[Catatonia in youth with developmental disabilities: challenges in recognition and management]. / Katatonie bij jongeren met een ontwikkelingsstoornis: uitdagingen in herkenning en aanpak.

Catatonia in children and adolescents is not rare and, as in adults, has a favorable outcome, provided it is recognized and treated promptly. Nevertheless, in clinical practice we encounter several obstacles in terms of diagnosis and treatment in this population of patients. We describe a 14-year-old boy with an intellectually disability and autism spectrum disorder (ASD) in which clinicians did not diagnose catatonia until 1 year after the development of symptoms. Moreover, hesitations surrounding the correct treatment led to its delayed initiation. With this case report we aim to contribute to reduced reluctance and increased alertness in the treatment of catatonia in adolescents with developmental disorders.

[Developing a decision tool: indicating care for mild intellectual disability]. / Ontwikkeling decision tool voor een lichte verstandelijke beperking: zorg aan de juiste doelgroep.

BACKGROUND: Children and youth with an intellectual disability and psychiatric problems are a complex group. By identifying clients who require highly specialized mental health care at an early stage, it is expected that the provided care can be utilized more effectively, there will be less non-response and clients will more efficiently receive the most appropriate care. AIM: To develop a decision tool which can identify clients who need highly specialized care at an early stage. METHOD: A review of the literature and qualitative research methods were used, including a Delphi study to get consensus on criteria that could be used as indicators for highly specialized care. These criteria were included in a decision tool, followed by validation of these criteria by testing them on the population of the Banjaard, a mental health care setting for young people with intellectual disability and psychiatric problems. RESULTS: Ten criteria emerged from the Delphi method that were seen to be predictive of the need for highly specialized care. After applying these criteria to the Banjaard population, it appeared that three or more criteria reliably identified clients needing highly specialized care (sensitivity 76.5% and specificity 75.6%). CONCLUSION: The decision tool developed in the current study is a reasonable instrument for identifying clients who could benefit from highly specialized mental health care.

[Linking mental healthcare- and Statistics Netherlands microdata to assess the effectiveness of care]. / Koppelen van ggz- en CBS-microdata om zorgeffectiviteit te meten.

BACKGROUND: The effectiveness of mental health care is currently monitored through routine quantitative symptom-driven measurements in most clinical settings. These measurements seem inadequate, especially for target groups with complex, multi-faceted problems. There is as yet no alternative method. AIM: 1. To describe why quantitative symptom-driven measurements are inadequate for measuring healthcare effectiveness; and 2. to introduce a new data platform that adjusts for socioeconomic and environmental factors to monitor the effectiveness of healthcare. METHOD: Overview of developments based on literature and introduction of a unique data platform. RESULTS: In the case of complex, multi-faced problems, such as in children with mild intellectual disability and comorbid psychopathology, mental health problems cannot be quantified, isolated, and individualized, i.e., decontextualized. To evaluate care for external benchmarking and scientific research, a shift is advised from measuring clinical symptoms within the treatment period to measuring longer-term group-level social functioning across multiple life domains, with a focus on socio-demographic differences. The Extramuraal LUMC Academisch Netwerk Gezond & Gelukkig Den Haag (ELAN-GGDH ; in English: Extramural LUMC Academic Network Healthy & Happy The Hague) data platform accomplishes this by combining mental health data with Statistics Netherlands microdata. CONCLUSION: The data platform could add value to external benchmarking and scientific research at group level.

Case report: NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology presenting in a 13-year-old managed with a neo-adjuvant TRK-inhibitor and surgical excision.

This case report reviews the case of a 13-year-old patient who presented with a 9 cm NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology. At presentation the lesion filled her vagina and pelvis and any attempt at surgical removal would have been morbid and led to loss of fertility. These neoplasms are extremely rare with 18 cases of the uterine cervix reported in the literature, none of which have occurred in a paediatric patient, and none of whom have received neo-adjuvant therapy prior to excision. Based upon evidence that has shown good tolerability and responses of paediatric NTRK fusion-positive solid tumours to TRK inhibitors, both in the neo-adjuvant and upfront setting, this patient was managed with neo-adjuvant entrectinib. Following a dramatic reduction in tumour size confirmed by imaging, she underwent conservative fertility sparing surgery with final histopathology showing no residual disease.

New technologies in screening for breast cancer: a systematic review of their accuracy.

We systematically reviewed the literature on the accuracy of new technologies proposed for breast cancer screening. Four potential tests were identified (ultrasound, magnetic resonance imaging (MRI), full-field digital mammography (FFDM), and computer-aided detection (CAD)) for which primary studies met quality and applicability criteria and provided adequate data on test accuracy. These technologies have been assessed in cross-sectional studies of test accuracy where the new test is compared to mammography. Ultrasound, used as an adjunct to mammography in women with radiologically dense breasts, detects additional cancers and causes additional false positives. Magnetic resonance imaging may have a better sensitivity (but lower specificity) than mammography in selected high-risk women, but studies of this technology included small number of cancers. Computer-aided detection may enhance the sensitivity of mammography and warrants further evaluation in large prospective trials. One study of FFDM suggests that it may identify some cancers not identified on conventional mammography and may result in a lower recall rate. The evidence is currently insufficient to support the use of any of these new technologies in population screening, but would support further evaluation.

Preventing phage lysis of Lactococcus lactis in cheese production using a neutralizing heavy-chain antibody fragment from llama.

Bacteriophage infection is still a persistent problem in large dairy processes despite extensive studies over the last decades. Consequently, new methods are constantly sought to prevent phage infection. In this paper, we show that phage neutralizing heavy-chain antibody fragments, obtained from Camelidae and produced at a large scale in the generally regarded as safe microorganism Saccharomyces cerevisiae, can effectively be used to impede phage induced lysis during a cheese process. The growth inhibition of the cheese starter culture by 10(5) pfu/ml cheese-milk of the small isometric-headed 936-type phage p2 was prevented by the addition of only 0.1 microg/ml (7 nM) of the neutralizing antibody fragment. The use of such antibody fragments in cheese manufacturing are a realistic and interesting option because of the small amount of antibody fragments that are needed. Moreover the antibodies are produced in a food grade microorganism and can easily be isolated from the fermentation liquid in a pure and DNA free form.

Trafficking and localisation of resident Golgi glycosylation enzymes.

The localisation of glycosylation enzymes within the Golgi apparatus is fundamental to the regulation of glycoprotein and glycolipid biosynthesis. Regions responsible for specifying Golgi localisation have been identified in numerous Golgi resident enzymes. The transmembrane domain of Golgi glycosyltransferases provides a dominant localisation signal and in many cases there are also major contributions from the lumenal domain. The mechanism by which these targeting domains function in maintaining an asymmetric distribution of Golgi resident glycosylation enzymes has been intensely debated in recent years. It is now clear that the targeting of Golgi resident enzymes is intimately associated with the organisation of Golgi membranes and the control of protein and lipid traffic in both anterograde and retrograde directions. Here we discuss the recent advances into how Golgi targeting signals of glycosylation enzymes function, and propose a model for maintaining the steady-state localisation of Golgi glycosyltransferases.

Lateral recognition of a dye hapten by a llama VHH domain.

Camelids, camels and llamas, have a unique immune system able to produce heavy-chain only antibodies. Their VH domains (VHHs) are the smallest binding units produced by immune systems, and therefore suitable for biotechnological applications through heterologous expression. The recognition of protein antigens by these VHHs is rather well documented, while less is known about the VHH/hapten interactions. The recently reported X-ray structure of a VHH in complex with a copper-containing azo-dye settled the ability of VHH to recognize haptens by forming a cavity between the three complementarity-determining regions (CDR). Here we report the structures of a VHH (VHH A52) free or complexed with an azo-dye, RR1, without metal ion. The structure of the complex illustrates the involvement of CDR2, CDR3 and a framework residue in a lateral interaction with the hapten. Such a lateral combining site is comparable to that found in classical antibodies, although in the absence of the VL.

Focusing strategies of condom use against HIV in different behavioural settings: an evaluation based on a simulation model.

Using a sexually transmitted diseases simulation model (STDSIM), we made projections of HIV spread for four profiles of sexual behaviour reflecting patterns encountered across the developing world: 1) much commercial sex, no short relationships; 2) commercial sex, concurrent short relationships; 3) concurrent relationships, no commercial sex; 4) serial short relationships, some commercial sex. We studied the effects of increasing condom use in three target groups: commercial sex workers (CSWs); men engaging in commercial contacts and short relationships; and females in steady relationships. The projections indicated that the CSW and male strategies were more effective in reducing HIV incidence than the strategy focusing on females in steady relationships. In the long run, even the group of men and women with one recent partner were better protected against HIV infection by condom use in high-risk contacts than by condom use in steady relationships. Furthermore, the numbers of HIV cases prevented per condom used were 7 to 500 times higher for condoms used by CSWs or men engaging in short relationships and commercial sex than for ones used by females in steady relationships. The results indicated the merit of focusing on high-risk groups irrespective of the pattern of sexual behaviour, even in epidemics that had already spread throughout populations.

The GRIP domain is a specific targeting sequence for a population of trans-Golgi network derived tubulo-vesicular carriers.

Vesicular carriers for intracellular transport associate with unique sets of accessory molecules that dictate budding and docking on specific membrane domains. Although many of these accessory molecules are peripheral membrane proteins, in most cases the targeting sequences responsible for their membrane recruitment have yet to be identified. We have previously defined a novel Golgi targeting domain (GRIP) shared by a family of coiled-coil peripheral membrane Golgi proteins implicated in membrane trafficking. We show here that the docking site for the GRIP motif of p230 is a specific domain of Golgi membranes. By immuno-electron microscopy of HeLa cells stably expressing a green fluorescent protein (GFP)-p230GRIP fusion protein, we show binding specifically to a subset of membranes of the trans-Golgi network (TGN). Real-time imaging of live HeLa cells revealed that the GFP-p230GRIP was associated with highly dynamic tubular extensions of the TGN, which have the appearance and behaviour of transport carriers. To further define the nature of the GRIP membrane binding site, in vitro budding assays were performed using purified rat liver Golgi membranes and cytosol from GFP-p230GRIP-transfected cells. Analysis of Golgi-derived vesicles by sucrose gradient fractionation demonstrated that GFP-p230GRIP binds to a specific population of vesicles distinct from those labelled for beta-COP or gamma-adaptin. The GFP-p230GRIP fusion protein is recruited to the same vesicle population as full-length p230, demonstrating that the GRIP domain is solely proficient as a targeting signal for membrane binding of the native molecule. Therefore, p230 GRIP is a targeting signal for recruitment to a highly selective membrane attachment site on a specific population of trans-Golgi network tubulo-vesicular carriers.

Model-based evaluation of single-round mass treatment of sexually transmitted diseases for HIV control in a rural African population.

OBJECTIVES: To compare the impact of single-round mass treatment of sexually transmitted diseases (STD), sustained syndromic treatment and their combination on the incidence of HIV in rural Africa. METHODS: We studied the effects of STD interventions by stochastic simulation using the model STDSIM. Parameters were fitted using data from a trial of improved STD treatment services in Mwanza, Tanzania. Effectiveness was assessed by comparing the prevalences of gonorrhoea, chlamydia, syphilis and chancroid, and the incidence of HIV, in the general adult population in simulations with and without intervention. RESULTS: Single-round mass treatment was projected to achieve an immediate, substantial reduction in STD prevalences, which would return to baseline levels over 5-10 years. The effect on syphilis was somewhat larger if participants cured of latent syphilis were not immediately susceptible to re-infection. At 80% coverage, the model projected a reduction in cumulative HIV incidence over 2 years of 36%. A similar impact was achieved if treatment of syphilis was excluded from the intervention or confined to those in the infectious stages. In comparison with sustained syndromic treatment, single-round mass treatment had a greater short-term impact on HIV (36 versus 30% over 2 years), but a smaller long-term impact (24 versus 62% over 10 years). Mass treatment combined with improved treatment services led to a rapid and sustained fall in HIV incidence (57% over 2 years; 70% over 10 years). CONCLUSIONS: In populations in which STD control can reduce HIV incidence, mass treatment may, in the short run, have an impact comparable to sustained syndromic treatment. Mass treatment combined with sustained syndromic treatment may be particularly effective.

Upper gastrointestinal disease, Helicobacter pylori and recurrent abdominal pain.

Over a 5-y period, 396 children complaining of recurrent abdominal pain (RAP) underwent upper gastrointestinal endoscopy in order to identify any underlying organic pathology and determine the prevalence of Helicobacter pylori (H. pylori) infection. Histologically confirmed mucosal inflammation was found in 338 out of 396 children (85.4%); in 113 of 396 patients (28.5%), H. pylori was identified on the gastric mucosa. Significant discriminating factors between H. pylori positive and negative children with RAP included age (mean age for positive 11 y vs. 8.1 y for negative, p < 0.01) and gender (male gender predominance in the H. pylori positive, p < 0.001). No significant difference was found between H. pylori positive and negative groups regarding incidence and character of the presenting symptoms. All H. pylori positive children (100%) had abnormal histology compared with 225 out of 283 negative ones (79.5%). Histologically confirmed gastritis was the most prominent finding in H. pylori positive children compared with H. pylori negative (98.2% vs. 19%, p < 0.001). Conversely, oesophagitis was more common in H. pylori negative children (47.7% vs. 27.4%, p < 0.001). The incidence of peptic ulcer was higher in H. pylori infected patients than in the H. pylori negative group (5.3% vs. 1%, p < 0.05). Our data suggest that gastrointestinal pathology is more common than previously thought in children with RAP, while H. pylori infection is a relatively important factor in the etiology of upper gastrointestinal inflammation in RAP syndrome.

The Golgi-targeting sequence of the peripheral membrane protein p230.

Vesicle transport requires the recruitment of cytosolic proteins to specific membrane compartments. We have previously characterised a brefeldin A-sensitive trans-Golgi network-localised protein (p230) that is associated with a population of non-clathrin-coated vesicles. p230 recycles between the cytosol and the cytoplasmic face of buds/vesicles of trans-Golgi network membranes in a G protein-regulated manner. Identifying the mechanism responsible for Golgi targeting of p230 is important for the elucidation of its function. By transfection of COS cells with deletion mutants of p230 we here demonstrate that the C-terminal domain is necessary for targeting to the Golgi. Furthermore, the C-terminal 98 amino acid domain of p230 attached to the green fluorescent protein (GFP-p230-C98aa) was efficiently Golgi-localised in transfected COS cells. Deletion mutants of GFP-p230-C98aa together with alanine scanning mutagenesis identified a minimum stretch of 42 amino acids that is essential for Golgi targeting, suggesting that the conformation of the domain is critical for efficient targeting. In COS cells expressing high levels of GFP-p230-C98aa fusion protein, endogenous p230 was no longer associated with Golgi membranes, suggesting that the GFP fusion protein and endogenous p230 may compete for the same membrane target structures. The Golgi binding of GFP-p230-C98aa is brefeldin A-sensitive and is regulated by G proteins. These studies have identified a minimal sequence responsible for specific targeting of p230 to the Golgi apparatus, which displays similar membrane binding characteristics to wild-type p230.

A novel Golgi-localisation domain shared by a class of coiled-coil peripheral membrane proteins.

The mechanism by which peripheral membrane proteins are targeted to the cytoplasmic face of the Golgi apparatus is poorly understood. Previously, we have identified a carboxy-terminal domain of the trans-Golgi-network (TGN) protein p230 that is responsible for Golgi localisation [1]. Here, we report the identification of a similar Golgi-localisation domain (GLD, also termed the 'GRIP' domain - see the paper by Munro and Nichols elsewhere in this issue) in a family of putative peripheral membrane proteins from lower and higher eucaryotes. The majority of family members have a domain structure similar to that of p230, with extensive coiled-coil regions (>80%) and the potential GLD located in a non-coiled-coil domain at the carboxyl terminus. Previously reported proteins in this family include human golgin-97 and Saccharomyces cerevisiae Imh1p. By constructing chimeric cDNAs encoding carboxy-terminal regions of these family members fused to green fluorescent protein (GFP), we have directly demonstrated that the GLD of p230, golgin-97, the newly identified human protein GCC1p and yeast Imh1p functions as a Golgi-targeting domain in transfected mammalian cells. Site-directed mutagenesis of the GLDs identified two conserved aromatic residues that are critical for the function of this targeting domain. Endogenous p230 was displaced from the Golgi membranes in transfected cells expressing high levels of GFP fused to the GLD of either p230 or golgin-97, indicating that different GLDs interact with similar membrane determinants. Thus, we have identified a family of coiled-coil proteins that share a domain shown to be sufficient for the localisation of peripheral membrane proteins to the Golgi apparatus.

Familial medulloblastoma.

Medulloblastomas account for 20% of all primary brain tumors. The vast majority of them are sporadic. Familial medulloblastoma is very rare--only a few cases have been reported worldwide. Most were observed in siblings of the same sex. The affected children presented at various ages and all of them have died, usually within the first 2 years following diagnosis. The authors describe a case of familial medulloblastoma with unusual characteristics: Two siblings of different sex and a second-degree relative have presented at exactly the same age of 18 months. The histologic pattern was the same in all patients, that of desmoplastic medulloblastoma. All patients are alive and remain in remission 12, 5, and 11 years, respectively, after diagnosis. The genetics and the pathogenesis of the disease remain obscure.

Substratum adhesion and gliding in a diatom are mediated by extracellular proteoglycans.

Diatoms are unicellular microalgae encased in a siliceous cell wall, or frustule. Pennate diatoms, which possess bilateral symmetry, attach to the substratum at a slit in the frustule called the raphe. These diatoms not only adhere, but glide across surfaces whilst maintaining their attachment, secreting a sticky mucilage that forms a trail behind the gliding cells. We have raised monoclonal antibodies to the major cell surface proteoglycans of the marine raphid diatom Stauroneis decipiens Hustedt. The antibody StF.H4 binds to the cell surface, in the raphe and to adhesive trails and inhibits the ability of living diatoms to adhere to the substratum and to glide. Moreover, StF.H4 binds to a periodate-insensitive epitope on four frustule-associated proteoglycans (relative molecular masses 87, 112, and > 200 kDa). Another monoclonal antibody, StF.D5, binds to a carbohydrate epitope on the same set of proteoglycans, although the antibody binds only to the outer surface of the frustule and does not inhibit cell motility and adhesion.