Prevalence of scoliosis and impaired pulmonary function in patients with type III osteogenesis imperfecta.

PURPOSE: Osteogenesis Imperfecta (OI) is a rare group of congenital genetic disorders that consists of a collagen synthesis defect. The most severe phenotype is type III OI. Characterized by progressive bone deformity, fragility and pulmonary impairment, causing significant morbidity and mortality. Also, multilevel spine deformities are observed, such as scoliosis. The literature on the pathophysiology of pulmonary impairment in relation to scoliosis in these patients is scarce and conflicting. This study aims to determine the prevalence of scoliosis and its relation to pulmonary function in type III OI patients. METHODS: This retrospective cohort study took place between April 2020 and November 2021. Forty-two patients with type III OI were included. Anterior-posterior spine radiographs were evaluated for scoliosis. Pulmonary function was assessed using spirometry and partial pressure of carbon dioxide. RESULTS: All 42 patients had scoliosis, with a mean curve of 66° (95% CI of range). Vital lung capacity was decreased, compared to a non-OI population (mean 1.57 L). This was correlated to the degree of scoliosis (st. ß - 0.40, P = 0.03), especially in increasing thoracic curves. Restrictive lung pathophysiology was shown in our study population with a mean FEV1/FVC ratio of 0.85. CONCLUSIONS: Increasing thoracic scoliosis was correlated with decreased vital lung capacity in our study population of type III OI patients. High FEV1/FVC ratios found in this study population show restrictive lung pathophysiology. Therefore, it is plausible that the pulmonary impairment found in type III OI patients is a combined issue, partly associated to scoliosis and partly intrinsic to OI.

ViBiBa: Virtual BioBanking for the DETECT multicenter trial program - decentralized storage and processing.

BACKGROUND: Liquid Biopsy (LB) in the form of e.g., circulating tumor cells (CTCs) is a promising non-invasive approach to support current therapeutic cancer management. However, the proof of clinical utility of CTCs in informing therapeutic decision-making for e.g., breast cancer in clinical trials and associated translational research projects is facing the issues of low CTC positivity rates and low CTC numbers - even in the metastasized situation. To compensate for this dilemma, clinical CTC trials are designed as large multicenter endeavors with decentralized sample collection, processing and storage of products, making data management highly important to enable high-quality translational CTC research. AIM: In the DETECT clinical CTC trials we aimed at developing a custom-made, browser-based virtual database to harmonize and organize both decentralized processing and storage of LB specimens and to enable the collection of clinically meaningful LB sample. METHODS: ViBiBa processes data from various sources, harmonizes the data and creates an easily searchable multilayered database. RESULTS: An open-source virtual bio-banking web-application termed ViBiBa was created, which automatically processes data from multiple non-standardized sources. These data are automatically checked and merged into one centralized databank and are providing the opportunity to extract clinically relevant patient cohorts and CTC sample collections. SUMMARY: ViBiBa, which is a highly flexible tool that allows for decentralized sample storage of liquid biopsy specimens, facilitates a solution which promotes collaboration in a user-friendly, federalist and highly structured way. The source code is available under the MIT license from https://vibiba.com or https://github.com/asperciesl/ViBiBa.

Reflections on the OECD guidelines for in vitro skin absorption studies.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16-18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Safety and efficacy of stenting for aortic arch hypoplasia in patients with coarctation of the aorta.

BACKGROUND: Despite a successful repair procedure for coarctation of the aorta (CoA), up to two-thirds of patients remain hypertensive. CoA is often seen in combination with abnormal aortic arch anatomy and morphology. This might be a substrate for persistent hypertension. Therefore, we performed endovascular aortic arch stent placement in patients with CoA and concomitant aortic arch hypoplasia or gothic arch morphology. The goal of this retrospective analysis was to investigate the safety and efficacy of aortic arch stenting. METHODS: A retrospective analysis was performed in patients who underwent stenting of the aortic arch at the University Medical Center Utrecht. Measurements collected included office blood pressure, use of antihypertensive medication, invasive peak-to-peak systolic pressure over the arch, and aortic diameters on three-dimensional angiography. Data on follow-up were obtained at the date of most recent outpatient visit. RESULTS: Twelve patients underwent stenting of the aortic arch. Mean follow-up duration was 14 ± 11 months. Mean peak-to-peak gradient across the arch decreased from 39 ± 13 mm Hg to 7 ± 8 mm Hg directly after stenting (p < 0.001). There were no major procedural complications. Mean systolic blood pressure decreased from 145 ± 16 mm Hg at baseline to 128 ± 9 mm Hg at latest follow-up (p = 0.014). CONCLUSION: This retrospective study shows that stenting of the aortic arch is successful when carried out in a state-of-the-art manner. A direct optimal angiographic and haemodynamic result was shown. No major complications occurred during or after the procedure. At short- to medium-term follow-up a decrease in mean systolic blood pressure was observed.

Validation of the 1 µg short synacthen test: an assessment of morning cortisol cut-off values and other predictors.

BACKGROUND: Clinical practice shows that many low-dose short synacthen tests (LD-SSTs) for diagnosing adrenal insufficiency in an outpatient setting have a normal outcome and could be considered superfluous. The objective of this study is to provide a guideline to safely reduce the number of unnecessarily performed LD-SSTs. METHODS: Data of LD-SSTs performed in outpatients were collected. Optimal morning cortisol cut-off values were determined using ROC analysis. Subsequently the predictive value of several variables was tested using univariable and multivariable logistic regression analyses. RESULTS: A morning cortisol lower cut-off value of 145 nmol/l (specificity 89.9%, positive predictive value 90.0%) and an upper cut-off value of 375 nmol/l (sensitivity 100.0%, negative predictive value 100.0%) were found. Chronic fatigue symptoms and symptoms of hypotension or orthostasis as the main reason for performing the test predict a normal outcome. The use of glucocorticosteroids predicts an abnormal outcome of the LD-SST. Oral, topical, nasal and inhaled glucocorticosteroids are each significant predictors when analysed specifically for predicting central adrenal insufficiency. CONCLUSION: By using morning cortisol cut-off values of 145 nmol/l and 375 nmol/l instead of the conventional cut-off values, the number of LD-SSTs performed in an outpatient setting can be reduced by 12%, while maintaining high sensitivity and specificity. Furthermore, the outcome of the LD-SST can be predicted by additional variables such as the indication for performing the test and the use of glucocorticosteroids. Different routes of administration of glucocorticosteroids such as inhalation or topical use should be taken into account when central insufficiency is suspected.

[Immunogenicity of biosimilars]. / Immunogeniciteit van biosimilars.

Biosimilars of more complex recombinant protein drugs, such as monoclonal antibodies and fusion proteins, are entering the market. The manufacturer should demonstrate that its product does not show any relevant differences in terms of quality characteristics, biological activity, safety and efficacy compared to the reference product, as outlined in EMA guidelines. This should be established with an extensive comparability exercise. One aspect that is subject to particular scrutiny is the immunogenicity of the biosimilar and the reference medicinal product. For three cases, one etanercept and two infliximab biosimilars, we describe how data are assessed and an opinion is reached by authorities. Not in all cases unanimity exists whether all remaining uncertainties on biosimilarity have been resolved satisfactorily before marketing authorisation. The Dutch Medicines Evaluation Board therefore emphasises that even after marketing authorisation, biosimilars and other biologicals should be properly monitored.

Fractures in pituitary adenoma patients from the Dutch National Registry of Growth Hormone Treatment in Adults.

PURPOSE: The effects of growth hormone (GH) replacement therapy on fracture risk in adult GH deficient (GHD) patients with different etiologies of pituitary GHD are not well known, due to limited data. The aim of this study was to investigate characteristics and fracture occurrence at start of (baseline) and during long-term GH replacement therapy in GHD adults previously treated for Cushing's disease (CD) or acromegaly, compared to patients with previous nonfunctioning pituitary adenoma (NFPA). METHODS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severe GHD adults, all patients using ≥30 days of GH replacement therapy with previous NFPA (n = 783), CD (n = 180) and acromegaly (n = 65) were selected. Patient characteristics, fractures and potential influencing factors were investigated. RESULTS: At baseline, patients with previous CD were younger, more often female and had more often a history of osteopenia or osteoporosis, whereas patients with previous acromegaly had more often received cranial radiotherapy and a longer duration between treatment of their pituitary tumor and start of adult GH replacement therapy. During follow-up, a fracture occurred in 3.8 % (n = 39) of all patients. Compared to patients with previous NFPA, only patients with previous acromegaly had an increased fracture risk after 6 years of GH replacement therapy. CONCLUSIONS: During GH replacement therapy, an increased fracture risk was observed in severe GHD adult patients previously treated for acromegaly, but not in those previously treated for CD, compared to severe GHD adult patients using GH replacement therapy because of previous NFPA. Further studies are needed to confirm these findings and to elucidate potential underlying mechanisms.

Tumor Recurrence or Regrowth in Adults With Nonfunctioning Pituitary Adenomas Using GH Replacement Therapy.

CONTEXT: GH replacement therapy (GH-RT) is a widely accepted treatment in GH-deficient adults with nonfunctioning pituitary adenoma (NFPAs). However, some concerns have been raised about the safety of GH-RT because of its potentially stimulating effect on tumor growth. OBJECTIVE: The aim of this study was to evaluate tumor progression in NFPA patients using GH-RT. DESIGN, SETTING, AND PATIENTS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severely GH-deficient adults (1998-2009), all NFPA patients with ≥ 30 days of GH-RT were selected (n = 783). Data were retrospectively collected from the start of GH-RT in adulthood (baseline). MAIN OUTCOME MEASURE: Tumor progression, including tumor recurrence after complete remission at baseline and regrowth of residual tumor. RESULTS: Tumor progression developed in 12.1% of the patients after a median (range) time of 2.2 (0.1-14.9) years. Prior radiotherapy decreased tumor progression risk compared to no radiotherapy (hazard ratio = 0.16; 95% confidence interval, 0.09-0.26). Analysis in 577 patients with available baseline imaging data showed that residual tumor at baseline increased tumor progression risk compared to no residual tumor (hazard ratio = 4.5; 95% confidence interval, 2.4-8.2). CONCLUSIONS: The findings in this large study were in line with those reported in literature and provide further evidence that GH-RT does not appear to increase tumor progression risk in NFPA patients. Although only long-term randomized controlled trials will be able to draw firm conclusions, our data support the current view that GH-RT is safe in NFPA patients.

Cerebrovascular events, secondary intracranial tumors, and mortality after radiotherapy for nonfunctioning pituitary adenomas: a subanalysis from the Dutch National Registry of Growth Hormone Treatment in Adults.

CONTEXT: Radiotherapy is frequently administered as adjuvant treatment in patients with clinically nonfunctioning pituitary adenomas (NFPAs). However, concerns have been raised about potential long-term side effects, including cerebrovascular events (CVEs) and secondary intracranial tumors. OBJECTIVE: The aim of this study was to analyze the risk of CVEs, secondary intracranial tumors, and mortality in irradiated (IRR) NFPA patients, compared with NFPA patients who were not irradiated (non-IRR). DESIGN, SETTING, AND PATIENTS: The study cohort included 806 patients with a NFPA from the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide long-term surveillance study in severe GH-deficient adult patients. IRR patients (n = 456) were compared with non-IRR patients (n = 350). MAIN OUTCOME MEASURES: CVEs, secondary intracranial tumors, and mortality were measured. RESULTS: Sixty-nine subjects developed a CVE. In men, but not in women, the incidence of a CVE was significantly higher in IRR patients than in non-IRR patients (hazard ratio 2.99, 95% confidence interval 1.31-6.79). A secondary intracranial tumor developed in five IRR patients and two non-IRR patients. After adjustment for age, radiotherapy was not associated with mortality. CONCLUSIONS: The incidence of secondary intracranial tumors and mortality did not differ between IRR and non-IRR patients. However, a CVE was found significantly more frequently in IRR men but not in women. Further research into the long-term effects of cranial radiotherapy seems mandatory. The potential risks of radiotherapy have to be taken into account when radiotherapy is considered in NFPA patients, and long-term follow-up is recommended.

In vitro permeation of platinum through African and Caucasian skin.

The majority of the South African workforce are Africans, therefore potential racial differences should be considered in risk and exposure assessments in the workplace. Literature suggests African skin to be a superior barrier against permeation and irritants. Previous in vitro studies on metals only included skin from Caucasian donors, whereas this study compared the permeation of platinum through African and Caucasian skin. A donor solution of 0.3 mg/ml of potassium tetrachloroplatinate (K2PtCl4) dissolved in synthetic sweat was applied to the vertical Franz diffusion cells with full thickness abdominal skin. Skin from three female African and three female Caucasian donors were included (n=21). The receptor solution was removed at various intervals during the 24 h experiment, and analysed with high resolution inductively coupled plasma-mass spectrometry (ICP-MS). Skin was digested and analysed by inductively coupled plasma-optical emission spectrometry (ICP-OES). Significantly higher permeation of platinum through intact African skin (p=0.044), as well as a significantly higher mass of platinum retention in African skin in comparison with Caucasian skin (p=0.002) occurred. Significant inter-donor variation was found in both racial groups (p<0.02). Results indicate that African workers have increased risk of dermal permeation and therefore possible sensitisation caused by dermal exposure to platinum salts. These results are contradictory to limited literature suggesting a superior barrier in African skin and further investigation is necessary to explain the higher permeation through African skin.

In vitro permeation of platinum and rhodium through Caucasian skin.

During platinum group metals (PGMs) refining the possibility exists for dermal exposure to PGM salts. The dermal route has been questioned as an alternative route of exposure that could contribute to employee sensitisation, even though literature has been focused on respiratory exposure. This study aimed to investigate the in vitro permeation of platinum and rhodium through intact Caucasian skin. A donor solution of 0.3mg/ml of metal, K2PtCl4 and RhCl3 respectively, was applied to the vertical Franz diffusion cells with full thickness abdominal skin. The receptor solution was removed at various intervals during the 24h experiment, and analysed with high resolution ICP-MS. Skin was digested and analysed by ICP-OES. Results indicated cumulative permeation with prolonged exposure, with a significantly higher mass of platinum permeating after 24h when compared to rhodium. The mass of platinum retained inside the skin and the flux of platinum across the skin was significantly higher than that of rhodium. Permeated and skin retained platinum and rhodium may therefore contribute to sensitisation and indicates a health risk associated with dermal exposure in the workplace.

The evaluation and quantification of respirable coal and silica dust concentrations: a task-based approach.

Silicosis and coal worker's pneumoconiosis are serious occupational respiratory diseases associated with the coal mining industry and the inhalation of respirable dusts containing crystalline silica. The purpose of this study (funded by the Mine Health and Safety Council of South Africa) was to evaluate the individual contributions of underground coal mining tasks to the respirable dust and respirable silica dust concentrations in an underground section by sampling the respirable dust concentrations at the intake and return of each task. The identified tasks were continuous miner (CM) cutting, construction, transfer of coal, tipping, and roof bolting. The respirable dust-generating hierarchy of the tasks from highest to lowest was: transfer of coal > CM right cutting > CM left cutting > CM face cutting > construction > roof bolting > tipping; and for respirable silica dust: CM left cutting > construction > transfer of coal > CM right cutting. Personal exposure levels were determined by sampling the exposures of workers performing tasks in the section. Respirable dust concentrations and low concentrations of respirable silica dust were found at the intake air side of the section, indicating that air entering the section is already contaminated. The hierarchy for personal respirable dust exposures was as follows, from highest to lowest: CM operator > cable handler > miner > roof bolt operator > shuttle car operator, and for respirable silica dust: shuttle car operator > CM operator > cable handler > roof bolt operator > miner. Dust control methods to lower exposures should include revision of the position of workers with regard to the task performed, positioning of the tasks with regard to the CM cutting, and proper use of the line curtains to direct ventilation appropriately. The correct use of respiratory protection should also be encouraged.

Low prevalence of hypopituitarism after traumatic brain injury: a multicenter study.

OBJECTIVE: Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, such as timing of evaluation and the severity of the trauma. Aim To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation. Study design Cross-sectional study. PATIENTS AND METHODS: We included 112 patients with TBI, hospitalized for at least 3 days and duration of follow-up >1 year after TBI from five (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (n=90) or, when contraindicated, ACTH stimulation and/or CRH stimulation tests and a GH releasing hormone-arginine test (n=22). Clinical evaluation included quality of life questionnaires. RESULTS: We studied 112 patients (75 males), with median age 48 years and mean body mass index (BMI) 26.7±4.8 kg/m(2). Mean duration of hospitalization was 11 (3-105), and 33% of the patients had a severe trauma (Glasgow Coma Scale <9) after TBI. The mean duration of follow-up was 4 (1-12) years. Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe GH deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (P=0.002). CONCLUSION: In this study, the prevalence of hypopituitarism during long-term follow-up after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI.

Dutch National Registry of GH Treatment in Adults: patient characteristics and diagnostic test procedures.

OBJECTIVE: The Dutch National Registry of GH Treatment in Adults was established in 1998 as an initiative of the Ministry of Health. The main goals were to gain more insight into long-term efficacy, safety, and costs of GH therapy (GHT) in adult GH-deficient (GHD) patients in The Netherlands. METHODS: Baseline patient characteristics and diagnostic test procedures were evaluated. RESULTS: Until January 2009 in roughly 10 years, 2891 patients (1475 men and 1416 women, mean age 43.5±16.5 years) were registered. GHD was of childhood-onset (CO) in over 20% of the patients and of isolated in 11%. The most common causes of GHD were pituitary tumors and/or their treatment, craniopharyngiomas, and idiopathic GHD. In 85% of the patients, a GH stimulation test was performed, in the majority an insulin tolerance test (ITT) (49%) or a combined GHRH-arginine test (25%). In 12% of the patients, IGF1 levels were ≤-2 s.d. combined with two or more additional pituitary hormone deficits, and in 2%, it concerned patients with CO-GHD continuing GHT in adulthood. Over the years, the test of first choice shifted from ITT toward GHRH-arginine test. CONCLUSION: Nearly, 2900 patients were included in the nationwide surveillance database of the Dutch National Registry of GH Treatment in Adults until January 2009. Baseline patient characteristics are comparable to that reported previously. In 85% of these patients, the diagnosis of GHD was established by provocative testing, particularly an ITT or a combined GHRH-arginine test, with an evident increase in the percentage of GHRH-arginine tests being performed in the last years.

Antithyroid drug regimens before and after 131I-therapy for hyperthyroidism: evidence-based?

BACKGROUND: In view of the new national guideline on thyroid dysfunction, the evidence base for current practice as well as the new guideline is assessed with regard to the use of antithyroid drugs (ATDs) before and after radioiodine (131I) therapy. METHODS: In December 2006, we surveyed 16 hospitals by telephone about different aspects of their antithyroid drug regimen: all eight academic centres and eight nonacademic teaching hospitals. The literature was searched for an evidence-based answer to each question in the inquiry. RESULTS: 13 of 16 hospitals (81%) use antithyroid drugs for pretreatment before 131I. ATDs are discontinued on average four days before 131I or diagnostic scan. However, 27% stop only three days beforehand, which may diminish the effect of 131I. Propylthiouracil (PTU) is also withdrawn four days before 131I, although the literature shows that PTU diminishes the effect of 131I even if it is stopped 15 days beforehand. Resumption of ATDs after 131I to prevent thyrotoxicosis is common practice (81%). One hospital (6%) never restarts ATDs, two (13%) only by indication. Adjunctive treatment consists of combination therapy in 93%, is usually resumed within two days after 131I therapy, and then continued for two to six months. Routine adjunctive treatment is not evidence-based and may be limited to a high-risk subset, especially elderly patients (>70 years) and patients with cardiac comorbidity. Resumption of ATDs within five to seven days after 131I may diminish the effect of 131I. CONCLUSION: Antithyroid drug regimens in the Netherlands are heterogeneous. The evidence base of current practice and the new guideline are discussed.

Two novel, putatively cell wall-associated and glycosylphosphatidylinositol-anchored alpha-glucanotransferase enzymes of Aspergillus niger.

In the genome sequence of Aspergillus niger CBS 513.88, three genes were identified with high similarity to fungal alpha-amylases. The protein sequences derived from these genes were different in two ways from all described fungal alpha-amylases: they were predicted to be glycosylphosphatidylinositol anchored, and some highly conserved amino acids of enzymes in the alpha-amylase family were absent. We expressed two of these enzymes in a suitable A. niger strain and characterized the purified proteins. Both enzymes showed transglycosylation activity on donor substrates with alpha-(1,4)-glycosidic bonds and at least five anhydroglucose units. The enzymes, designated AgtA and AgtB, produced new alpha-(1,4)-glycosidic bonds and therefore belong to the group of the 4-alpha-glucanotransferases (EC 2.4.1.25). Their reaction products reached a degree of polymerization of at least 30. Maltose and larger maltooligosaccharides were the most efficient acceptor substrates, although AgtA also used small nigerooligosaccharides containing alpha-(1,3)-glycosidic bonds as acceptor substrate. An agtA knockout of A. niger showed an increased susceptibility towards the cell wall-disrupting compound calcofluor white, indicating a cell wall integrity defect in this strain. Homologues of AgtA and AgtB are present in other fungal species with alpha-glucans in their cell walls, but not in yeast species lacking cell wall alpha-glucan. Possible roles for these enzymes in the synthesis and/or maintenance of the fungal cell wall are discussed.

Minor disturbances in central nervous system function in familial neurohypophysial diabetes insipidus.

Familial neurohypophysial diabetes insipidus (FNDI) is caused by a defect in vasopressin synthesis and release as a result of a heterozygous mutation in the gene for the vasopressin prohormone. The predominant characteristic of FNDI is excessive thirst and urine production. However, vasopressin not only has peripheral endocrine effects, but also regulates numerous brain functions. We investigated whether central functions are affected in FNDI, by studying neuropsychological functioning of 23 affected members (15 males, 8 females) of a large family carrying a T/G transition mutation at nucleotide 2110 (codon 116) of the vasopressin prohormone gene (Cys116Gly). The relatively large number of family members with FNDI made it possible to compare cognitive and other CNS effects in these subjects with those of family members without FNDI. Thirty-seven adult volunteers (20 males, 17 females) from the same family and 11 non-family members (2 males, 9 females) from northern part of The Netherlands were tested. The mean age of the subjects was 35+/-12 years. Of the 63 quantified neuropsychological parameters few were statistically different between the subjects with FDNI and control subjects. Memory retrieval processes and sustained attention were worse in the subjects with FDNI. Moreover, these individuals reported significantly fewer symptoms of agoraphobia and miscellaneous symptoms, and had significantly lower scores on a scale measuring anger. The performance of FNDI subjects on an auditory verbal learning test (the 15-word test learning trial) was worse, but not significantly so, than that of the subjects without FDNI. There were subjective complaints of forgetfulness and slow recalls and those were observed in daily life by non-affected family members. These moderate differences in neuropsychological performance indicate that in human FNDI parvocellular vasopressin systems that supply the brain may be less affected or give no such serious disabilities, than the magnocellular hypothalamo-neurohypophysial system that provides vasopressin for endocrine regulation of water homeostasis.