosynthesis. A BRET-based assay allowed us to identify phenoxybenzamine as the first conformational modulator of LINGO-1 dimers. In HEK-293 cells, phenoxybenzamine was a positive modulator of LINGO-1 function, increasing the LINGO-1-mediated inhibition of EGF receptor signalling and Erk phosphorylation. CONCLUSIONS AND IMPLICATIONS: Our data suggest that LINGO-1 forms constitutive cis-dimers at the plasma membrane and that low MW compounds affecting the conformational state of these dimers can regulate LINGO-1 downstream signalling pathways. We propose that targeting the LINGO-1 dimerization interface opens a new pharmacological approach to the modulation of its function and provides a new strategy for drug discovery.

NF1 gene analysis focused on CpG-rich exons in a cohort of 93 patients with neurofibromatosis type 1.

We studied the NF1 gene in 93 unrelated patients with neurofibromatosis type1, focusing the analysis on four exons that contain the highest number of possible mutations occurring at CpG sites. We used denaturing gradient gel electrophoresis to analyse exons 16, 28, 29 and 49, which contain 45 (25%) of the 183 possible mutations that could occur at the 120 CpG dinucleotides of the coding sequence. Six different mutations were identified, five of which are novel: two truncating mutations, W1810X and 5448insG, located in exon29; two splice defects leading to exon29 skipping, 5206-2A>G and 5546G>A; and one missense mutation, L844F, located in exon16. The already described R1748X mutation located in exon29 was found in two unrelated patients. The 5546G>A and R1748X mutations are located at CpG sites, whereas the W1810X involves a CpNpG site. Four novel polymorphisms, which may be helpful for family studies, were also identified. Overall, all but one mutations were found in exon29, a result which suggests that all the CpG sites of the NF1 coding sequence do not have the same mutability, and that exon29, the most CpG-rich exon, contains mutational hotspots associated with NF1.

Characterization of human lutropin carboxyl-terminus isoforms.

Human lutropin (hLH) exhibits both carbohydrate and peptidic heterogeneities that affect its biological potency and the duration of its activity in vivo. Peptidic changes within the hLH beta-subunit are characterized as intrachain proteolytic nicking and carboxyl terminus heterogeneity. To date, the carboxyl terminus of hLHbeta appears to end at either position Gln114 or Gly117, as determined by sequencing of purified subunit. Furthermore, the complementary DNA for hLHbeta predicts a protein containing an additional peptidic stretch, which would make the beta-subunit 121 residues long. This extension may be responsible for the particular intracellular behavior of hLHbeta. To investigate the carboxyl terminus polymorphism of natural hLHbeta, monoclonal antipeptide antibodies were raised against a synthetic peptide mimicking the 104-119 portion of hLHbeta. One antibody, designated LHP09, was found to specifically react with the recombinant hLHbeta ending at position hLHbeta[Leu119] but not with other recombinant forms ending at [Ser116], [Phe120] or [Leu121]. Immunochemical analysis of hLH, either pituitary or urinary in origin, indicated that only pituitary hLH contains a Leu119-ending form of hLHbeta. Finally, immunohistochemical detection was performed using LHP09 and showed specific staining of a normal adult pituitary gland. These observations support the in vivo existence of intrapituitary molecular forms of hLHbeta ending at various positions between Gln114 and Leu121.

Free luteinizing-hormone beta-subunit in normal subjects and patients with pituitary adenomas.

Most clinically nonfunctioning pituitary adenomas (NFPA) are found to be gonadotropinomas when assessed by immunocytochemistry. However, they are rarely associated with increased basal plasma levels of FSH, LH and/or alpha-subunit. It has been claimed that the paradoxical free LHbeta response to TRH may be a useful clinical tool for determining the gonadotropic nature of NFPA. We used a very specific and sensitive immunoradiometric assay (IRMA) for free LHbeta measurement and another specific IRMA to check the absence of free CGbeta, to study normal subjects and 26 patients with NFPA. Basal plasma levels of LHbeta were undetectable in normal men and premenopausal women in the early follicular phase. In contrast, normal postmenopausal women had increased basal plasma LHbeta, parallel to dimeric LH and alpha-subunit levels. In healthy subjects, stimulation with GnRH elicited an increase in LHbeta while TRH was ineffective. In patients with NFPA, LHbeta hypersecretion was found basally and/or after stimulation with TRH in 3 of 16 men, 3 of 5 premenopausal women, and 1 of 5 postmenopausal women, i.e. 7 of 26 patients (26%). In 3 of these 7 cases, alpha-subunit and/or FSH levels were also increased. The LHbeta measurement was thus truly informative on the gonadotropic nature of NFPA in only 4 out of 26 cases (15%). In addition, increased LHbeta levels and/or a positive response of free LHbeta to TRH was observed in 3 patients with pure prolactinomas but in no patients with GH-secreting adenomas. Thus, using this very sensitive and specific IRMA, free LHbeta measurement is rarely helpful for determining the gonadotropic nature of NFPA.

Measurement of plasma free luteinizing hormone beta-subunit in women.

Little is known about the physiological secretion of the free beta-subunit of LH (LHbeta). The aim of this study was to compare in women the secretion of LHbeta, using sensitive and specific two-site immunoassays, with dimeric LH and the free common alpha-subunit (FAS). The LHbeta assay does not recognize the dimeric LH and cross-reacts only with free hCG beta-subunit (CGbeta). Thus, all of the plasma samples were also tested with a highly specific immunoradiometric assay for free CGbeta. Molar concentrations (i.e. picomoles per L) were used to compare the plasma levels of LH and its free subunits. Plasma LH, LHbeta, FAS, and CGbeta levels were measured in five normally cycling women during the early follicular phase and the ovulatory peak of LH. The pulsatile profiles of LH, LHbeta, FAS, and CGbeta were studied in five postmenopausal women before and 21 days after injection of a depot preparation of the GnRH agonist D-Trp6 (3.75 mg, im) and in five women with functional hypothalamic amenorrhea (FHA), i.e. low plasma LH levels, during pulsatile GnRH administration (20 microg/pulse, 90 min, sc). Afterward, one of the patients with FHA received a single sc injection of 1350 U recombinant human LH, and plasma LH, LHbeta, FAS, and CGbeta levels were measured and compared with the high plasma levels of one postmenopausal woman. In cycling women, basal plasma LHbeta and CGbeta levels were below the detection limit of the assays (1.34 and 0.65 pmol/L, respectively), and plasma FAS levels were 13.60 +/- 0.13 pmol/L. During the LH surge, there was a parallel increase in LH, LHbeta, and FAS. Plasma CGbeta levels remained undetectable. In normal postmenopausal women, basal plasma dimeric LH, LHbeta, and FAS levels were increased in parallel, and their pulsatile profiles were similar, without measurable plasma CGbeta levels. After D-Trp6 administration, plasma LH and LHbeta levels were completely suppressed, whereas plasma FAS levels increased, and plasma CGbeta remained below 0.65 pmol/L. In FHA women, basal plasma levels of LH and FAS were low, without detectable LHbeta and CGbeta levels. During pulsatile GnRH administration, LHbeta became detectable, and pulses were synchronous with those of LH and FAS. The secretion of LH and LHbeta was almost equimolar. Plasma CGbeta levels remained undetectable. In the patient with FHA, administration of recombinant human LH increased only plasma LH levels, whereas plasma LHbeta and FAS levels remained very low. In conclusion, when the production of dimeric LH increases, a concomitant, parallel, and almost equimolar hypersecretion of uncombined and biologically inactive LHbeta occurs. Like the alpha-subunit, LHbeta may be secreted in the dissociated free form. This can lead to pitfalls during clinical investigations if assays of free CGbeta display some cross-reaction with free LHbeta.

G-CSF plasma levels in clozapine-induced neutropenia.

BACKGROUND: Clinical reports emphasize the therapeutic usefulness of granulocyte colony-stimulating factor (G-CSF) in clozapine-induced granulocytopenia. Only sparse information exists, however, on the natural course of endogenous G-CSF plasma levels in this condition. METHODS: We monitored G-CSF and white blood cell (WBC) counts in a 73-year-old patient who developed granulocytopenia while being treated with clozapine for schizoaffective disorder. Clozapine treatment was discontinued immediately, and G-CSF serum levels were determined repeatedly during the clinical course. RESULTS: Whereas WBC counts increased again within 6 days after discontinuation of clozapine, G-CSF level decreased significantly within the same period. The rapid decrease of endogenous G-CSF levels paralleled by a normalization of neutrophil count was interpreted as the result of an intact regulatory mechanism of granulocytopoesis. Therefore G-CSF therapy was not initiated. Owing to lack of therapeutic alternatives, it was decided to reintroduce clozapine. G-CSF levels decreased further, accompanied by an increase of WBCs, indicating stable bone marrow functioning. CONCLUSIONS: Based on this observation, we assume that the course of G-CSF and WBC counts indicated an abortive form of toxic bone marrow damage with subsequent recovery. We conclude that monitoring of G-CSF levels may serve as a useful tool in the follow-up of patients in whom clozapine-induced bone marrow damage is suspected.