Development and effectiveness of struma prevention in East Germany

For the control of iodine deficiency disorders in man and animal since 1985/1986 measures have been introduced which were interdisciplinary attuned: 84% of the paketed salt are iodized (32 mg KIO3/kg) and iodized mixtures of mineral substances are used in the animal production of agricultural useful animals. The effectiveness of the iodine prevention becomes visible by an increase of the renal iodine excretion, regression of the frequency of connatal goitre and iodine deficiency disorders in the animal production. Increased manifestations of cases of hyperthyroidism as sequelae are of transient importance.     

The genome sequence of Clostridium tetani,the causative agent of tetanus disease

Tetanus disease is one of the most dramatic and globally prevalent diseases of humans and vertebrate animals, and has been reported for over 24 centuries. The manifestation of the disease, spastic paralysis, is caused by the second most poisonous substance known, the tetanus toxin, with a human lethal dose of approximately 1 ng/kg. Fortunately, this disease is successfully controlled through immunization with tetanus toxoid; nevertheless, according to the World Health Organization, an estimated 400,000 cases still occur each year, mainly of neonatal tetanus. The causative agent of tetanus disease is Clostridium tetani, an anaerobic spore-forming bacterium, whose natural habitat is soil, dust, and intestinal tracts of various animals. Here we report the complete genome sequence of toxigenic C. tetani E88, a variant of strain Massachusetts. The genome consists of a 2,799,250-bp chromosome encoding 2,372 ORFs. The tetanus toxin and a collagenase are encoded on a 74,082-bp plasmid, containing 61 ORFs. Additional virulence-related factors could be identified, such as an array of surface-layer and adhesion proteins (35 ORFs), some of them unique to C. tetani. Comparative genomics with the genomes of Clostridium perfringens, the causative agent of gas gangrene, and Clostridium acetobutylicum, a nonpathogenic solvent producer, revealed a remarkable capacity of C. tetani: The organism can rely on an extensive sodium ion bioenergetics. Additional candidate genes involved in the establishment and maintenance of a pathogenic lifestyle of C. tetani are presented.     

Role of trace elements in the dynamics of arteriosclerosis

According to the present state of knowledge 7 quantitative elements and possibly 18 trace elements are of vital importance for the animal. Their metabolism is antagonistically or synergistically influenced by the inorganic and organic constituents of the food of different kind. More than 30 elements (Cu, Zn, Mg, Mn, Cr, V and so on) shall be connected with the process of arteriosclerosis. Cu-deficiency as well as Cu-abundance may increase the cholesterol content of the blood serum. Under conditions of Cu-deficiency the formation of the crosslinks of the elastin of the blood vessels is disturbed. Under conditions of Zn-deficiency the serum cholesterol content is as a rule, but not exceptionally decreased in the animal. Similarly unclear is the influence of high administrations of Zn on the process of arteriosclerosis. An Mg-deficit may lead to a whole chain of changes (disturbances of the cardiac rhythm, necrotic changes, atheromatous plaques, high values of total cholesterol, low values of HDL-cholesterol). Via the glucose tolerance factor a Cr-deficit possibly takes influence on the arteriosclerotic process. Hardness of the water, Mn, Pb, Ni, Mn shall also become effective. The Cu-Zn-relation as factor evoking arteriosclerosis further needs analysis. The investigations concerning arteriosclerosis in the animal experiment should in future be performed by means of semisynthetic rations, in order to render the results of the experiments comparable and to be able to control the large number of evoking factors.     

Interim thymus and activation regulated chemokine versus interim 18F-fluorodeoxyglucose positron-emission tomography in classical Hodgkin lymphoma response evaluation

Serum thymus and activation regulated chemokine (TARC) levels reflect classical Hodgkin lymphoma (cHL) disease activity and correspond with treatment response. We compared mid-treatment interim TARC (iTARC) with interim ¹⁸F-fluorodeoxyglucose positron-emission tomography (iPET) imaging to predict modified progression-free survival (mPFS) in a group of 95 patients with cHL. High iTARC levels were found in nine and positive iPET in 17 patients. The positive predictive value (PPV) of iTARC for a 5-year mPFS event was 88% compared to 47% for iPET. The negative predictive value was comparable at 86% for iTARC and 85% for iPET. Serum iTARC levels more accurately reflect treatment response with a higher PPV compared to iPET.     

Utilization of Health Care Services and Satisfaction with Care in Adults Affected by Disorders of Sex Development (DSD)

BACKGROUND

Disorders of sex development (DSD) are a heterogeneous group of rare genetic disorders of sex determination or differentiation. Evidence-based guidelines concerning gender assignment and surgical and hormonal treatment are limited for many DSD entities, and health care is highly fragmented across various sub-specialties and settings. A lack of informed consent, secrecy about the condition, shame, and impaired sexual and psychosocial functioning may affect satisfaction with care.

OBJECTIVES

The main goal of this study was to describe satisfaction with care in individuals with DSD and to identify factors associated with low satisfaction with care.

METHODS / MAIN MEASURES

Using both biological (chromosomes) and social categories (sex of rearing), we classified participants according to the nomenclature of the European Society for Pediatric Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES) consensus statement. We used standardized measures to assess satisfaction with care (CSQ-8), health-related quality of life (SF-36), psychological symptoms (BSI), and gender identity (FGI), in addition to self-constructed questionnaires probing experiences with health care and access to self-help groups.

PARTICIPANTS

A total of 110 adults were recruited between January 2005 and December 2007 in four study centers in Germany, Austria, and German-speaking Switzerland.

RESULTS

Reports of half the participants scored below the cut-off indicating low quality of care. Women with XX DSD conditions and virilization (i.e., congenital adrenal hyperplasia) reported the highest scores for satisfaction with care, and women with XY DSD conditions and complete lack of androgen effects reported the lowest scores. Satisfaction with care was positively associated with indicators of psychological well-being.

CONCLUSIONS

Satisfaction with care is lowest among participants with the rarest conditions, highlighting the lack of evidence-based recommendations and the lack of coordination of care. Associations of satisfaction and well-being indicate the need to ensure access to mental health services.

     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Natural history-driven,plant-mediated RNAi-based study reveals CYP6B46’s role in a nicotine-mediated antipredator herbivore defense

Manduca sexta (Ms) larvae are known to efficiently excrete ingested nicotine when feeding on their nicotine-producing native hostplant, Nicotiana attenuata. Here we describe how ingested nicotine is co-opted for larval defense by a unique mechanism. Plant-mediated RNAi was used to silence a midgut-expressed, nicotine-induced cytochrome P450 6B46 (CYP6B46) in larvae consuming transgenic N. attenuata plants producing MsCYP6B46 dsRNA. These and transgenic nicotine-deficient plants were planted into native habitats to study the phenotypes of larvae feeding on these plants and the behavior of their predators. The attack-behavior of a native wolf spider (Camptocosa parallela), a major nocturnal predator, provided the key to understanding MsCYP6B46’s function: spiders clearly preferred CYP6B46-silenced larvae, just as they had preferred larvae fed nicotine-deficient plants. MsCYP6B46 redirects a small amount (0.65%) of ingested nicotine from the midgut into hemolymph, from which nicotine is exhaled through the spiracles as an antispider signal. CYP6B46-silenced larvae were more susceptible to spider-attack because they exhaled less nicotine because of lower hemolymph nicotine concentrations. CYP6B46-silenced larvae were impaired in distributing ingested nicotine from midgut to hemolymph, but not in the clearing of hemolymph nicotine or in the exhalation of nicotine from hemolymph. MsCYP6B46 could be a component of a previously hypothesized pump that converts nicotine to a short-lived, transportable, metabolite. Other predators, big-eyed bugs, and antlion larvae were insensitive to this defense. Thus, chemical defenses, too toxic to sequester, can be repurposed for defensive functions through respiration as a form of defensive halitosis, and predators can assist the functional elucidation of herbivore genes.Plants produce a pharmacopeia of potent chemical defenses that prevent the attack of unadapted herbivores and thwart the growth of adapted ones. Frequently, lepidopteran herbivores co-opt these diet-acquired toxins for their own defensive purposes. The eastern tent caterpillar (Malacosoma americanum) regurgitates hydrogen cyanide and benzaldehyde ingested from their cyanogenic hostplants when attacked by ants (1). The Atala butterfly (Eumaeus atala) acquires a toxic azoxyglycoside from its cycad hosts and becomes unpalatable to bird and ant predators (2). Similarly, rattlebox moths (Utetheisa ornatrix) co-opt pyrrolizidine alkaloids that their larvae sequester while feeding on rattlebox legume hostplants (Crotalaria spp.) to deter predatory spiders (3). Prey frequently advertise their toxic status with warning colorations, odors, and behaviors, and predators readily learn these aposematic signals to avoid consuming toxic prey (4). The molecular mechanisms of how herbivores co-opt plant defenses for their own defense remain largely unexplored.The pyridine alkaloid nicotine is a defense metabolite of several Nicotiana spp. Nicotine is extremely effective against herbivores because of its ability to poison the essential neuromuscular junction common to all animals that use muscles to move: the acetylcholine receptor (5, 6). Nicotiana spp. hostplants respond to the herbivore attack with large increases in nicotine accumulation (7). However, the tobacco hornworm (Manduca sexta, Ms), a specialist lepidopteran herbivore that feeds on nicotine-producing Nicotiana plants, tolerates doses of nicotine that are lethal for unadapted herbivores (8). More endoparasitoid wasps (Cotesia congregata) emerged as adults from parasitized M. sexta larvae fed on low nicotine varieties of cultivated tobacco than from larvae fed on nicotine-rich varieties (9). The generalist predatory argentine ant (Iridomyrmex humilis) also preferred M. sexta larvae reared on artificial diets (AD) without nicotine over those reared on high nicotine diets, and were deterred by topical nicotine treatments (10). These results suggest that M. sexta larvae might be able to use this diet-derived toxin for their own protection. How this happens remains a mystery, as the larvae’s resistance of ingested nicotine does not appear to include sequestration and storage of this toxin.The exact mechanisms responsible for M. sexta’s nicotine resistance remain unclear, but both efficient excretion and metabolism appear to be involved. Some researchers have focused on the polar metabolites of nicotine, such as cotinine and the N-oxides of both nicotine and cotinine, which are commonly found in the urine and blood of human smokers (8, 11, 12); cytochrome P450s (CYPs) are thought to mediate nicotine’s oxidation to these metabolites (8, 11, 13–15), but other researchers have been unable to find the oxides in M. sexta’s excretions and propose that nicotine is rapidly excreted without modification (16–18). Although this theory is widely accepted, most studies have not been able to recover all of the ingested nicotine in the frass and nicotine can be found in the hemolymph of larvae feeding on nicotine-containing diets. Hence, within these physiological limits of M. sexta’s excretory-based tolerance lie opportunities for the defensive use of nicotine. Whether nicotine-resistance and co-option are regulated by a common mechanism remains unknown.Here we examine how M. sexta larvae co-opt diet-ingested nicotine for their own defense. In a previous unbiased microarray study, we found that a midgut-expressed cytochrome P450 (CYP6B46) was strongly down-regulated in larvae that were fed genetically modified hostplants with suppressed nicotine production (19, 20). To evaluate if this CYP6B46 is involved in nicotine resistance and co-option, we used a reverse genetics approach, plant-mediated RNA interference (PMRi) (20, 21), to silence this gene in larvae feeding on nicotine-containing, native coyote tobacco (Nicotiana attenuata) hostplants transformed to harbor the silencing construct. Lepidopteran herbivores appear to lack the RNA-dependent RNA polymerase required to sustain gene silencing by RNAi; however, a continuous supply of double-stranded (ds)RNA administered via the hostplant (or diet) effectively silences genes in these herbivores (21, 22).N. attenuata plants were transformed with an expression vector containing a 300-bp fragment of CYP6B46 in an inverted repeat (ir) orientation. Continuous dsRNA ingestion efficiently silenced CYP6B46 in the midguts of larvae feeding on these plants in a highly target-sequence–specific manner, as the most similar CYP expressed in larval midguts, CYP6B45, was not cosilenced (20). These PMRi plants were planted into the native habitat of both hostplant and larvae, the Great Basin Desert, Utah, which teems with larval predators—such as bugs, mantids, ants, antlions, spiders, and lizards—but lacks the Argentine ants and C. congregata endoparasitoids previously reported to be nicotine-sensitive. One of these predators, a wolf spider [Camptocosa parallela (Lycosidae)], selectively attacked CYP6B46-silenced larvae just as it did larvae feeding on nicotine-free hostplants. The particular predatory behavior of these spiders revealed the function of MsCYP6B46 in externalizing ingested nicotine for defensive use. The combination of natural history studies and the plant- and herbivore-reverse genetic procedures can fruitfully dissect the molecular mechanisms governing the tritrophic interactions.