There are three pathways of L-threonine catabolism. The enzyme L-threonine aldolase (TA) has been shown to catalyse the conversion of L-threonine to yield glycine and acetaldehyde in bacteria, fungi and plants. Low levels of TA enzymatic activity have been found in vertebrates. It has been suggested that any detectable activity is due to serine hydroxymethyltransferase and that mammals lack a genuine threonine aldolase.Thermotoga maritima TA. Almost all known functional residues are conserved between the two proteins including Lys242 that forms a Schiff-base with the cofactor, pyridoxal-5'-phosphate. The human TA gene is located at 17q25. It contains two single nucleotide deletions, in exons 4 and 7, which cause frame-shifts and a premature in-frame stop codon towards the carboxy-terminal. Expression of human TA mRNA was undetectable by RT-PCR. In mice, TA mRNA was found at low levels in a range of adult tissues, being highest in prostate, heart and liver. In contrast, serine/threonine dehydratase, another enzyme that catabolises L-threonine, is expressed very highly only in the liver. Serine dehydratase-like 1, also was most abundant in the liver. In whole mouse embryos TA mRNA expression was low prior to E-15 increasing more than four-fold by E-17.The 7-exon murine L-threonine aldolase gene (GLY1) is located on chromosome 11, spanning 5.6 kb. The cDNA encodes a 400-residue protein. The protein has 81% similarity with the bacterium Mice, the western-clawed frog and the zebrafish have transcribed threonine aldolase/GLY1 genes, but the human homolog is a non-transcribed pseudogene. Serine dehydratase-like 1 is a putative L-threonine catabolising enzyme. Elucidating the factors involved in threonine homoeostasis is important for the development of nutritional strategies in human clinical diets for treating patients suffering from wasting diseases. In farmed animals the regulation of livestock feed is required to ensure optimal growth and to reduce nitrogen excretion which poses environmental disposal problems. Threonine is required for protein synthesis and the removal of excess threonine by oxidation is needed to prevent its accumulation both intracellularly and in the circulation. The rate of catabolism of many amino acids, including threonine, increases when dietary protein exceeds the body's requirements. Gluconeogenesis occurs mainly in the liver where it helps maintain blood glucose homeostasis in mammals. During starvation amino acid catabolism increases to support gluconeogenesis. Glucocorticoids and glucagon hormones are known to up regulate and insulin down regulate the gene expression of many amino acid-catabolising enzymes .4+ and 2-ketobutyrate and TDH to yield 2-amino-3-ketobutyrate. The subsequent reaction between 2-amino-3-ketobutyrate and coenzyme A to form glycine and acetyl-CoA is catalysed by 2-amino-3-ketobutyrate coenzyme A ligase (KBL)(EC 2.3.1.29), also called glycine acetyltransferase (gene abbreviation GCAT).There are three L-threonine  degradation pathways in living organisms; via L-threonine aldolase (L-TA)EC 4.1.2.5)(gene abbreviation GLY1), via L-serine/threonine dehydratase (SDH)(EC 4.2.1.16)(gene abbreviation SDS) and via L-threonine 3-dehydrogenase (EC 1.1.1.103)(TDH) ) was used as a measure of abundance. A comparative Ct method was used to determine gene expression. Expression levels in each tissue cDNA sample were normalised to the average expression levels of the housekeeping genes beta-actin and G3PDH (ΔCt). Ratios of gene of interest mRNA/housekeeping mRNA from each tissue were standardised to that of the highest expressing tissue for that gene which was taken as 100% (ΔΔCt). Formula E-ΔΔCt was used to calculate relative expression levels where E is the efficiency of the PCR per cycle. Amplification specificity was confirmed by melting curve analysis and agarose gel electrophoresis.Quantitative PCR was carried out on a GeneAmp 5700 Sequence Detection System (AB Applied Biosystems) and a Rotor Gene 3000 utilising a CAS-1200 robotic precision liquid handling system  using a SYBR Green I double-stranded DNA binding dye assay . For the determination of TA, SDH, SDH1, TDH and KBL mRNA expression in adult mouse tissues and whole mouse embryos, cDNAs were generated from polyAeviously . AmplifiT. maritima [The predicted start site of transcription of murine TA mRNA was determined using the program Eponine . The premaritima  using 3Dmaritima . Mitochomaritima . Cleavagmaritima .A.J.E. initiated and carried out the molecular genetic studies, drafted the manuscript and approved the final manuscript.


Proper management of patients with Kallmann syndrome (KS) allows them to attain a normal reproductive health. The purpose of this study is to demonstrate the presentation modalities, phenotypes and the modes of inheritance among 32 patients with Kallmann syndrome in Jordan. Recognition of the syndrome allows for prompt proper management and provision of genetic counselling.Over a period of five years (1999–2004), the clinical and inheritance profiles of 26 male and 6 female patients with Kallmann syndrome from 12 families were evaluated at the National Center for Diabetes, Endocrinology and Genetics in Jordan.The patients belonged to twelve Jordanian and Palestinian families and their age at presentation ranged from 4 – 46 years. Nine boys aged 4–14 years presented with cryptorchidism and microphallus, all other males presented with delayed puberty, hypogonadism and/or infertility. The main presentation among six female patients was primary amenorrhea. Intrafamilial variability in clinical phenotype was specifically evident for renal abnormalities and sensorineural hearing impairment. Familial KS was diagnosed in 27 patients belonging to five families with the X-linked mode of inheritance and two families with the autosomal recessive mode of inheritance.(1) the majority of cases in this study represented the X-linked form of KS, which might point to a high prevalence of Kal 1 gene in the population. (2) Genetic counselling helps these families to reach a diagnosis at an early age and to decide about their reproductive options. (3) Children presenting with cryptorchidism and microphallus in our population should be investigated for KS. One of the most common causes of hypogonadotropic hypogonadism is Kallmann syndrome (KS). KS is a genetically heterogeneous condition that affects approximately one in 8000 males and one in 40,000–70,000 females -3. This To our knowledge, no data is available on the incidence of this syndrome in Jordan or in the Arab world.In addition to the sporadic form which is the most common , KS has Over a period of five years, thirty-two male and female patients from twelve Jordanian and Palestinian families were referred to the National Center for Diabetes, Endocrinology and Genetics (NCDEG) in Amman, Jordan for evaluation of hypogonadism among adults, or microphallus among children.Prospective evaluation was performed including pedigree construction fig , and comOlfactory testing was performed through a smell identification test designed by our department using odours that can be easily identified among all social classes in the local population. These odours included cinnamon, coffee, camomile, thyme, soap, oriental perfume and tobacco. The specific odoriferous substance was approximated to the nostrils while the patient had his eyes closed. The patient is then asked to name the olfactory stimulus. According to the number of substances identified by smelling, patients were divided into anosmic and hyposmic. Those who failed to identify all odours were categorized as anosmic, while those who identified three or less odours were categorized as hyposmic. Those who identified four to all seven odours were considered normosmic. First-degree relatives of the probands were also questioned and tested for the smell sensation in a similar fashion. The same investigator carried out olfactory testing for all patients and family members.In addition to the assessment of smell sensation among relatives of probands, their answers to specific questions were recorded. These questions addressed the issues of surgery to correct cryptorchidism, administration of testosterone and whether there were any complaints of delayed puberty or infertility. The specific questions and the olfactory testing led to the identification of further cases of KS in the family.Patients were asked to perform a screwdriver motion in one hand while the examiner watches for any similar non-voluntary movement in the other hand to assess mirror image movements. Subjects were also asked to perform alternate supination and pronation of one forearm while the examiner watches for a similar movement in the other arm . PhallusThe criteria for diagnosis of KS among adults included the presence of anosmia or hyposmia with clinical signs and symptoms of hypogonadism and a testosterone level <100 ng/dl among males 16 years and older, and estradiol level <20 pg/dl among adult females, together with basal low gonadotrophin level. In family II, loss of contact of three brothers hindered testing their hormonal levels. They were, however, included among our patients because clinical examination revealed hypogonadism, anosmia and micropenis. Among prepubertal males, the criteria for diagnosis of KS included presence of microphallus with anosmia/hyposmia, and/or absent olfactory bulbs on MRI.Pedigree analysis was used to establish the modes of inheritance of KS in the familial cases. Inheritance in a family was classified as X-linked if only males were affected in more than one sibship connected by females, or if two or more males were affected in the sibship with a negative family history and with associated synkinesia. Inheritance was classified as autosomal recessive if all affected individuals were members of the same generation and included at least one female.Over a period of five years (1999–2004), thirty-two patients were prospectively diagnosed with Kallmann syndrome at the National Center for Diabetes, Endocrinology and Genetics (NCDEG) in Amman, Jordan. The patients belonged to twelve Jordanian and Palestinian families and their ages at presentation ranged between 4 – 46 years. They included 26 males and 6 females with a male/female ratio of 4.34/1. Nine male patients were aged 14 years and younger.The clinical features among male patients are presented in table Twenty seven patients were anosmic and five patients were hyposmic table . In famiCryptorchidism was found or previously operated on in 19/26 (73%) and microphallus in 17/26 (65%) male patients respectively. All patients included in this study manifested high-arched palate. Renal abnormalities including unilateral renal agenesis, malrotated kidney, and horseshoe kidney were detected in 11/19 (58%)cases with the X-linked form of KS. Two sporadic cases showed renal anomalies. A variable degree of sensorineural hearing impairment was found in 4/19 patients with X-linked KS, and in none of the other mode of inheritance or the sporadic cases. Olfactory MRI revealed olfactory tract agenesis among 19/24 cases for which the investigation was done in the series.Among females diagnosed as KS in this series primary amenorrhea was the main presenting feature.Pedigrees were constructed for all families figure . Five caThis study points to the higher proportion of the X-linked form of Kallmann syndrome among all KS cases seen at an endocrine/genetic clinic in Jordan over a period of 5 years. Among 7 families with inherited KS, the X-linked form was the mode of inheritance in 5 families . None of the pedigrees was consistent with autosomal dominant inheritance in this series. In the two families with autosomal recessive inheritance, the probability of a non-penetrant autosomal dominant gene in either parent was considered remote because of absence of any relevant family history. Autosomal dominant inheritance was also considered a very remote possibility in the X-linked families because of absence of affected individuals in earlier generations and the pattern of inheritance as revealed by pedigree construction , and was not related to a specific mode of inheritance or etiology. Microphallus was present among 17/26 (65%) patients in this study, with several other patients reporting a history of treatment with testosterone; the exact number of treated patients or the treatment profile could not be precisely determined. Seminal fluid analysis was done for all patients of 16 years and above. The test showed azoospermia for all tested males except patient 1 in family IX, where oligospermia was reported with a sperm count of 10,000,000 per ml. None of the patients with the X-linked form manifested ichthyosis, mental retardation, short stature or ocular albinism, pointing to the underlying etiology being a mutation in the Kal 1 gene rather than a contiguous-gene deletion syndrome .Olfactory MRI revealed olfactory tract agenesis in 80% of cases for which the investigation was done in the series (19/24). Quinton et al, 1996, indicate that KS may be present with no pathology detected in the olfactory tract on MRI, and that phenotypic characterization of KS was effectively achieved by accurate estimation of olfactory sensation . KallmanThe majority of Kallmann syndrome cases in our study showed the X-linked mode of inheritance, which might indicate a high prevalence of Kal1 gene in the population. However, molecular studies for the Kal1 gene were not performed in this study. Patients in our series manifested a wide range of phenotypic heterogeneity with intrafamilial variability of clinical manifestations. We recommend an evaluation for Kallmann syndrome in our population in any child presenting with microphallus and cryptorchidism. Further studies are needed to establish the prevalence rate of Kallmann syndrome in Jordan and to define the causative mutations.The authors declare that they have no competing interests.MAJ and KA were the main researchers. HH and MAJ drafted the manuscript. All authors were part of the team that evaluated the patients


By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.The JAMM  motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EX Protein structure studies suggest that deubiquitination in the proteasome is carried out by a protein with features of a zinc metalloprotease Many cellular proteins are degraded by the proteasome after they become covalently modified with a multiubiquitin chain. The 26S proteasome is a massive protein composed of a 20S core and two 19S regulatory particles . The 20SArabidopsis thaliana from genetic studies of constitutively photomorphogenic mutant plants (nHS/THX7SXXD), referred to as the JAMM motif, that is embedded within the larger JAB1/MPN/Mov34 domain (hereafter referred to as the JAMM domain) and is critical for Csn5 function in vivo  regulatory modification from the Cullin 1 (Cul1) subunit of the SCF (Skp1/Cdc53/Cullin/F-box receptor) Ub ligase is catalyzed by the COP9 signalosome (CSN) . The CSNt plants . It latet plants . Csn5 of in vivo . Removal in vivo . The JAM in vivo , and pro in vivo . Taken t in vivo , indicatEscherichia coli a variety of JAMM motif-containing proteins to find a suitable candidate for crystallographic analysis. The expression of all candidates except for AfJAMM led to insoluble aggregates. Unlike many JAMM proteins that contain an additional domain, the AfJAMM protein consists entirely of the JAMM domain. We were able to purify and crystallize native and selenomethionine-substituted AfJAMM; the latter was used for phasing by employing the multiwavelength anomalous diffraction (MAD) technique , flanked by a long α helix (α1) between the first and second strand, and a short α helix (α2) between the fourth and fifth strand. This β sheet resembles a β barrel halved longitudinally and curled around α1 A. The α2subtilis  can be ssubtilis A. Conseqsubtilis  and Ub-ssubtilis .The two AfJAMM subunits in the asymmetric unit are connected through a parallel β sheet formed at the dimer interface B. The suɛ2 of H67 and H69 on β4, the carboxylate of D80 on α2, and a water molecule. The latter hydrogen-bonds to the sidechain of E22 on β2. Thus, the crystal structure confirms previous predictions that the histidine and aspartic acid residues in the JAMM motif are ligands for a metal , and neurolysin, a mammalian metalloprotease  into the pCRT7 vectors . During cloning, the alternate start codon, GTG, was replaced with the canonical start codon, ATG. The construct was expressed in BL21(DE3)pLysS cells . The cells were grown to midlog phase in terrific broth media and induced with 0.5 mM IPTG. The cells were lysed by sonication and the protein was isolated by immobilized metal ion chromatography using a Ni-NTA resin . The protein was further purified by gel filtration on a Sephacryl S100 column  and concentrated. The amino-terminal tag was removed by limited digestion with trypsin. Mass spectrometry analysis revealed that trypsin only cut AfJAMM in the amino-terminal tag region, and only a single band was evident on a Coomassie-stained polyacrylamide gel. The tag and uncut protein were removed with Ni-NTA resin followed by anion-exchange chromatography with SOURCE 30Q resin (Amersham Pharmacia Biotech). The processed protein was then concentrated to approximately 30 mg/ml by ultrafiltration. The selenomethionine protein was produced as described elsewhere  using vapor diffusion with sitting drops and hanging drops. Crystals were incubated for approximately 1 min in a cryo-solution of equal volumes of reservoir solution and 35% meso-erythritol for the selenomethionine crystals and supplemented with 5 mM ZnCl2 for the native crystals. The crystals belonged to the space group P65, with cell dimensions of a = b = 76 Å, c = 94 Å and two subunits per asymmetric unit. Data for the selenomethionine crystals were collected on Beamline 9.2 at the Stanford Synchrotron Radiation Laboratory (SSRL)  and data for the native crystals were collected on Beamline 8.2.1 at the Advanced Light Source (ALS)   see .Phases were obtained by the MAD technique using data collected from selenomethionine-substituted crystals see . Three S2 (0.54πl). As a result, reflections with l-indices such that cos2 (0.54πl) < ½ are systematically weak, leading to an R-factor higher than would be expected for a nonpseudocentered crystal structure. However, when only the reflections with cos2 (0.54πl) > ½  are used for the R-factor calculation, reasonable values for R are obtained.Since two monomers in the unit cell are related by a fractional translation along c of approximately 0.54, the intensities of the diffraction pattern are modulated by a factor of cosS. pombe were performed as previously described by The geometry of the final model was analyzed with PROCHECK . The RamThe accession numbers for the proteins discussed in this paper are 20S proteasomes (PDB ID 1RYP), AfJAMM , AMSH (Entrez Protein ID NP_006454), AtCSN5/AJH1 (Entrez Protein ID NP_173705), AtRpn11 (Entrez Protein ID NP_197745), C6.1A (Entrez Protein ID NP_077308), CeCSN5 (Entrez Protein ID NP_500841), CeRpn11 (Entrez Protein ID NP_494712), Csn5 (Entrez Protein ID NP_593131), Cul1 (Entrez Protein ID NP_594259), cytidine deaminase (PDB ID 1JTK), DmCsn5/CH5 (Entrez Protein ID NP_477442), DmRpn11/p37b (Entrez Protein ID AAF08394), EcRadC (Entrez Protein ID NP_418095), HsAMSH (Entrez Protein ID NP_006454), HsC6.1A (Entrez Protein ID NP_077308), HsCsn5 (Entrez Protein ID NP_006828), HsRpn11/POH1 (Entrez Protein ID NP_005796), JAB1 (Entrez Protein ID AAC17179), lambdaK (Entrez Protein ID AAA96551), Mov34 (Entrez Protein ID NP_034947), Mpr1p (Entrez Protein ID AAN77865), Nedd8 (Swiss-Prot ID Q15843), neurolysin (PDB ID 1I1I), Pad1p (Entrez Protein ID NP_594014), phage λ tail assembly protein K (Entrez Protein ID AAA96551), RadC (Entrez Protein ID NP_418095), Rpn11 (Entrez Protein ID AAN77865), SCF (PDB ID 1LDK), ScNP (PDB ID 1C7K), ScRpn11 (Entrez Protein ID AAN77865), Sic1 (Entrez Protein ID 1360441), SpCsn5 (Entrez Protein ID NP_593131), SpRpn11/Pad1 (Entrez Protein ID NP_594014), thermolysin (PDB ID 1FJQ), ubiquitin (Swiss-Prot ID P04838), UBP (PDB ID 1NB8), and UCH (PDB ID 1UCH).http://www.ncbi.nlm.nih.gov/entrez/ (Entrez Protein), http://www.rcsb.org/pdb/ (Protein Data Bank [PDB]), and http://us.expasy.org/sprot/ (Swiss-Prot).These databases may be found at


We sought to determine how quickly carbon monoxide would accumulate in the passenger compartment of a snow-obstructed vehicle.A 1992 sedan was buried in snow to the level of the undercarriage, the ignition was then engaged and carbon monoxide levels recorded at 2.5-minute intervals. The primary outcome was the time at which a lethal carbon monoxide level was detected. Six trials were conducted: windows closed; windows open one inch; windows open 6 inches; windows closed and tailpipe swept clear of snow; windows closed and one cubic foot of snow removed around tailpipe; windows closed and tailpipe completely cleared of snow to ground level in a path 12 inches wide.Lethal levels of carbon monoxide occurred within 2.5 minutes in the vehicle when the windows were closed, within 5 minutes when the widows were opened one inch, and within 7.5 minutes when the widows were opened six inches. Dangerously high levels of carbon monoxide were detected within the vehicle when the tailpipe had been swept clear of snow and when a one cubic foot area had been cleared around the tailpipe. When the tailpipe was completely unobstructed the carbon monoxide level was zero.Lethal levels of carbon monoxide occurred within minutes in this snow-obstructed vehicle. Carbon monoxide poisoning is the number one cause of toxin related death in the United States . It has One of the manners in which people die from carbon monoxide poisoning is hypoxia secondary to entrapment within a snow-obstructed vehicle. Recommendations for prevention of these poisonings has been well documented but not thoroughly studied. The Centers for Disease Control (CDC) recommends that "following heavy snowfall, the public should be reminded to inspect vehicles to ensure that exhaust pipes are cleared of snow before engines are started" . Brian HIn reviewing case reports regarding snow emergencies, it appears that there have been situations where venting carbon monoxide through an open window may not have been sufficient to prevent dangerously high levels of carbon monoxide from accumulating within the passenger compartment . This raWe performed a pilot study with a single vehicle to simulate a snow emergency whereby a person stranded in a vehicle during a snowstorm would perform a safety maneuver. Our hypothesis was that opening a window a few inches for ventilation or clearing a tailpipe of snow would be sufficient to keep carbon monoxide levels in a non-lethal range.In 1995, a 1992 four-door sedan whose exhaust system had been inspected by the State of Massachusetts and found to be functioning normally was placed in a driveway and snow was shoveled around its base on all four sides until the car was obstructed by snow to the level of the bumpers. A Nighthawk, battery powered, digital readout, 80 mAmp carbon monoxide detector was attached to the front of the driver's seat headrest. The instrument had the ability to detect carbon monoxide levels in the range of zero to nine hundred ninety nine parts per million (0 – 999 ppm) [Six trials were performed. Between each trial all doors and windows were opened, the carbon monoxide was allowed to exhaust from the vehicle until the detector registered zero parts per million.Dangerously high carbon monoxide concentrations were recorded in the passenger compartment within three minutes when the windows were closed, within five minutes when the front windows were open one inch and within 7.5 minutes when the windows were opened six inches Table . With thCarbon monoxide is an odorless, tasteless by-product of fossil fuel combustion . When itIn this study, only opening a window was not enough to prevent accumulation of carbon monoxide within the passenger compartment of the vehicle. As the guidelines suggest -6, snow The authors declare that they have no competing interests.JG gathered data and prepared the manuscript. SP conceived of the project and gathered data. BO gathered data and presented the abstract at the Society for Academic Emergency Medicine. HS oversaw the project and provided statistical support.The pre-publication history for this paper can be accessed here:


Endometrial cancer represents a tumor entity with a great variation in its incidence throughout the world (range 1 to 25). This suggests enormous possibilities of cancer prevention due to the fact that the incidence is very much endocrine-related, chiefly with obesity, and thus most frequent in the developed world. As far as treatment is concerned, it is generally accepted that surgery represents the first choice of treatment. However, several recommendations seem reasonable especially with lymphadenectomy, even though they are not based on evidence. All high-risk cases are generally recommended for radiotherapy.A literature search of the Medline was carried out for all articles on endometrial carcinoma related to diagnosis and treatment. The articles were systematically reviewed and were categorized into incidence, etiology, precancerosis, early diagnosis, classification, staging, prevention, and treatment. The article is organized into several similar subheadings.In spite of the overall good prognosis during the early stages of the disease, the survival is poor in advanced stages or recurrences. Diagnostic measures are very well able to detect asymptomatic recurrences. These only seem justified if patients' chances are likely to improve, otherwise such measures increases costs as well as decrease the patients' quality of life. To date neither current nor improved concepts of endocrine treatment or chemotherapy have been able to substantially increase patients' chances of survival. Therefore, newer concepts into the use of antibodies e.g. trastuzumab in HER2-overexpressing tumors and the newer endocrine compounds will need to be investigated. Furthermore, it would seem highly desirable if future studies were to identify valid criteria for an individualized management, thereby maximizing the benefits and minimizing the risks. Nearly 170,000 new cases of endometrial carcinomas were estimated worldwide in 1997 .Endometrial carcinomas occur in advanced age . The age-related incidence for Germany is shown in Figure The etiology of the endometrial carcinoma is not fully understood. Most cases appear sporadically whereas about 10% are hereditary. Chief among the latter is the autosomal dominantly inherited hereditary non-polyposis colorectal cancer (HNPCC) -5. The rWithin the current concept of multi-step progression of normal cells to malignancy, recent molecular work has identified several gene alterations important for tumor development. In summary, mutations and amplifications of oncogenes K-ras and HER2/neu, mutations or deletions of tumor suppressor genes p53, p21, p16, and pTEN/MMAC1 as well as impaired DNA repair functions through mutations of hMLH1, hMSH2, and hMSH6 have been connected with the development of endometrial carcinomas .Environmental, dietary and hormonal factors as well as an aging female population have been attributed to an observed increase of endometrial carcinomas over the past few years. Epidemiologic studies have observed correlations between the incidence of endometrial cancer and the usage of estrogens, especially when applied to alleviate perimenopausal and postmenopausal symptoms. Therefore, it appears that estrogen plays a key role in the development and progression of endometrial carcinomas.There is also convincing evidence that high body mass increases the risk of endometrial carcinomas. Current estimations figure that about 40% of these relate to excess body weight . A plausPrevious irradiation of the pelvis, estrogen replacement therapy (HRT)  and tamoxifen therapy represent exogenous risk factors. Prolonged and exclusive intake of synthetic estrogens is associated with an up to 15-fold higher incidence of endometrial carcinomas ,17. TamoRecently a case-control study identified antipsychotic drugs as being a great risk factor for endometrial cancer . These fIn some cases endometrial cancer develops from atypical endometrial hyperplasia. The likelihood of this happening correlates with the degree of hyperplasia Table  20]. Ac. Ac20]. Endometrial hyperplasia is regarded as a preliminary stage of endometrioid carcinomas. Serous and clear cell carcinomas are on the other hand frequently associated with an atrophic endometrium . A precuTo prevent an outbreak of the disease in menopausal and postmenopausal women long-term estrogen replacement therapy  should be supplemented by intermittent application of gestagens. A recent study suggested the use of intrauterine devices (IUD) also possibly reducing the risk for endometrial cancer due to improved elimination or decrease of hyperplastic endometrial cells . Numerou® intrauterine system maintains that irregular menstrual bleeding should not be treated simply with this system without prior diagnostic . D. D139].


This study examined the use of the Folstein Mini Mental Status Exam (MMSE) and the Clock Drawing Test (CDT) in predicting retrospective reports of driving problems among the elderly. The utility of existing scoring systems for the CDT was also examined.T-test, correlation, and regression procedures were used to analyze the data.Archival chart records of 325 patients of a geriatric outpatient clinic were reviewed, of which 162 had CDT results . Both CDT and MMSE scores were significantly worse among non-drivers than individuals who were currently or recently driving. Among current or recent drivers, scores on both instruments correlated significantly with the total number of reported accidents or near misses, although the magnitude of the respective correlations was small. Only MMSE scores, however, significantly predicted whether or not any accidents or near misses were reported at all. Neither MMSE nor CDT scores predicted unique variance in the regressions.The overall results suggest that both the MMSE and CDT have limited utility as potential indicators of driving problems in the elderly. The demonstrated predictive power for these instruments appears to be redundant, such that both appear to assess general cognitive function versus more specific abilities. Furthermore, the lack of robust prediction suggests that neither are sufficient to serve as stand-alone instruments on which to solely base decisions of driving capacity. Rather, individuals who evidence impairment should be provided a more thorough and comprehensive assessment than can be obtained through screening tools. Assessment of cognitive function pertaining to capacity for safe and independent living among elderly patients is a central responsibility of many geriatric medical clinics and service agencies. Specific concerns pertaining to judgments of driving capacity are also befalling upon the medical profession in primary care settings . To aid The MMSE is a widely used cognitive screening tool, due to its brevity, ease of administration, and relative breadth . NumerouIn addition to the MMSE, results on the CDT are often used in clinical settings to inform clinical impressions pertaining to whether or not patients are impaired to such an extent that they should not be driving . AlthougDespite this apparent widespread use, there appears to be a dearth of research addressing the validity of the CDT for detecting driving impairment. Although a small number of studies exist that suggest CDT scores may relate to driving problems, the size of this literature base coupled with methodological concerns indicate a need for further research. For example, one study  examinedAdditional evidence for the potential utility of the CDT in predicting driving behaviors is provided in an examination of neurophysiologic phenomena related to caregiver reports of driving impairment in 79 individuals with Alzheimer's disease . Single A pilot study examining the comparability of simulated driving tests in predicting actual driving problems also suggested that CDT scores may be significant predictors . A smallGiven the typically low rate of follow-up for patients referred for more formal driving assessments, it would be beneficial to further investigate the relations between scores on the CDT and reports of actual driving problems. Furthermore, the predictive power of the CDT alone and in conjunction with other assessment tools in predicting reported driving problems has yet to be fully assessed. Additionally, previous studies examining CDT scores and driving behaviors have employed markedly small sample sizes, warranting future research with greater numbers of participants. Finally, previous studies differ in terms of what, if any, scoring systems were used to score the clock drawings. Thus, further investigation of the comparability of different scoring systems is needed.To address these concerns, this study explored the relations of patient scores on the CDT and MMSE to patient or family reports of driving problems. In so doing, the utility and comparability of three scoring systems for the CDT that are commonly used by researchers and practitioners, namely the Shulman et al. , SunderlExploratory analyses also were conducted to examine the predictive utility of the CDT and MMSE in predicting whether driving problems, namely accidents or near misses, were reported. Further analyses examined whether linear relationships existed between CDT and MMSE scores and the reported number of such incidents. Finally, regression tests examined whether the CDT and MMSE uniquely predicted the number of reported incidents.IRB approval was obtained for the study, and data was collected from archival records of patients seen over a 10-year period at a geriatric assessment center of a general teaching hospital in the Midwest. The center operated as a full-service outpatient clinic, where new patient assessments included a full medical and psychosocial history. This history included patients' and collateral others' reports of driving behaviors within the past year, including whether patients were currently driving or had recently stopped driving within the past year, and number of driving accidents or near misses. The data was often collected during the initial intake assessment, when both the patient and available family members or caregivers were interviewed by a geriatrician, social worker, and/or a nurse specialist. In addition, the MMSE and CDT were typically administered to patients to assess cognitive functioning.Chart records did not clarify whether the reported driving problems were acknowledged by the patient or caregiver, nor the extent to which any discrepancies existed, but rather only reported the number of incidents. The content of the incidents was also not always documented, but examples that were provided typically included crashes or minor accidents for which the patients were at fault. Nevertheless, despite the subjectivity inherent to such reports, it was the intent of these authors to remain true to the figures documented in the patient charts. Indeed, given that medical professionals typically must rely to some extent on subjective reports of patients or caregivers during intake evaluations to inform initial judgments about patient safety, it was decided that incorporation of such data in the present study would nonetheless be useful.SD = 6.67), and ranging from 58 to 99 years of age. As is typical of many outpatient geriatric populations, there was a range in type and severity of presenting concerns, with some patients reporting relatively few problems and others evidencing diagnoses of vascular dementia, Alzheimer's disease, or depression in addition to other health concerns. Of these, concerns due to cognitive function predominated; approximately 60% of the patient sample was referred to the clinic for evaluation of memory loss, cognitive decline, or dementia. MMSE data was available for 311 patients; of these, 159 also had CDT data sufficient for analysis. Of the 162 charts that had CDT data, only 3 did not also have MMSE data.Data was obtained from charts of 325 patients, including 162 original clock drawings that were scored according to the systems provided by Shulman et al. , and WolThe raters' corresponding CDT scores for each scoring system correlated above 0.70, suggesting adequate inter-rater correspondence. The corresponding scores for each scoring system were then averaged to create three composite scores for each clock drawing, one for each scoring system. Descriptive data pertaining to scores for the overall sample on the MMSE and CDT is provided in Table t-tests were conducted to examine whether CDT scores and MMSE scores differed between individuals who had been currently or recently driving, versus those who had not been reported to be driving for a more extensive time period. In each case, current and recent drivers evidenced better scores on all of the cognitive measures than individuals who had not been driving. Results for these analyses are provided in Table Initial exploratory t-tests were incorporated to examine whether CDT and MMSE scores differed among individuals for whom driving problems had been reported, versus those with none. Drivers with reported problems evidenced significantly lower MMSE scores, but no significant differences were obtained for CDT scores. Nevertheless, the trends for the overall mean differences on CDT scores, although small, were in the same direction as the findings for the MMSE. Specifically, in every case the CDT scores for each scoring system were worse for drivers with reported problems than those with none. Overall, these results suggest that the presence of driving problems may have been reflective of greater levels of cognitive impairment, although the overall differences reflected in CDT scores were nonetheless very small in magnitude. These results are detailed in Table Further analyses examined whether CDT or MMSE scores predicted the presence of reported driving problems among individuals who had been current or recent drivers. Patients who had not been driving for a longer period of time were excluded from the analyses, since no driving problems would have been reported as a function of not driving. Specifically, n of the resultant cases is included for each cell.Next, the linear relations for both CDT and MMSE scores in predicted the number of reported problem incidents were examined. Specifically, correlation coefficients were calculated separately for number of reported accidents or near misses, and scores on the CDT and MMSE. Patients who had not been currently or recently driving were excluded from the analysis, since no problems would have been reported if they had not been driving. The number of reported incidents correlated significantly and positively with the level of cognitive impairment as measured by MMSE and CDT scores. Additionally, each of the CDT scoring systems appeared to evidence similar predictive utility, as they correlated highly (above 0.80). Means, standard deviations, and correlations for these variables are provided in Table Finally, hierarchical regression analyses examined whether MMSE or CDT scores uniquely predicted number of reported accidents or near misses. The non-significant R-squared change term in the second step of each regression indicates that neither the MMSE nor set of CDT scores predicted significant incremental variance. Thus, it appears that the variance in reported accidents or near misses predicted by the MMSE and CDT was redundant. Regression results are provided in Table n-sizes within each cell may have limited statistical power.The results of this study suggest that both the MMSE and the CDT appear to have only limited utility in predicting retrospective reports of driving problems among elderly drivers. The finding that MMSE and CDT scores were worse among patients who had not been currently or recently driving may be due to a number of factors, including the possibility that some individuals may have never driven at all before. Nevertheless, it appears likely that many of these individuals probably had been driving in the past, but may have since stopped due to problems related to cognitive impairment. This assertion is supported by the finding that individuals who had been currently or recently driving at the time of the assessment, and who had lower MMSE scores, were more likely to have had reports of accidents or near misses. Although similar mean tests with the CDT were not significant, it is notable that the direction of the obtained differences for each scoring system of the CDT was consistent with the findings of the MMSE. Furthermore, the relatively modest More robust findings were obtained, however, for the correlations examining number of reported accidents or near misses to CDT and MMSE scores. Among individuals who had been currently or recently driving at the time of assessment, greater levels of cognitive impairment as evidenced by MMSE and CDT scores also predicted greater numbers of reported accidents or near misses. This finding held regardless of which CDT scoring system was incorporated, suggesting that each may have equal utility.Finally, the results of the regression analyses appear to indicate that the predictive power of the CDT and MMSE are somewhat redundant, since neither added significant incremental variance to prediction. Although it is possible that the regressions may have had limited power to detect significant incremental differences due to the relatively small sample sizes, in each case the increment to R-squared was small nonetheless. Thus, it appears that both the MMSE and CDT served as gross assessments of general cognitive function, versus more specific cognitive capacities, in predicting reported numbers of accidents or near misses.Although the current results appear to suggest limited predictive utility for the MMSE and CDT in predicting driving problems, an additional cautionary note is in order. The significant predictive power for each instrument as demonstrated by the magnitudes of the correlation coefficients was nevertheless small. Furthermore, significant predictive utility was not obtained for every test in the current research. Additionally, the use of a retrospective design does not necessarily allow for definitive conclusions about predicting instances of future driving problems. Thus, although poor CDT or MMSE scores appear to indicate greater potential for driving problems, the current data do not support the use of the CDT or MMSE alone in making definitive decisions pertaining to driving competence. Rather, the empirical findings of the current research appear to best support the use of the CDT and MMSE solely as their originally intended purpose as screening tools. Thus, scores evidencing impairment on either of these instruments may indicate a need for driver caution, followed by more comprehensive and extensive assessment of driving capacity on which to base decisions regarding safety. As such, the role and utility of these instruments in predicting driving problems may be more fully understood through future research that incorporates a prospective design, along with a more comprehensive assessment of specific and relevant cognitive skills (like psychomotor speed or executive function) and objective assessment of driving abilities (such as can be obtained through simulated or practice driving situations).The author(s) declare that they have no competing interests.ND, AG, and JM conceived of the study purpose and design. ND, EB, and MM collected, entered, and analyzed the data. ND conducted the literature review and critique, and drafted the manuscript. AG, JM, EB, and MM provided comments on the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Great apes are threatened with extinction, but precise information about the distribution and size of most populations is currently lacking. We conducted orangutan nest counts in the Malaysian state of Sabah (North Borneo), using a combination of ground and helicopter surveys, and provided a way to estimate the current distribution and size of the populations living throughout the entire state. We show that the number of nests detected during aerial surveys is directly related to the estimated true animal density and that a helicopter is an efficient tool to provide robust estimates of orangutan numbers. Our results reveal that with a total estimated population size of about 11,000 individuals, Sabah is one of the main strongholds for orangutans in North Borneo. More than 60% of orangutans living in the state occur outside protected areas, in production forests that have been through several rounds of logging extraction and are still exploited for timber. The role of exploited forests clearly merits further investigation for orangutan conservation in Sabah. A new aerial method for surveying orangutan densities provides robust estimates of their number and could be used for large- scale surveying of great ape populations in Asia and Africa Pongo abelii in Sumatra and Pongo pygmaeus in Borneo, are threatened with extinction in the near future [The two orangutan species, r future ,2. A prer future . Densitir future ,5. In orr future . In addir future .The latest estimates available for orangutan populations in the Malaysian state of Sabah (North Borneo) range from 20,000  to less 2R = 0.86, n = 13, p < 0.001), by the second observer , by both observers , and with the average value obtained for both observers at each site .Ground densities estimated with Distance 3.5 and aerial densities predicted with our model are given in We recorded 2,708 orangutan nests during ground surveys  and 6,936 nests from the helicopter . The size of the sampling areas ranged from 0.001% to 1% (ground survey) and from 1.8% to 16.9%  of the total size of each forest surveyed .Our surveys confirmed that orangutans were patchily distributed throughout their range in Sabah , occurri2 locally) were identified in the semi-inundated lowland forests of Kinabatangan (population 13) and Segama floodplains (population 16), Kulamba (population 12), and Tabin (population 14). Most of these forests were highly disturbed, fragmented, and located at the edge of newly established oil palm plantations.The highest nest abundances were recorded in lowland forests below 300 m asl, although we recorded a few nests as high as 1,300 m asl, which appeared to be the upper altitudinal limit for the species in Sabah. The highest orangutan densities  than in areas where more conventional practices were implemented : Mann–Whitney U test, U = 5.5, p = 0.03. Hunting pressure was low in all these forests  yielded higher orangutan densities in old exploited areas and in areas that were exploited under sustainable logging practices  were present in Sabah at the time of our surveys . Two majAerial surveys are widely used for estimating animal abundance and population trends in open and semi-open landscapes . In SabaNest detectability from the helicopter depends on observers and canopy structure. Ideally, specific models for deriving nest densities from aerial indexes (number of nests detected per kilometer of flight) should be designed for different human observation skills and for different habitat types. However, observer bias can be avoided if the same team of skilled people conducts the entire survey. The second source of bias could be overcome with the design of several habitat-specific models. Before these types of models are designed, ground-truthing must be conducted in different habitat types in order to validate a baseline model and to determine habitat-specific correction factors when necessary.Nest parameters used for obtaining the final orangutan density estimates  are a major source of inaccuracy in aerial and ground nest surveys , and theP. p. morio subspecies [Our survey shows that there are currently about 11,000 orangutans present in Sabah, making the state the main stronghold for the bspecies . Howeverbspecies . This debspecies .P. p. morio found in Borneo (population 16).The current network of protected areas in Sabah harbors about 4,000 orangutans, representing about 40% of the total number found in the state. About 60% of the total number of orangutans survives in commercial forest reserves subjected to timber extraction, and these forests harbor the largest unfragmented population of the subspecies The impacts of forest exploitation on ape abundance and ecology depend on several factors, such as (1) the forest types that existed initially and the quality of the regrowth forest , (2) typOur results tend to indicate that the mosaic of habitats found in the semi-inundated mixed dipterocarp forests that were originally occurring in the floodplains of east Sabah could potentially still harbor a significant number of animals following high disturbance levels . However, we can assume that the very high orangutan densities documented in some of the areas located close to oil palm plantations partly result from the influx of newcomers following recent land conversion to agriculture ,30. We cLess diverse habitats (dry lowland dipterocarp forests) located in the interior of the state appear to maintain fewer orangutans, particularly following conventional, nonsustainable logging practices (populations 15 and 16). In the extensive tracts of dry lowland dipterocarp forests exploited for timber (populations 15 and 16), our data suggest that, when hunting pressure is low, orangutan abundance is directly related to the degree of logging and associated damage. For these two populations, the highest orangutan densities were identified in Deramakot, a commercial forest reserve (part of population 15) implementing sustainable logging practices , suggestP.p. morio are not necessarily valid for other Bornean orangutan subspecies and for the Sumatran species [Possible inter- and intraspecific differences in general ecology and feeding behavior of orangutans may also influence population responses to habitat disturbances , and the species ,33,34,35All great ape species require large forest areas to survive. An ecological network combining protected areas with seminatural landscape elements and production forests could be seen as an option to conserve biodiversity, while also providing opportunities for the sustainable use of natural resources ,37. HoweFinally, aerial nest surveys may also be of use in Africa, although it may be difficult to detect nests of African great apes from a helicopter because they tend to be lower in the canopy and it may be impossible to distinguish between gorilla and chimpanzee nests in those areas where the two species are sympatric .2 in the northern portion of the island of Borneo. It is one of the 13 states in the federation of Malaysia. Approximately half of the total land mass is covered with forests , some emergent trees; (3) recently exploited forests (timber extraction was conducted less than 15 y ago): logging roads not entirely colonized by pioneer tree species; few emergent trees; (4): active exploitation: logging activities were ongoing at the time of the survey.All major forest blocks in Sabah were identified from 1:50,000 vegetation maps, and these were divided into 16 different blocks. For each block, we determined a systematic stratified sampling using equidistant parallel line transects, the location of the first line being randomly selected . BecauseFrom the back seats, two observers looked for orangutan nests from either side of the helicopter. All visible nests were recorded. It was impossible to estimate the impact of nest age on nest detection, and the observers acknowledged that a few days-old fresh nests (still green in color) and nests at their latest stages of decay (just a few branches visible) were difficult to detect in the canopy. These nest categories are likely to have been underdetected. The two observers indicated all sightings to a nest recorder seated between them. The nest recorder noted the number of nests detected by the observers per each 30-s period. All crew members were in constant radio contact during the flights. After the flight, data collected by the copilot and the nest recorder were matched in order to determine the location of all sightings along the aerial line transect precisely. The same team of observers conducted all aerial surveys in order to avoid the observer bias.For technical reasons, it was impossible to fit external devices to the helicopter to estimate the distance of the nests to the aerial transects. This prevented us from determining the detection function from our data alone . TrailinBecause the proportion of the actual nest population existing in the forest that was detected from the helicopter was unknown, it was impossible to directly estimate nest densities from our aerial results . We thusth percentile). Heaping was assessed from histograms, and data were grouped where necessary [Nest densities and their variances were estimated by ground line transects using distance sampling ,12. A seecessary ,14. The ecessary . The adeecessary . Finallyecessary . Resultsecessary .D^ was a linear function of both the logarithm of the aerial index AI and the observer effect obs, plus their interaction, in order to include possible differences between observers. We weighted the general regression by the estimated variances of ground nest densities, thus giving a greater emphasis to precise density estimates. The least squares method was used for model fitting by incorporating weights 1/σ^i)log(D^where σ^i)log, and X was the matrix of covariates:where N26, where Σwas a 26 × 26matrix with σ2 · diag(var(logD^i))in the diagonal and zeroes elsewhere.βwas a 4 × 1 vector of parameters to be estimated, and ɛ was a 26 × 1 vector of errors with multivariate normal distribution D^ rewritten using the quantities log (D^)w = W · log(D^), wX = W · X, and ɛw = W · ɛ, with W = diag(σ^−1i)log was w has a more familiar distribution N26, allowing the use of linear regression tools to estimate model parameters via least square theory. We used the backward model selection procedure [p value and greater than a 10% cutoff were then removed one by one, and each new model was retested until all p values of the remaining covariates were less than the cutoff value. We assessed the goodness of fit of the best model by computing the coefficient of determination 2R. The best model supported by the data considered only the aerial index effect  withUnlike ɛ, ɛrocedure  to selec0,AI recorded during helicopter flights, asUsing this model (5), we predicted an orangutan nest density from any new aerial index values, . This mowithX, the matrix defined above, once the observer effect had been removed, s2 the residual mean square up to a constant that was an estimate of σ2, and t23,0.025 the appropriate two-sided t-distribution percentile [and rcentile . Followircentile , this inwhereandA numerical application gaveThese intervals are shown in t-test, n = 5, t = −1.738, p = 0.157; 95% confidence interval of the difference: −110 to 25; ratio between ground and aerial nest densities = 0.94). This result showed that nest detectability was similar in forests that had been exploited for timber in Sabah and in Kinabatangan. Thus, we used the baseline model without any correction for all recent and old exploited forests of the state. Exploited swamp forests had a very open canopy, and predicted aerial nest densities were higher than estimated ground densities, although the difference was not significant . However, in order to not overestimate the final densities, we applied a correction factor of 0.54 to aerial indexes obtained in two areas of extensive exploited swamp forests (parts of populations 12 and 14). In primary lowland dipterocarp forest, the predicted aerial nest density was lower than the estimated ground density in the only site that was tested . Aerial indexes obtained for Danum (part of population 16), the only site of primary lowland forest with a significant orangutan population assessed during our survey, were multiplied by a correction factor of 1.5.Model (5) was obtained with results from the old and recently exploited semi-inundated mixed lowland dipterocarp forests of Kinabatangan. We tested its validity by comparing nest densities predicted from aerial data and estimated from ground line transects at several sites. We found no significant differences for five sites of old and recently exploited dry lowland dipterocarp forests . This interval was then back-transformed to obtain a confidence interval for D^whereThe numerical application gavewithThe results of the ground and aerial surveys were processed with a geographic information system , using a combination of administrative maps and satellite images. When necessary, we stratified each forest block according to (1) disturbance type: no disturbance, old or recently exploited forests, ongoing exploitation; (2) altitude: lowland, below 500 m above sea level (asl); upper land, 500–1,000 m asl; lower mountain, 1,000–1,500 m asl; mountain, above 1,500 m asl; and (3) habitat type: swamp forests, semi-inundated mixed lowland dipterocarp forests, dry lowland dipterocarp forests. We then determined the percentage of habitat actually occupied by orangutans as the ratio between the total length of aerial transects and the length flown over areas with no visible orangutan nests . This percentage was applied to the total size of each forest block determined from maps in order to estimate the final size of “habitat occupied by orangutans.” We then multiplied the estimated orangutan densities by the estimated size of orangutan habitat occupation to obtain overall population estimates.A confidence interval for the population estimate was computed via parametric bootstrapping for the whole population in Sabah . We assuOver a 2-y period (2002–2003), ground surveys  and aerial surveys (72 “man days”) were conducted in all major forests of the state . Recce w


A high frequency of childhood abuse has often been reported in adult psychiatric patients. The present survey explores the relationship between psychiatric diagnoses and positive and negative life events during childhood and adulthood in psychiatric samples.A total of 192 patients with diagnoses of alcohol-related disorders (n = 45), schizophrenic disorders (n = 52), affective disorders (n = 54), and personality disorders (n = 41) completed a 42-item self-rating scale . The TAQ assesses personal positive experiences (competence and safety) and negative experiences  during four developmental periods, beginning from early childhood to adulthood. Patients were recruited from four Psychiatric hospitals in Germany, Switzerland, and Romania; 63 subjects without any history of mental illness served as controls.The amount of positive experiences did not differ significantly among groups, except for safety scores that were lower in patients with personality disorders as compared to the other groups. On the other side, negative experiences appeared more frequently in patients than in controls. Emotional neglect and abuse were reported in patients more frequently than physical and sexual abuse, with negative experiences encountered more often in late childhood and adolescence than in early childhood. The patients with alcohol-related and personality disorders reported more negative events than the ones with schizophrenic and affective disorders.The present findings add evidence to the relationship between retrospectively reported childhood experiences and psychiatric diagnoses, and emphasize the fact that a) emotional neglect and abuse are the most prominent negative experiences, b) adolescence is a more 'sensitive' period for negative experiences as compared to early childhood, and c) a high amount of reported emotional and physical abuse occurs in patients with alcohol-related and personality disorders respectively. It is difficult to assess the impact of childhood traumatic events on the psychiatric disorders in adulthood, as neither prospective research studies, nor experimental approaches are possible. Nevertheless, an increasing number of retrospective reports suggest that psychiatric disorders may be related to childhood psychological traumas such as neglect, physical or emotional abuse -6. In paAny conclusion to such reports, however, must be drawn by taking into consideration that the validity of childhood memories, particularly in psychiatric patients, may be questioned, as the range of childhood traumas indexed in these studies is generally limited, and often only childhood sexual abuse is targeted. Moreover, the observed relationships are correlational in nature, and do not justify the conclusion that childhood trauma favors the development of psychiatric disorders. Antecedents of developing psychopathology may also provoke certain parental behavior. Also, a third variable, such as social conditions, may have caused both childhood abuse and later pathological development. Another notable finding is that the prevalence rates of antecedent traumatic events vary considerably across studies. This may be due to different definitions of abuse which include more detailed  or more The present study sets out to evaluate reported positive and negative life events from early childhood to adulthood in psychiatric patients. We addressed some of the above-mentioned problems by examining abuse histories across a range of several psychiatric diagnoses within a controlled cross-national design. We sought to examine whether (a) negative life experiences are positively associated with psychiatric diagnoses in adulthood, and (b) early childhood and adolescence were 'sensitive periods', that is, whether psychiatric diagnoses were more closely related to negative experience in these developmental periods.The present study includes a German/Swiss and a Romanian psychiatric group, in order to determine whether reports vary between cultural backgrounds.Patients were recruited from four Psychiatric Hospitals within two different cultural settings, Switzerland/Southern Germany versus the Moldavia region in Romania: the Center for Psychiatry Reichenau and the Center for Psychiatry Weissenau in Germany, the Psychiatric Hospital Münsterlingen in Switzerland, and the Psychiatric Hospital "Socola", Jassy in Romania. A total of 192 psychiatric inpatients  filled in the questionnaire. Sixty-three control subjects without any history of psychiatric diagnosis were recruited from the clinical staff and the university employees  as controls (38 Germans and 25 Romanians). The control subjects have been simply inquired whether they had any stationary hospitalization in the psychiatry; no further assessments have been done. After a full explanation of the study, written informed consent was obtained from all subjects.By considering the clinician-made diagnoses which were written down from the medical files available in the psychiatric clinics the patients were recruited from, the patients were distributed in four diagnostic groups: alcohol-related disorders (n = 45), schizophrenic disorders (n = 52), affective disorders (n = 54), and personality disorders (n = 41). At all psychiatric clinics in Germany/Switzerland and Romania the diagnoses were made according to the ICD-10 criteria. Within our patient groups, the following lifetime mental disorders were assessed by using the ICD-10: alcohol-related disorders , schizophrenic disorders , affective disorders , and personality disorders . A few patients within our sample were diagnosed with comorbid symptoms: 4 patients with affective disorders had symptoms of substance abuse and 7 of them had anxiety symptoms; also, within the schizophrenic disorders group, 2 patients had symptoms of alcohol abuse and 6 had depressive symptoms. There were also patients who received two diagnoses: one of which was a personality disorder . In these cases, we considered the other diagnosis for the distribution into the diagnostic groups.Table Life experiences were assessed with the Traumatic Antecedents Questionnaire (TAQ) . The TAQComparisons of demographic data were made with analysis of variance (ANOVA) and with two-tailed unpaired t-tests for continuous variables. Chi-square analysis was used to compare nominal data. The differences between groups were evaluated individually for each TAQ scale by repeated-measures ANOVA with the cultural background (German/Swiss versus Romanian), psychiatric status , and gender  as between-subjects factors, and developmental period (4 periods) as within-subjects factor. The probability level for rejecting the null hypothesis was set at P < 0.05. Post-hoc comparisons were carried out to evaluate main effects and interactions using Bonferroni/Dunn tests. A principal components analysis was also applied to the entire sample in order to identify those factors, which could account for individual variability across the eleven scales of the TAQ. The principal components were derived by using varimax rotation to orthogonalize solutions.competence did not differ between diagnostic groups  or cultural samples . A main effect of developmental period  was explained by the increase of competence from early childhood to adolescence (P < 0.05), and by the decrease of competence in adulthood as compared to adolescence (P < 0.05).Table safety subscale than any of the other groups . Post hoc tests showed that patients with personality disorders (P < 0.001) and those with affective disorders (P < 0.01) reported less such experiences as compared to the controls. The reported level of safety increased through adolescence , but the interaction of the developmental period with the psychiatric status revealed a decrease in safety accounts from the age of 13–18 years towards adulthood in all patient groups .For both cultural samples, patients with personality disorders reported lower values on the Table neglect, the psychiatric patients reported higher rates than the controls , the post hoc tests revealing that all patient groups reported more such experiences as compared to the controls: patients with personality disorders (P < 0.001), alcohol-related disorders (P < 0.05), schizophrenic disorders (P < 0.05), and affective disorders (P < 0.05). There was an increase of the amount of reported neglect experiences across developmental periods . Across developmental periods there were significant effects of the psychiatric status : the post hoc tests showed that patients with personality disorders (P < 0.001) and with alcohol-related disorders (P < 0.01) reported a highly significant increase of the amount of neglect experiences across developmental periods as compared to the controls  = 6.4, P < 0.05]. Romanian patients, particularly those with schizophrenic disorders, reported a higher incidence of neglect experiences than their German counterparts (P < 0.01), as revealed by the interaction between the psychiatric status and cultural background . As indicated by the interaction between the developmental period and the cultural background, the mean scores of neglect experiences were higher in the Romanian sample as compared to the German/Swiss one for the earliest (0–6 years) period .Patients, particularly those with alcohol-related disorders, personality disorders, and affective disorders reported more often separation experiences than controls . Mean scores on separation increased with age, and were highest in adulthood .Higher patient mean scores were confirmed by the main effect of the psychiatric status , especially for those with personality disorders (P < 0.001) and with schizophrenic disorders (P < 0.001), as revealed by post-hoc tests. There was also an indication of sensitivity to the cultural background , as there was an increase in these scores in the Romanian sample, irrespective of the diagnosis and developmental period.Emotional abuse was more frequently reported by patients than by controls  and more frequently by patients with personality disorders (P < 0.01) and by schizophrenic patients (P < 0.05) than the ones with a history of alcohol-related disorders  = 5.7, P < 0.001]  = 8.0, P < 0.001]. Post-hoc tests showed that patients with affective disorders (P < 0.01) and with alcohol-related disorders (P < 0.05) also reported more experiences of trauma witnessing than the controls. Irrespective of the diagnosis, Romanian patients, but not controls, reported higher mean scores on this variable and more often than their German/Swiss counterparts . The interaction between the cultural background and developmental period indicated in the Romanian sample an increase of trauma witnessing in adulthood .Similar to the pattern of trauma witnessing, all patients reported a greater number of traumatic events than the control group : alcohol-related disorders (P < 0.001), personality disorders (P < 0.001), schizophrenic disorders (P < 0.01), and affective disorders (P < 0.01), as explained by post-hocs. An increase in the amount of other traumas reports across the developmental periods with highest values in adulthood for all patient groups  was also revealed.As previously expected, patients treated for alcohol-related disorders reported more alcohol and drug abuse than all the other groups . The post-hoc tests showed that the other patient groups also reported more alcohol and drug abuse when compared to the control group: affective disorders (P < 0.001), personality disorders, (P < 0.001) and schizophrenic disorders (P < 0.05). As also anticipated, abuse increased across developmental periods until adulthood , particularly in patients with alcohol-related disorders, as revealed by the interaction between the developmental period and psychiatric status . Irrespective of the diagnosis, Romanian patients, but not controls, showed higher mean scores on reporting alcohol and drug abuse than their German/Swiss counterparts , as shown by the interaction between the psychiatric status and cultural background. Compared to the German group, alcohol and drug abuse in the Romanian sample was higher, particularly in adulthood .physical abuse, sexual abuse, trauma witnessing, and other traumas, obviously explains the traumatic experiences. The second factor showed high positive loadings on competence and safety, apparently accounting for variance attributed to positive experiences. The third factor showed high positive loadings on the first year of illness with alcohol and drug abuse. The fourth factor, consisting of separation, evidently explains disruptions of attachment. The fifth factor, which included secrets and emotional abuse, appeared to account for family chaos. Thus, the structure of the study instrument was well reproduced for the present sample, which included different psychiatric diagnoses and different cultural backgrounds.A principal components factor analysis was performed to explore interrelationships among TAQ subscales. The results of this analysis indicated that the most appropriate solution involved five factors that jointly accounted for 56.2% of the total variance in the dataset. Table The study aimed at exploring whether psychiatric diagnoses, e.g. alcohol-related disorders, schizophrenic disorders, affective disorders, and personality disorders are related to retrospectively reported positive and negative life events across developmental periods, and if so, whether special developmental periods are characterized by more negative experiences than others.Our findings demonstrate a strong association between reports of traumatic events and certain psychiatric disorders. In other studies, negative experiences were reported by individuals with diagnoses such as affective disorders ,41 and sIf the present findings are consistent with some prior studies ,9,16 in Furthermore, experiences of parental loss or separation were prominent in adulthood especially for the patients with alcohol-related disorders and with affective disorders. The high incidence of such negative experiences during this period in the patients with alcohol-related disorders could be, at the same time, a direct consequence of the behavioral deviance of these individuals and contribute to the maintenance of alcohol abuse.The present data has to be considered in the light of several possible limitations. First, the information obtained by self-report and without external evidence could be less reliable and valid, especially if we take into account the sensitive nature of this research. Herman and Schatzow, however, provide empirical support for the validity of abused patients' self-reports as well . They foBoth individual interviews and self-report questionnaire methods present higher figures than chart reviews do, indicating that patients usually do not spontaneously offer such information to their therapists. When offered, the information is not reliably documented . HoweverRomanian patients diagnosed with schizophrenic disorders differed significantly, with respect to the number of negative events, as compared to their German counterparts. One factor accounting for this difference might be the stressful environment during the former Ceausescu regime in Romania. During this 25-year period violations of human rights, terror, and corruption prevailed ,62. ThisThe present study demonstrates an association between negative life events in childhood and psychiatric diagnoses in adult life, which is in line with a number of other studies ,63. UnliAlthough one cannot assume a direct causal relationship between childhood abuse and adult psychopathology from the present data, the present study provides further preliminary and explorative evidence for the high load of negative life events in psychiatric patients. An advantage of this study is the examination of the abuse histories across a range of four psychiatric diagnoses within a controlled comparison design. Our findings are important and clinically highly relevant for further etiological research of causal and maintenance factors of psychiatric symptomatic, as well as for the research on the treatment of these conditions.The special value of the study lies in its cross-national comparison from a clinical psychological point of view including a highly underresearched country like Romania. More attention should be paid to the sad situation of the patients in Romania who are often under inadequate pharmacological and insufficient psychotherapeutic treatment, as well as under inappropriate hospitalization conditions. Further research should concentrate on the epidemiology and developmental psychopathology of psychiatric populations in other countries than the usually researched ones. Generally, reports of traumatic experiences during the whole lifespan should be more carefully considered in the clinical diagnosis process and in the development of treatment programs for the psychiatric patients.The author(s) declare that they have no competing interests.ES carried out the study in Germany, performed the statistical analysis and drafted the manuscript. DB carried out the study in Romania and drafted the manuscript. BR conceived of the study and drafted the manuscript. FN participated in the design of the study. MS participated in the design of the study. KS participated in the coordination of the study. KH participated in the coordination of the study. TE conceived of the study and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


In recent years, Australian state and territory governments have reviewed and restructured the health systems they lead and regulate. This paper examines the outcomes of the most recent official published reviews of systems and structures; identifies the common themes; and addresses two questions: what problems are being addressed? And how would we know if the changes were successful?In all the broad, systemic reviews, the main health system problems identified were money, hospital utilisation and a weak primary health care system. The solutions are various, but there is a common trend towards centralisation of governance, often at state health authority level, and stronger accountability measures. Other common themes are hospital substitution (services to avoid the need for admission); calls for cooperation across the Commonwealth:state divide, or for its abolition; and the expected range of current efficiency and effectiveness measures  and ideas in good currency . The top-down nature of the public review process is noted, along with the political nature of the immediate catalysts for calling on a review.The long-standing tension between the pull to centralisation of authority and the need for innovation in care models is heightened by recent changes, which may be counterproductive in an era dominated by the burden of chronic disease. I argue that the current reforms will not succeed in achieving the stated goals unless they make a difference for people with chronic illness. And if this is correct, the most useful focus for evaluation of the success of the reforms may be their impact on the system's ability to develop and deliver better models of care for this growing group of patients. In recent years, there has been a rolling (and sometimes repetitive) tide of structural change in the way state and territory governments organise to lead and/or provide health care within their jurisdictions, with every state and territory of Australia involved at least once in the last 10 years.This paper examines the outcomes of the most recent official published reviews of systems and structures; identifies the common themes; and addresses two questions: what problems are being addressed? And how would we know if the changes were successful?This analysis focuses on those reviews which are 'systemic' in the sense that they examine broadly the structure and performance of a state/territory health system, and/or address governance of the system. The NSW restructure has been included, although it differs from the others in the absence of an independent review process and in the related lack of detailed documentation of the rationale for change.The most recent wave of systemic reviews in the Australian public health system saw New South Wales , South ANSW has relinquished its status as an island of relative stability, which had been maintained since 1986 in spite of several reviews, penultimately by IPART [Queensland stays with central control  while Tasmania is reviewing hospital services only , having The pattern of systemic reviews over the last 10 years is summarised in Table In what has emerged as a strong centralising tendency, 6 of 8 jurisdictions have centralised governance authority for public sector health care agencies at the level of the state or territory health authority. Victoria and South Australia are mixed, with regionalised or 'networked' structures predominating in the capital city; and several different approaches to both regional and institutional governance elsewhere. As Somgen points out, Victoria and South Australia were the states most strongly influenced by the 1990's trend to privatisation, outsourcing and output-based funding , with leTable The recent NSW decision means that there is now a strong predominance of governance at state health authority level, with two-thirds of the Australian population living in areas served by centralised health services.The second notable trend is the virtual end of 'atomised' structures – stand-alone, single-service agencies  in the public sector. There are of course exceptions , and the picture is different for non-government organisations (like district nursing) which are less amenable to restructuring.The most recent reviews in WA and SA are characterised by claims to radical change, based on both financial and health goals:'...incremental reform is no longer the pathway to a financially sustainable vision for WA. A fundamental re-prioritisation of the public health system is needed, and should be carried out over the next decade in a systematic and integrated way' [p v).ted way' , p v).'The people of South Australia have a decision to make on what type of health system they need now and for the future generation...there needs to be a significant shift from a system focused on illness to a health system reoriented towards health promotion, illness prevention and early intervention' [p xiii.vention' p xiii.Western Australia is taking on the tertiary hospitals, and reducing the number of tertiary sites from 5 to 2 . All state-run health services are to report through three metropolitan regions  and one rural region, with the CEO's reporting directly to the Department – there are to be no boards of governance. South Australia has succeeded in amalgamating most of Adelaide's hospital and community health boards to form 2 regional health services and 1 child, youth and women's health service . This is a notable achievement for a minority government, after at least five separate attempts in the last 20 years to rebalance power and responsibility had largely failed -17.Not all of the systemic reviews claim to set a bold new vision, but there are strong common themes. The reports tell a familiar story of the need to bring increases in state health spending to sustainable levels, set against the trend of increasing costs due to increasing incidence of chronic disease, and more technologies for intervention, in an ageing population. They all focus on the need to improve quality and safety for patients.The reviews also find that the health system is too fragmented to meet the needs of patients with long-term complex conditions well. This is seen to be partly because the system was designed for acute illness, with the current funding mechanisms also designed primarily on the pattern of acute interventions. The reviews call for better integration of services, so that navigating the system is easier for patients, their carers and care providers.The reviews consistently argue that in order to achieve this, the primary care system needs to be more effective in managing or coordinating patients' needs for several different kinds of services when and where they are needed. The inevitable corollary is that inpatient care and hospitals have to become less central in the organisation and funding of the system. What can be done elsewhere should be; and the primary care level must have more of the action and more of the pulling power.In turn, this will require different facilities for different modes of service delivery; different funding allocations and methods of allocation; and a solution to the atomisation of primary care caused by the Commonwealth/state split and the current model of fee-for-service medicine. The need for changes in the private sector is noted in the reviews, but proposals are not developed, because the states have such a limited role here.Much is also made of the need for providers to be more accountable to government and the community, and/or better governed and managed. While the reports mostly call for less micro-managing from the head offices of health authorities, and a better separation between the roles of central policy-makers and peripheral service providers , there is also a countervailing tendency to recommend tighter engagement and control. For example, the Kibble review of governance in Victoria (2003) notes confusion about relative roles and responsibilities and calls for the Department of Human Services to reduce 'attention to the day-to-day operations of Health Services and monitoring of detailed activities' (p 27) but later recommends 'a standardised reporting template' for internal reports to boards across the system (p 35), along with stronger accountability for the CEOs to the Secretary of the Department. More public reporting of service outcomes and activity levels is a related common theme, intended to inform the public and to underpin attention to safety and quality.The final major common theme in the reviews is the inclusion of an opportunistic range of technical efficiency and effectiveness measures, picking up ideas in good currency or known productivity opportunities. For example, almost everyone recommends a call centre; a web-based method of sharing innovations; amalgamation of support services where relevant; and improvements in the effectiveness of information systems and the use of information.are the providers  or because intended changes to the service provider level of the system require changes to the roles of central health authorities.There are two other commonalities worth noting. Firstly, it is a fact of organisational and political life that official reviews are a top-down affair, commissioned by one level of the system to examine a lower level. Thus it is not surprising that there are no published official reviews of the roles and responsibilities of the Commonwealth health authority in the last twenty years. When the published reviews do address the roles and responsibilities of state health authorities, it is either because they This is an important limitation in the current environment, when some of the key barriers to improving the effectiveness of health care delivery lie in the system's seldom seen upper reaches. As the reviews note, the way that the Commonwealth/state split of responsibility for health is enacted and managed is probably the single most significant problem in health system design. But it is not the only one. I refer not so much to important policy settings  which are studied and articulated in publicly-available documents, but rather to the influence of administrative decisions  and the effectiveness of relationships with health care provider organisations (as judged from the bottom up as well as the top down). The administrative actions of health authorities seem to go largely unexamined.Secondly, while the underlying problems the reviews set out to address are all about money, hospital utilisation and a weak primary health care system, the immediate context is often the election of a new government , the appointment of a new minister or health authority CEO (WA), media unrest about health in a state with a looming election (ACT) or scandal (NSW). This observation may simply be another way of saying that the health portfolio is highly politically sensitive as well as complex, and so risky that reference to independent expertise is seen as essential.The main line of logic running through the recent reviews seems sound. The primary care system needs strengthening; what can be done outside hospitals should be; and a continuing focus on safety, performance and accountability is necessary.The reports also make it clear that this is all about responding to the major challenge for the system: to improve its capacity to prevent, intervene early in, and manage chronic disease, the main driver of increased demand. Such a focus is clearly justified. Chronic disease is responsible for approximately 80% of the total burden of disease, with an estimated three million Australians suffering from one or more chronic illnesses . About 4If this is the imperative, the trend away from atomised governance structures, and towards bringing multiple agencies which serve (at least some) common patients together, seems like the right direction. But there is another important requirement which may not be served by these moves – that is, a stronger focus on innovation in care models. While recommendations abound, we don't yet really know what will work best for the new pattern of illness – how do you best coordinate care around the needs of the chronicly ill?Uncertainty about care models, and the institutional and policy arrangements needed to support them, can only be resolved through the continued development and testing of innovative approaches, on the ground in health care delivery, as happened most notably with the Coordinated Care Trials . As manyThis reality implies that there is a secondary criterion by which the effectiveness of health system structural changes might be judged: do the changes enhance or inhibit the system's ability to innovate? The requirement for innovation and experimentation may not sit comfortably with government requirements for standardisation of known good practice. However in an area where best practice is not known, innovation is critical, and must be supported.Unfortunately, the Commonwealth:state responsibility split, the one structural barrier most central to the systemic weakness of Australian primary care (and therefore most important for the capacity to develop and support new models of care for chronic diseases), is one that a state can't address, at least not alone. The Productivity Commission's recent call for an independent public review of the whole health system , focusedThe other pessimistic sign is the trend to more direct control of health care provision by state governments, related no doubt to the twin problems of increasing demand (and therefore cost) and increasing disclosure of safety and quality problems, both of which can only politicise the system more. Research on innovation, in relation to quality and safety as well as other performance measures, indicates that micro-management from above is not helpful ,23.Local evidence to support this view is scant. While the effectiveness of the new arrangements during Queensland's brief period of devolved governance was judged harshly when it came time to re-centralise, some commentators suggest that this period also allowed Queensland to catch up to other states in areas like accreditation, casemix, IT and 'attention to performance management and outcomes' .This may be a critical problem. While recognising that perspectives on this question are highly related to one's place in the structure, I would suggest that real innovation in public hospitals and health services is less likely to be driven by clinicians who are more tightly controlled, staff who have learnt to be risk-averse, or managers who are increasingly frightened of tomorrow's headlines, and whose planning horizon extends to next month's financial and activity data. This problem is only compounded while hospitals and community health services on the one hand, and GPs on the other, continue to work with so little in the way of common incentives.The recent reviews were established largely to address financial imperatives in an environment of upward pressure on demand for services, and accountability concerns , mostly in a highly political context. The reviewers rightly sought to take a longer-term strategic perspective. They attempted (with varying degrees of success) to focus on good system design and capacity to meet the broad and complex purposes of public health systems, recognizing the growing challenges the systems face.Structural reform is hardly ever evaluated, other than when its weaknesses are articulated by those proposing the next round of changes, as part of the rationale for their efforts. There are many reasons for this failure, some of them political. One pertinent reason is that outcomes like containing the pressure of future growth in demand, or improving health outcomes for the population, cannot be judged within a realistic time frame.However, in the current environment, with strong convergence in the themes addressed by a fairly comprehensive round of reviews of Australian health systems, an argument can be made for evaluation 'at the pointy end' of the changes. Given the challenges the reviews were intended to address, there are grounds to suggest that the current reforms will not succeed in achieving the stated (shorter- and longer-term) goals unless they make a difference for people with chronic illness. And if this is correct, the most useful immediate focus for evaluation of the success of the reforms may be their impact on the system's ability to develop and deliver better models of care for this growing group of patients.The 'data' for this project were the published reports of systemic reviews of the health systems, and related material published on departmental websites and in the professional and academic literature.These sources were analysed to generate an understanding of the recommended governance authority structures; and the common themes emerging from the reasoning on which the recommendations were based. The themes underpinning the recommendations were then assessed in the light of the overarching goals of reform.I was a member of the South Australian 'Generational Health Review' Steering Committee, chaired its Governance and Funding Task Force and continue to consult to the SA Department of Human Services. I worked for twenty years in health care agencies, and only one in a central health authority.