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Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks. Copyright

Aim: To assess the effects of recombinant human growth hormone (rhGH) treatment in children with Prader–Willi syndrome. Design: A 1-year study and an observational follow-up visit 10 years later. Methods: In 20 patients with Prader–Willi syndrome (PWS): clinical assessment, laboratory tests, body composition analysis by dual energy X-ray absorptiometry, sleep polygraphy, health-related quality of life assessed by 16D. Results: Only two patients had normal growth hormone secretion at baseline. All patients were significantly shorter than their expected heights, but experienced catch-up growth during growth hormone treatment. At follow-up, 13 patients had reached adult heights and were markedly taller than historical controls. The cumulative dose of rhGH over 10 years correlated inversely with the total body fat percentage (p = 0.033). However, patients remained severely obese at 10 years. Sleep polygraphy was abnormal in more than half of the patients. Health-related quality of life of the patients remained substantially below that of normal population. Conclusion: Growth hormone markedly improved adult height in subjects with PWS when compared to historical data. The cumulative dose of growth hormone correlated with reduction in body fat; nevertheless, patients remained severely obese.

Viime vuosina elintarvikealalla on noussut erityisen huomion kohteeksi tuorevihannesten turvallisuus. Vihanneksilta vaaditaan entistä pitempää säilyvyyttä, mutta mikrobiologisen turvallisuuden takaavista tuotantomenetelmistä ei ole riittävästi luotettavaa näyttöä. Vuonna 2009 käynnistyneen Tuorevihannesten hygienia (Tuovi) -hankkeen tavoitteena on tuorevihannesten viljely- ja tuotantoprosessien kehittäminen. Vihanneksista tarkastellaan erityisesti porkkanaa ja salaattia. Hankkeessa tarkastellaan koko tuotantoketjua, raaka-aineen tuotantoa, varastointia, prosessointia ja kylmäketjua aina vähittäiskauppaan saakka. Hankkeessa selvitetään tuotantotilojen, raaka-aineiden ja tuotteiden hygieenistä laatua, sekä kehitetään menetelmiä ja erilaisia teknologisia ratkaisuja tuorevihannesten hygieniatason nostamiseksi ja ylläpitämiseksi. Hankkeessa selvitetään myös vihannesten prosessoinnista aiheutuvia ympäristövaikutuksia. Tavoitteena on prosesseja kehittämällä vähentää syntyvien jätteiden ja jätevesien määrää sekä minimoida niistä aiheutuvaa riskiä ympäristölle ja ihmisten terveydelle.Haitalliset mikrobit voivat päätyä vihanneksiin peltomaasta tai kasteluvedestä. Mikrobit voivat olla kasvin pinnalla, mutta myös ehjän kasvin sisällä, joten mikrobien pääsy kosketuksiin kasvisten kanssa voi olla riski kuluttajien turvallisuudelle. Suomessa on viime vuosina todettu mm. Yersinia-epidemioita, joiden yleistymisen estämiseksi tarvitaan lisätutkimusta tuotanto-olosuhteista ja prosessihygieniasta. Alkuvaiheessa ongelmia voidaan ehkäistä noudattamalla hyviä viljelymenetelmiä (GAP, Good Agricultural Practice) ja omavalvontaa. Nämä ohjeet sisältävät toimenpiteitä, jotka kohdistuvat mm. kasteluveteen, lannoitteisiin, biojätteisiin, työntekijöiden terveyteen, hygieniaan, tuotantolaitoksiin ja käsittelytiloihin, pakkauksiin, kuljetuksiin, jakeluun sekä jäljitettävyyteen. Mikrobit voivat päästä vihanneksiin myös vihannesten prosessoinnin aikana. Omavalvonta, jossa hyödynnetään mikrobiologisia testausmenetelmiä, on tärkeä työväline prosessien turvallisuuden seurannassa. Tämän lisäksi voidaan tarvittaessa käyttää erilaisia teknisiä käsittelymenetelmiä. Tuorevihannesten jatkojalostuksessa on tarpeen soveltaa uutta tutkimustietoa vihannesten mikrobiologisen laadun turvaamiseksi.

Hankkeen tavoitteena oli elinkaariarvioinnin menetelmin arvioida hunajamarinoitujen broilerin fi­leesuikaleiden tuotannon aiheuttama ympäristökuormitus todelliseen toimintoverkkoon ja ­prosesseihin perustuen, sekä arvioida niiden pohjalta tuotannosta aiheutuvat ympäristövaikutukset. Tavoitteena oli selvittää, mitkä tuotantovaiheet vaikuttavat ympäristövaikutuksiin eniten, sekä etsiä ja tarkastella järjestelmän ympäristökestävyyttä parantavia mahdollisuuksia.Elinkaariarviointi perustui broilerin fileesuikaleiden todellisiin tuotantoprosesseihin vuosina 2003­–2005, ja siihen sisällytettiin kaikki olennaiset vaiheet rehuntuotannossa tarvittavien tuotanto­panosten valmistamisesta ja untuvikkojen tuotannosta aina kaupassa myytäviin valmiisiin tuotteisiin asti. Elinkaaren vaiheista selvitettiin primäärienergian käyttö, viljelyyn tarvittava peltopinta­ala, sivu­virtojen lajit, määrät ja käyttökohteet, kaatopaikkajätteen määrä sekä suorat ja välilliset päästöt ilmaan ja vesistöihin. Ympäristökuormitustiedoista laskettiin vaikutukset ilmastonmuutokseen, happamoitu­miseen, vesien rehevöitymiseen ja alailmakehän otsonin muodostumiseen.Tutkituissa ympäristövaikutusluokissa broilerien kasvatus ja rehun tuotanto muodostivat valta­osan koko toimintoverkon aiheuttamista vaikutuksista. Broilerien rehuketjun merkitys näkyi selvim­min ilmastonmuutosvaikutuksessa (36 % koko toimintoverkon ilmastonmuutosvaikutuksesta), primää­rienergian kulutuksessa (25 %) ja rehevöitymisessä (66 %). Broilerien kasvattamisen merkitys oli mer­kittävin tuotantovaihe happamoitumisen (60 %) ja alailmakehän otsonin muodostumisen (57 %) kan­nalta.Toimintoverkon primäärienergian tarpeesta noin 90 % katettiin uusiutumattomilla energianläh­teillä. Rehuketjun lisäksi broilerien kasvatus, pakkausten valmistaminen ja vähittäiskauppa olivat mer­kittäviä energian käyttäjiä. Energiankulutuksen ja hiilidioksidipäästöjen välillä oli selvä yhteys, mutta muihin päästöihin energiankulutus ei koko toimintoverkon tasolla heijastunut. Hiilidioksidi oli eniten ilmastonmuutosta aiheuttava kasvihuonekaasu. Sen päästöt myös jakaantuivat tasaisemmin toiminto­verkon eri osiin kuin muut kasvihuonekaasupäästöt, jotka olivat pääosin rehuntuotannon ja broilerin­kasvatuksen metaani­ ja dityppioksidipäästöjä. Torjunta­aineiden ekotoksisuusvaikutustarkastelu pal­jasti marinadin valmistamiseen tarvittavan rypsin viljelyn aiheuttavan noin 95 % toimintoverkon kai­kesta torjunta­aineiden käytöstä johtuvasta ekotoksisuusvaikutuksesta, vaikka rypsin osuus pellonkäy­töstä oli vain kymmenesosa.Yhdennetyssä ympäristövaikutusten tarkastelussa rehevöittävät päästöt muodostivat lähes puolet ja happamoittavat päästöt noin neljäsosan tuotejärjestelmän kokonaisympäristövaikutuksista. Näin ollen rehuviljan viljelyn ja broilerien kasvattamisen päästöjen vähentämisellä saavutettaisiin merkittä­vimmät ympäristöhyödyt.

Esikäsitellyn perunan ja juuresten kysyntä on jatkuvassa kasvussa. Pienimuotoista kuorimotoimintaa harjoitetaan tiloilla, jotka viljelevät itse kuorittavat perunat ja juurekset. Monet kuorimot ovat kuitenkin laajentuneet yrityksiksi, jotka ostavat muualta osan tai kaiken kuorittavan raaka-aineen. Raaka-aineen määrä tilakuorimoilla vaihtelee sadasta tonnista tuhansiin tonneihin vuodessa. Perunan- ja juuresten kuorinta on ympäristöluvanvaraista toimintaa ja uusissa luvissa edellytetään mm. tehokasta orgaanisen aineen sekä ravinteiden poistoa jätevesistä.Pesu- ja kuorintaprosesseissa syntyy erilaisia jätevesiä, joiden laatu ja määrä vaihtelevat suuresti kuorintamenetelmästä riippuen. Perunoiden ja juuresten pesusta tulee multavettä ja multalietettä, kuorinnasta taas solunestettä ja kasviainesta sisältäviä vesiä sekä juuresten huuhteluvesiä. Tilojen ja laitteiden puhtaanapidosta muodostuu erilaisia pesuvesiä. Jätevesimäärät tilakuorimoilla vaihtelevat toiminnan koosta ja kuorintamenetelmistä riippuen yleensä 5 – 50 m3 päivässä. Keskikokoisen peruna- tai juureskuorimon jätevesikuormitus vastaa jopa tuhannen asukkaan taajaman puhdistamattomien jätevesien kuormitusta.Kuorimotoiminnan jätevedet sisältävät paljon orgaanista ainetta, mikä on pääosin liukoisessa muodossa. Biologinen hapenkulutus on yleensä välillä 2 000 – 10 000 mg/l. Jätevedet ovat myös happamia, pH 4 – 5, ja sisältävät runsaasti ravinteita, kuten fosforia ja typpeä.Kuorimojätevedet on käsiteltävä tehokkaasti ennen niiden pääsyä ympäristöön. Jätevesien käsittelystä aiheutuu yritykselle huomattavia kustannuksia. Yrittäjän kannalta helppo ja kokonaiskustannuksiltaan edullinen ratkaisu olisi jäteveden johtaminen kunnalliseen tai paikalliseen jätevedenkäsittelylaitokseen. Haja-asutusalueilla viemäriverkkoon liittyminen on kuitenkin harvoin mahdollista.Hankkeessa oli mukana kahdeksan kuorimoa, joiden jätevedenkäsittelyä seurattiin. Yhdessä yrityksessä oli panospuhdistamo ja toiseen sellainen rakennettiin hankkeen aikana, yhdessä oli biosuodin, kahdessa kohteessa kemiallinen jätevedenkäsittely ja laskeutusallas, yhdessä kohteessa laskeutusallas+imeytyskenttä+lammikko -käsittely. Yhdessä kohteessa selvitettiin mahdollisuutta liittyä kunnallisen jätevedenkäsittelyn piiriin.Tutkituista jätevedenkäsittelymenetelmistä vain panospuhdistamolla päästiin tavoiteltuihin puhdistustuloksiin, typpi saatiin poistettua jopa yli odotusten.

Contains fulltext : 71147raaijmakers.pdf (Publisher’s version ) (Open Access) BACKGROUND: Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear. PATIENTS AND METHODS: A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy. RESULTS: At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height. CONCLUSION: This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

Exercise-induced hyperinsulinism (EIHI) is a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. We aimed to identify the molecular basis of this novel disorder of beta -cell regulation. EIHI mapped to chromosome 1 (LOD score 3.6) in a genome scan performed for two families with 10 EIHI-affected patients. Mutational analysis of the promoter of the SLC16A1 gene, which encodes monocarboxylate transporter 1 (MCT1), located under the linkage peak, revealed changes in all 13 identified patients with EIHI. Patient fibroblasts displayed abnormally high SLC16A1 transcript levels, although monocarboxylate transport activities were not changed in these cells, reflecting additional posttranscriptional control of MCT1 levels in extrapancreatic tissues. By contrast, when examined in beta cells, either of two SLC16A1 mutations identified in separate pedigrees resulted in increased protein binding to the corresponding promoter elements and marked (3- or 10-fold) transcriptional stimulation of SLC16A1 promoter-reporter constructs. These studies show that promoter-activating mutations in EIHI induce SLC16A1 expression in beta cells, where this gene is not usually transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin release despite ensuing hypoglycemia. These findings describe a novel disease mechanism based on the failure of cell-specific transcriptional silencing of a gene that is highly expressed in other tissues.

Background: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. Aim: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. Methods: Patients were randomized to either 0.1 IU/kg (n=18) or 0.2 IU/kg (n=17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y. Results: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change. Conclusion: GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature. (Less)

Summary Objective Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is characterized by chronic mucocutaneous candidiasis and autoimmune destruction of endocrine organs. The resulting endocrinopathies and their treatment may impact bone health. The purpose of our study was to assess bone health and its correlates in adult patients with APECED. Patients and methods Twenty-five adults (12 males) with APECED were prospectively assessed. Data on their previous medical history were collected from hospital records. Areal bone mineral density (aBMD) for the lumbar spine (L1–L4), femoral neck and whole body as well as volumetric BMD (vBMD) for the lumbar spine (L2–L4) were measured with dual-energy X-ray absorptiometry (DXA). Results Mean age was 34 years (range 21–59 years). All patients had 1–4 autoimmune endocrinopathies, the most common being adrenocortical failure (20 patients) and hypoparathyroidism (18 patients). Osteopaenia or osteoporosis was present in 28%. The median (range) aBMD Z-scores were for the lumbar spine −0·3 (−2·3 to +3·3) and for the femoral neck, −0·1 (−2·2 to +2·0). The BMD Z-scores tended to be higher in patients with hypoparathyroidism than in patients with normal parathyroid function (at the lumbar spine +0·4 vs.–1·2, P = 0·016, and at the femoral neck +0·3 vs.−0·4, P = 0·090). Adrenocortical failure had a negative impact on BMD. Six patients had had low-impact fractures and three were diagnosed with compression fractures. Conclusions Despite the complex endocrine problems, the overall prevalence of symptomatic osteoporosis is low in adults treated for APECED. Osteopaenia is frequently observed and warrants follow-up. Treated hypoparathyroidism may have a positive, and adrenocortical failure a negative, impact on bone health.

Item does not contain fulltext Aarskog syndrome is an X-linked disorder characterized by faciogenital dysplasia and short stature. The present study set out to determine the effect of growth hormone (GH) therapy in patients with Aarskog syndrome enrolled in KIGS--the Pharmacia International Growth Database. Twenty-one patients (20 males) were evaluated. Median age at start of treatment was 8.3 years (10-90th percentiles, 5.1-14.1 years) and median height SDS was -2.8 (10-90th percentiles, -2.1 to -3.7). The median dose of GH was 0.22 mg/kg/week (10-90th percentiles, 0.15-0.30 mg/kg/week) given at a median frequency of six (4-7) times per week. Prepubertal patients were followed longitudinally for 1 year (n = 13) or 3 years (n = 7). After 1 year, the median height SDS had improved from -2.8 to -2.3 in 13 patients. After 3 years, height SDS had improved significantly (p

Forty-one children5 years of age at kidney transplantation (TX) were investigated for growth, bone age, and renal function up to 7 years ( n=26) after TX. All children received triple immunosuppression, including alternate-day corticosteroid treatment. Catch-up growth was seen in 81% of 30 children without growth hormone (GH) treatment. Children2 years of age without GH had a mean height standard deviation score (hSDS) of -1.1+/-0.8 at TX and -1.1+/-0.5 at 7 years; children between 2 and 5 years improved their hSDS from -1.9+/-0.9 to -0.4+/-0.8 ( P0.0001). The hSDS at TX correlated inversely with the DeltahSDS from TX to 7 years ( r=-0.80, P=0.0002). Glomerular filtrations rate (GFR) at 5 years post TX correlated with the subsequent growth rate from 5 to 7 years TX ( r=0.58, P=0.01). Catch-up growth was seen in all 11 children receiving GH. Their mean hSDS improved from -2.5+/-0.9 to -1.1+/-0.9 ( P0.0001). In the majority of children receiving a kidney graft in early life, triple immunosuppression with alternate-day steroids can ensure catch-up growth. In children5 years of age at TX, growth is predicted better by the degree of stunting than by age.

Summary Background The role of oestrogens in the closure of growth plates in both sexes is unequivocal. We postulated that inhibition of oestrogen synthesis in boys with delayed puberty would delay maturation of the growth plates and ultimately result in increased adult height. Methods We did a randomised, double-blind, placebo-controlled study in which we treated boys with constitutional delay of puberty with testosterone and placebo, or testosterone and letrozole. Boys who decided to wait for the spontaneous progression of puberty without medical intervention composed the untreated group. Findings Letrozole effectively inhibited oestrogen synthesis and delayed bone maturation. Progression of bone maturation was slower in the letrozole group than in the placebo group. In 18 months, bone age had advanced 1·1 (SD 0·8) years in the untreated group and 1·7 (0·9) years in the group treated with testosterone and placebo, but only 0·9 (0·6) years in the letrozole group (p=0·03 between the treatment groups). Predicted adult height did not change significantly in the untreated group and in the placebo group, whereas in the group treated with letrozole the increase was 5·1 (3·7) cm (p=0·004). Interpretation Our findings suggest that if oestrogen action is inhibited in growing adolescents, adult height will increase. This finding provides a rationale for studies that aim to delay bone maturation in several growth disorders.

Linear growth is often impaired after successful liver transplantation. The cause is multifactorial; poor graft function and long term glucocorticoid treatment are the main factors responsible. The efficacy and safety of recombinant human GH (rhGH) treatment were assessed in eight growth-retarded children (five boys and three girls) with liver transplants. Immunosuppression comprised azathioprine, cyclosporin, and methylprednisolone. rhGH was administered in a dose of 1 IU/kg x week, given by daily sc injections. The median age at the start of treatment was 9.7 yr (range, 5.9-14.9 yr). All but one of the patients remained prepubertal during treatment. The median growth rate increased from 3.2 to 7.l cm/yr (P = 0.025) and height SD score increased from -3.9 to -3.1 (P = 0.036) during the first year of rhGH treatment. Serum insulin-like growth factor I and insulin-like growth factor-binding protein-3 levels increased significantly during treatment. Graft function was normal in all except one patient, and no rejections or other serious side-effects were documented. In conclusion, rhGH treatment is effective in short, non-GH-deficient, liver-transplanted children receiving long term glucocorticoid treatment. Due to potential risk of allograft rejection, close monitoring of liver function and immunosuppression is required.

Linear growth is more often impaired after liver than after renal transplantation (Tx) in childhood. As similar triple immunosuppression was used in our liver and renal transplant recipients, we were able to compare growth and endocrine function between 19 prepubertal liver and 35 renal transplant recipients. There were no significant differences in median age, weight-for-height index, or height standard deviation score at Tx. Seventy-eight percent of the liver Tx patients, but only 7% of the renal Tx patients, were below the normal range for height 3 years after Tx. Graft function was good in both liver and renal transplant recipients 3 years after Tx. There was no significant difference in growth hormone secretion, serum insulin-like growth factor (IGF)-I, and IGF-binding protein-3 levels, or in methylprednisolone and cyclosporine doses. However, the blood cyclosporine levels were significantly higher in the liver transplant recipients (P = 0.001 1 year and P = 0.005 2 years after Tx). Cortisol production was significantly lower in the liver transplant recipients (P = 0.002 1 year and P = 0.049 2 years after Tx), which suggests greater steroid-mediated suppression of adrenal function. Growth inhibition is more often observed in liver than in renal transplant recipients on similar triple immunosuppression, and may not be related to deficient function of the growth hormone-IGF-I axis. Similar cyclosporine doses result in higher plasma levels of the drug and similar methylprednisolone doses result in more inhibited adrenal cortisol production in liver transplant recipients. In children with organ transplants, cyclosporine and methylprednisolone should be administered on an individual basis.

Testicular function was studied in 109 males aged 16 to 25 years surviving leukemia or solid tumors in childhood. The mean follow-up time was 10.3 years after diagnosis. Of the patients studied, 18 had received testicular radiotherapy, 35 central nervous system radiotherapy, and 3 total body radiotherapy. Twenty-one patients presented with incomplete puberty and 85 presented with small testicles (20 mL). Of the 109 patients, 43 had elevated concentrations of serum follicle-stimulating hormone (FSH) or serum FSH and leutinizing hormone. Compared with survivors of solid tumors, the patients surviving acute lymphoblastic leukemia (ALL) had inferior testicular status. This was also the case even when those treated with testicular radiotherapy were excluded. Twenty-six patients were receiving testosterone substitution therapy at the time of the study; 25 of whom were survivors of ALL. The probability of normospermia was 50% if both testicular volume and serum FSH were within normal limits and 0% if they were abnormal. Of the 86 patients over 18 years of age, 16 had evidence of normal testicular function. Of these 16, 8 patients had normospermia, only 1 of whom was a survivor of ALL. These findings suggest that ALL survivors have inferior testicular function compared with patients surviving solid tumors. Our findings confirm that testicular radiotherapy inevitably results in testicular damage, the degree of which is generally severe but variable in some individuals. We were unable to find an explanation for the individual tolerance to therapy, eg, age at diagnosis.

We studied 36 children with short stature during the initial 6 months of recombinant human growth hormone treatment and found an elevation in the mean concentration of hemoglobin (p < 0.001). The elevation was highest in the eight patients with bone dysplasia (p < 0.001). The mean concentration of serum ferritin decreased (p < 0.01) and that of serum transferrin increased (p < 0.001). The prevalence of iron deficiency increased from 6 patients (17%) with initial deficiency to 20 (56%) patients after therapy, indicating that iron supplementation should be considered in children treated with recombinant human growth hormone. (J PEDIATR 1994;125:242-5)

The aims of this national multicentre study in Finland were to evaluate whether the height velocity of patients with Turner syndrome would increase with the conventional human growth hormone (GH) therapy regimen normally given to GH-deficient children and whether girls with Turner syndrome actually show GH neurosecretory dysfunction. Finally, the study should show whether GH therapy improves height prognosis and, eventually, final height. Twenty-five girls with Turner syndrome, aged 7.5-14.4 years, entered the study. Their ability to secrete GH was determined and, surprisingly, several would have been classified as having GH deficiency. All girls received GH, 0.1 IU/kg/day (maximum dose 4 IU/day) s.c., and once over 12.5 years old, they also received oestradiol valerate and fluoxymesterone. They showed a convincing increase in height velocity, and rapid growth continued during the second year of therapy. The effect of GH therapy on final height is still unknown. The therapy was remarkably free of side-effects.

To assess the effects of recombinant human growth hormone (rhGH) treatment in children with Prader-Willi syndrome.A 1-year study and an observational follow-up visit 10 years later.In 20 patients with Prader-Willi syndrome (PWS): clinical assessment, laboratory tests, body composition analysis by dual energy X-ray absorptiometry, sleep polygraphy, health-related quality of life assessed by 16D.Only two patients had normal growth hormone secretion at baseline. All patients were significantly shorter than their expected heights, but experienced catch-up growth during growth hormone treatment. At follow-up, 13 patients had reached adult heights and were markedly taller than historical controls. The cumulative dose of rhGH over 10 years correlated inversely with the total body fat percentage (p = 0.033). However, patients remained severely obese at 10 years. Sleep polygraphy was abnormal in more than half of the patients. Health-related quality of life of the patients remained substantially below that of normal population.Growth hormone markedly improved adult height in subjects with PWS when compared to historical data. The cumulative dose of growth hormone correlated with reduction in body fat; nevertheless, patients remained severely obese.

This study highlights the need for the development of simple, efficient, and cost-effective farm-scale applications to treat wastewater arising from vegetable-peeling operations. The aim was to evaluate two full-scale biological wastewater treatment systems, a sequencing batch reactor (SBR) and a biofilter, and a chemical wastewater treatment system on farms carrying out peeling of vegetables. The types, design criteria and parameters of the processes, as well as properties of the untreated and treated wastewaters were presented and evaluated. Seven-day biochemical oxygen demand (BOD7) entering the SBR was 3100 +/- 529 mg l(-1) (mean +/- standard deviation). The results showed that the SBR was very stable and effective in the treatment of carrot-processing wastewaters, the BOD7 for effluent being about 10 mg l(-1). The biofilter examined did not operate well because the pH too low: the reduction for BOD7 was 63% and, for COD, 58%. When wastewater from potato processing was treated with aluminium sulphate and conveyed to an artificial pond, removal of BOD7 was 67% and that of COD 69%. This method is only suitable for pre- or post-treatment of these wastewaters. Control of the treatment processes appeared to be essential for their proper functioning.

Rapid infantile growth was the first clinical sign in patients (n = 51) with aspartylglycosaminuria, a lysosomal storage disorder. Even if young children with aspartylglycosaminuria were tall for their age, an early but weak pubertal growth spurt in both sexes resulted in reduced adult heights.

To define the clinical picture and course of the autosomal recessive disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), we report data from our 10-month to 31-year follow-up of 68 patients from 54 families, now 10 months to 53 years of age. The clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patients (60 percent), intestinal malabsorption in 6 (9 percent), and keratopathy in 2 (3 percent). All the patients had candidiasis at some time. The earliest endocrine component appeared at 19 months to 35 years of age. Hypoparathyroidism was present in 54 patients (79 percent), adrenocortical failure in 49 (72 percent), and gonadal failure in 15 (60 percent) of the female patients greater than or equal to 13 years of age and 4 (14 percent) of the male patients greater than or equal to 16 years of age. There were multiple endocrine deficiencies in half the patients. From 4 to 29 percent of the patients had periodic malabsorption, gastric parietal-cell atrophy, hepatitis, alopecia, vitiligo, or a combination of these conditions. Dental-enamel hypoplasia and keratopathy were also frequent but were not attributable to hypoparathyroidism. In the patients whose initial manifestation (other than candidiasis) was adrenal failure, the other components developed less often than in the remaining patients. We conclude that the clinical spectrum in patients with APECED is broad. The majority of patients have three to five manifestations, some of which may not appear until the fifth decade. Therefore, all patients need lifelong follow-up for the detection of new components of the disease.

Background: GH may improve phosphate balance and height in X-linked hypophosphatemic rickets (XLH). This study evaluated the impact of exclusive rhGH therapy on phosphate homeostasis and growth. Methods: Ten children (median age 12.2 years) with XLH were included in a 12-month trial with GH. Conventional treatment was discontinued 1 month prior GH (0.033 mg/kg/day); 1α-hydroxyvitamin D was added at 6 months and oral phosphate at 12 months, when GH was discontinued. Patients were followed 1–3 monthly until 18 months for clinical, biochemical and radiographic parameters. Results: Serum phosphate Z-score increased significantly from baseline at 6 months (p = 0.005) and 9 months (p = 0.009) but returned to baseline by 12 months. Serum 1,25-dihydroxyvitamin D also increased significantly. Parathyroid function normalized. The median height Z-score was –2.2 (–2.7 to +0.4) at GH onset and –1.7 (–2.3 to +0.3) at 12 months. One patient showed a significant increase in radiographic rickets activity and 3 patients aggravation of lower limb deformity; the others showed no changes or improvement in these parameters. Conclusions: GH treatment improved serum phosphate and 1,25-dihydroxyvitamin D, normalized parathyroid function and improved longitudinal growth in XLH. It may however aggravate pre-existing skeletal deformities.

Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature.In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia.Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y.Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change.GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.

After induction of puberty, hypogonadal girls require continuous estrogen replacement to ensure the development of secondary sexual characteristics and to support female identify. It is possible to stimulate uterine growth and endometrial development, as well as menstrual cycles, should embryo transfer be considered in adulthood. This study evaluated a percutaneous estrogen gel in 23 girls with Turner syndrome (TS) who participated in an uncontrolled, open multicenter study. The girls, more than 12 years of age and having a skeletal age exceeding 9 years at the outset, all had elevated serum gonadotropin levels and low estrogen levels. The medication consisted of estradiol in hydroalcohol gel: single-dose sachets contained 0.1 mg of estradiol. The gel was applied once a day, preferably by the girls themselves in the evening, to the skin of the lower trunk or thighs. The dose rose from 0.1 mg in the first year to 0.2 mg in the second, 0.5 mg in the third, 1.0 mg in the fourth, and 1.5 mg in the fifth year. Compliance with gel treatment was good. Serum estradiol levels increased steadily during treatment, whereas gonadotropin levels declined. Serum levels of dehydroepiandrosterone sulfate increased. Serum testosterone levels remained low. Ten girls received growth hormone for a mean of 4.4 years, but this did not appear to influence body weight, acceleration of bone age, or adult height. Puberty advanced gradually as the estrogen dose increased. The uterus increased in length and volume on ultrasonographic assessment. Progestins induced regular menstrual periods. One girl had an elevated alanine transaminase level. Mild skin irritation occurred infrequently. Percutaneous estradiol gel appears to provide an effective, safe, and well-accepted means of inducing puberty in hypogonadal girls such as those with TS. Secondary sexual characteristics and uterine growth develop gradually, mimicking natural puberty.

BACKGROUND Hyperinsulinism in childhood is often caused by genetic defects involving the regulation of insulin secretion leading to recurrent episodes of hypoglycaemia. We report two patients with exercise induced hypoglycaemia. METHODS Standardised short exercise tests with frequent blood glucose and plasma insulin measurements were performed in the patients and young healthy controls. RESULTS Short term exercise resulted in insulin induced hypoglycaemia 15 to 50 minutes after the end of exercise. A massive burst of insulin secretion was observed within a few minutes of the start of exercise in both patients. By contrast glucose and insulin concentrations remained unchanged in healthy controls. CONCLUSIONS Hyperinsulinaemic hypoglycaemia after moderate physical exercise represents a rarely described phenotype of hyperinsulinism with an as yet unknown defect in the regulation of insulin secretion. It should be suspected in individuals with recurrent exercise related syncope or disturbance of consciousness.

To elucidate the role of the urinary cystine concentration for the formation of urinary stones, 190 stone-formers were evaluated in this prospective study. Seven patients (3.8%) were heterozygous and one patient (0.5%) was homozygous for cystinuria; only two (1%) of them were cystine stone-formers. Two patients with calcium stones were heterozygous for cystinuria. This study confirms the observation that elevated concentrations of urine cystine are relatively infrequent among patients with urinary stones.

Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomal recessive inheritance that is caused by deficient activity of aspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly described enzyme family of N-terminal hydrolases. An AGU mouse model was generated by targeted disruption of the AGA gene designed to mimic closely one human disease mutation. These homozygous mutant mice have no detectable AGA activity and excrete aspartylglucosamine in their urine. Analogously to the human disease, the affected homozygous animals showed storage in lysosomes in all analyzed tissues, including the brain, liver, kidney and skin, and lysosomal storage was already detected in fetuses at 19 days gestation. Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions. Magnetic resonance images (MRI) facilitating monitoring of the brains of living animals indicated cerebral atrophy and hypointensity of the deep gray matter structures of brain-findings similar to those observed in human patients. AGU mice are fertile, and up to 11 months of age their movement and behavior do not differ from their age-matched littermates. However, in the Morris water maze test, a slow worsening of performance could be seen with age. The phenotype mimics well AGU in humans, the patients characteristically showing only slowly progressive mental retardation and relatively mild skeletal abnormalities.

After liver transplantation in children, growth is often impaired, but the underlying mechanisms are unknown. Glucocorticoids used for immunosuppression are believed to be partly responsible. After renal transplantation in children, reduced growth hormone (GH) secretion and increased serum insulin-like growth factor-binding protein-3 (IGFBP-3) levels have been reported. We attempted to find endocrine factors predicting growth in 18 prepubertal children followed for more than 1 y (mean 2.4 y) after liver transplantation. Spontaneous and stimulated GH secretion, serum IGF-I, IGFBP-3 concentrations, and endogenous Cortisol production were measured. GH secretion was reduced in only two patients. Serum IGF-I concentration was normal, but serum IGFBP-3 was elevated or 1 SD above the mean for age in 62% of the patients. Endogenous Cortisol production was reduced in most patients during the first year and improved later in only a few. Growth velocity after transplantation did not correlate with GH secretion, scrum IGF-I or IGFBP-3 concentration, or with methylprednisolone dose, but correlated positively with serum basal (rs = 0.44, p < 0.05) and stimulated (rs = 0.53, p < 0.005) Cortisol concentration. In conclusion, after liver transplantation 1) the normal pulsatile character of nocturnal GH secretion is sustained, and the GH response to stimulation is reduced in only a few patients; 2) serum IGF-I concentrations are normal; 3) serum IGFBP-3 concentrations are elevated or in the upper part of the normal range in most patients; and 4) endogenous Cortisol production is reduced in most patients and correlates positively with growth velocity.

Prior to 1987 all pts with HT in Finland died in early years. In 1987 OLT on children was introduced in our country and since then 5 pts wirh HT have been diagnosed by high plasma tyrosine and urinary succinyl acetone (SAA) concentrations and enzyme analysis. In one pt, HT manifested acutely with bleeding, ascites and edema at 6 wks. Four presented with liver insufficiency and tubulopathy at 3 to 7 mos. Serurm α-fetoprotein (AFP) was 130-11000 times age matched median and liver CT showed tumor like nodules in most pts. The pts were treated by low tyrosine + low phenylalanine diet. In the pt with acute HT, blood exchanges and i.v. glutathione were used. One pt had several porphyria episodes which responded well to i.v. hemiarginate.

In a group of 18 infants with birth weights of 1,500 gm or less, either preterm, transitional or mature human milk was given during the, time of initial hospitalization. Half of the infants were given protein supplement isolated from mature human milk which increased the protein content of the ingested milk by 0.8 gm/dl. The protein intake of these infants was increased by 0.6 to 1.6 gm/kg/day between two and 12 weeks after birth. The infants in the unsupplemented group developed hypoproteinemia at 8 to 12 weeks of age whereas those who received protein supplementation did not. We conclude that the hypoproteinemia resulted from nutritional lack of protein and did not represent a physiologic phenomenon of preterm development. There was no difference in the growth of the two groups. There was no evidence of any imbalance in amino acid metabolism even though there were significant correlations between individual protein intakes and plasma concentrations of tyrosine and phenylalanine. Protein intake of more than 3 gm/kg/day resulted in a mean serum urea nitrogen concentration of more than 15 mg/dl at 2 weeks of age, indicating that excessive protein intake should be avoided soon after birth.

Gyrate atrophy of the choroid and retina (GA) is an autosomal recessive chorioretinal degeneration with a 10-20-fold elevation of plasma ornithine due to deficient activity of ornithine aminotransferase. Type II fibres of the skeletal muscle are atrophic and contain tubular aggregates in electron microscopy. Deficient creatine and creatine phosphate formation have been postulated to be involved in the pathogenesis of GA. The five-year follow-up results of oral creatine supplementation in 13 patients are presented. Visual function tests and fundus photographs showed progression of GA during the treatment. The velocity of the progression varied considerably between individuals. Generally, the progression was rapid in the young patients and slow in the more advanced stages. Abnormalities in the skeletal muscle decreased or disappeared rapidly. They reappeared in the few patients who discontinued the medication. The difference in the therapeutic effect on the skeletal muscle and eye is discussed.

Hyperornithinemia disappeared in three children with Gyrate atrophy of the choroid and retina during a low-arginine diet for 3 to 4 1/2 years. Because of the young age of the patients, we had an exceptional opportunity to follow the progression of the disease during this period. Despite the excellent biochemical control, electroretinographic changes progressed in two patients, and the chorioretinal atrophy progressed steadily in all the patients throughout the diet. Dark adaptation and color vision remained stable. In these patients, the normo-ornithinemia has not been able to halt the progression of the chorioretinal degeneration.

Hereditary fructose intolerance (HFI) is a rare autosomally recessive disease which leads to severe hypoglycemia. The fructose-free diet of these patients apparently influences dental health. Half of the patients are free of caries, but there are no reports on their periodontal condition nor on the composition of their subgingival microflora. Therefore 18 patient with HFI were examined for the following parameters: radiographic bone loss, caries rate, gingival bleeding, occurrence of calculus, pocket depths, salivary flow rate, buffer capacity and pH from paraffin wax-stimulated saliva. Salivary S. mutans and lactobacilli were also enumerated. Specific antibody titers from whole saliva and serum to Actinobacillus actinomycetemcomitans gamma 4, Bacteroides gingivalis, and Capnocytophaga ochracea were determined with ELISA. Finally the subgingival plaque was analyzed by culture. Altogether 196 anaerobic or microaerophilic isolates representing 29 different species were obtained from the HFI patients and 164 isolates of 26 species from the controls. The frequency of Actinomyces odontolyticus, Veillonella parvula, and Wolinella recta in the HFI patients was significantly high The DMF-induces were lower in the study group than in the controls and so was the occurrence of S. mutans and lactobacilli in the saliva. Of the periodontal parameters examined, the only difference found was an increased incidence of gingival bleeding and calculus formation in the HFI patients. The results suggest that in the HFI patients the common gingival bleeding is associated with the more frequent occurrence of Actinomyces odontolyticus, Veillonella parvula, and Wolinella recta.

The inhibitory effect of ornithine on l -arginine:glycine amidinotransferase (EC 2.1.4.1) was studied in crude rat kidney homogenates. The enzyme activity was linear with time up to 45 min and with protein up to 200 μg. The apparent K m and V of amidinotransferase were 9.21 mM and 1.53 μmol/g protein per min, respectively. The enzyme was competitively inhibited by ornithine, with a K i of 0.253 mM. Kidney arginase was inhibited only slightly and non-competitively. The inhibition of amidinotransferase by ornithine may thus be important in creatine biosynthesis. In gyrate atrophy of the choroid and retina with hyperornithinemia, a human autosomal recessive disease caused by decreased ornithine aminotransferase activity, plasma ornithine concentrations are elevated 10–20-fold (0.65–1.35 mM during fasting). In consequence, endogeneous creatine production probably is severely decreased because of inhibition of the rate-limiting transamidination step by ornithine. The deficiency of creatine and further of readily available energy in the form of phosphocreatine is suggested to be involved in the pathogenesis of the choroidal, retinal and type II muscle fiver atrophies in gyrate atrophy.

We studied 21 patients with gyrate atrophy of the choroid and retina and hyperornithinemia. Although the patients were not weak, type 2 muscle fibers were almost universally atrophic and had tubular aggregates. Gyrate atrophy is the first disease in which females are shown to have tubular aggregates; the sexes were affected equally. In gyrate atrophy the number of type 2 fibers decreases with age. The muscle and eye changes are probably related to abnormal creatine synthesis, caused, in gyrate atrophy, by the increased body pool of ornithine; muscle abnormalities may also be present in other tapetoretinal dystrophies.

Gyrate atrophy of the choroid and retina is a disease characterized by progressive constriction of visual fields, a 10-fold to 20-fold elevation in plasma ornithine, and depressed activity of L-ornithine:2 oxoacid aminotransferase. Morphologically conspicuous but clinically unimportant atrophy of Type II muscle fibers progresses concomitantly with the eye disease. A pathogenic component of the disease may be deficient formation of creatine, caused by hyperornithinemia, which leads to a shortage of cellular phosphocreatine energy stores. To test the therapeutic value of replenishing the postulated deficiency of creatine, we supplemented the diet of seven patients with 1.5 g of creatine daily. During one year of this treatment the diameters of Type II muscle fibers increased from 34.1 +/- 7.1 to 49.9 +/- 7.0 micron (mean +/- S.D.) (P less than 0.001). There was no significant increase in the diameters of Type I fibers. The visual-field tests showed no further constriction during the therapy. Fundus photography revealed slow impairment at an age otherwise associated with rapid progression of the disease. These promising preliminary results need further evaluation with long-term follow-up studies.

The 21-OHB gene encoding the enzyme 21-OH of steroid biosynthesis, and a closely-related pseudogene 21-OHA, are located in the MHC, adjacent to the C4 genes. We have performed HLA, Bf, and C4 typings, and RFLP analysis of the 21-OH and C4 genes in ten families with a patient having a 21-OH deficiency.

We report two methods for potential prenatal diagnosis of gyrate atrophy of the retina and choroid caused by an inborn error of ornithine aminotransferase activity. A high pressure liquid chromatography assay measures ornithine aminotransferase accurately and directly in cultured amniotic fluid cells. The differential incorporation of 14C-ornithine and 3H-leucine into cell protein measures OAT directly but rapidly and simply.

Gyrate atrophy of the retina and choroid is an autosomal recessive disease characterized by progressive retinal degeneration and ornithine aminotransferase deficiency. We report here the new histological findings and ultrastructural changes in 3 iridectomy specimens from 2 Finnish patients with gyrate atrophy. The iridectomy specimens were removed during routine cataract extraction and studied with a transmission electron microscope. The dilator muscle showed atrophy, abnormall mitochondria, and tubular aggregate type structures similar to those found in skeletal muscle. Degenerative changes such as extracted cellular matrix, dropout of cellular organelles, and dilated intercellular spaces were observed in the pigmented posterior epithelium and the anterior iris epithelium.

We have identified patients in whom strenuous physical exercise leads to hypoglycemia caused by inappropriate insulin release (exercise-induced hyperinsulinism [EIHI]). The aim of the present study was to test the hypothesis that the increased levels of lactate and/or pyruvate during anaerobic exercise would trigger the aberrant insulin secretion in these patients. A total of 12 patients (8 women and 4 men from two families) were diagnosed with EIHI, based on hypoglycemia and a more than threefold increase in plasma insulin induced by a 10-min bicycle exercise test. The mode of inheritance was autosomal dominant in these families. The acute response of insulin release to a bolus of intravenous pyruvate (13.9 mmol/1.73 m2) was studied in the patients and eight healthy control subjects. Insulin secretion did not respond to the pyruvate bolus in healthy control subjects. However, all EIHI patients responded to pyruvate, displaying a brisk increase in plasma insulin. The 1 + 3-min peak response was 5.6-fold in the patients and 0.9-fold in the control subjects (P < 0.001). To test the hypothesis that the pathogenesis of EIHI would involve monocarboxylate transport or metabolism in the β-cell, we sequenced the genes encoding the known monocarboxylate transporter proteins and tested the transport of pyruvate into patient fibroblasts. The results revealed normal coding sequences and pyruvate transport. In conclusion, EIHI represents a new autosomal-dominant hyperinsulinemia syndrome that may be more common than has been realized. The pyruvate test provides a simple, safe, and specific diagnostic test for this condition.

Background Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet. Methods Nine adolescents with celiac disease, aged 12 to 16 years, were assessed using the semi-structured K-SADS-Present and Lifetime Diagnostic interview and several symptom scales. Seven of them were followed at 1 to 2, 3, and 6 months on a gluten-free diet. Results Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients' baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs. Conclusion Although our results of the amino acid analysis and prolactin levels in adolescents are only preliminary, they give support to previous findings on patients with coeliac disease, suggesting that serotonergic dysfunction due to impaired availability of tryptophan may play a role in vulnerability to depressive and behavioural disorders also among adolescents with untreated coeliac disease.

Controlled water use is an important component of sustainable fresh-cut vegetable production because of limited water resources, and also for controlling the quality of wastewater re-used in vegetable processing or for irrigating on fields. In our study the water consumption in vegetable processing plants varied from 1.5 to 5.0 m3 t-1 of finished product. In one plant, monitored over three years, almost 90% of water was used for washing and rinsing of vegetables, but more than 90% of the organic load of the wastewater was generated from the processing stage. The results including organic load and the microbial quality of the wastewaters showed that the wastewater should be treated beforere-use.Separate treating of wastewaters from processing stage is recommended. Pre-treatment of wastewater using precipitation chemicals and sedimentation in basins decreased the organic load and total solids in the water, allowing further treatment of the waters.

Defects in the enzyme steroid 21-hydroxylase (21-OH) result in congenital adrenal hyperplasia (CAH), a frequent disorder of steroid biosynthesis. The gene encoding the enzyme, 21-OHB, has been mapped adjacent to the complement component C4B gene in the human HLA gene complex. DNA-level analyses of patients with CAH have shown that the 21-OHB gene has often been deleted, but the detection of 21-OHB delections in heterozygotes is often problematic because it is based on relative band intensities. We here report a DNA polymorphism in the C4A91 gene unique to one particular type of 21-OHB deletion occurring solely with a complement phenotype BfF C4A91 B null, shown earlier to be frequent in CAH patients. This marker makes direct detection of the 21-OHB deletion in heterozygotes possible.