Genetics of preeclampsia: paradigm shifts

Segregation of preeclampsia into early-onset, placental and late-onset, maternal subtypes along with the acknowledgement of the contribution of epigenetics in placentally expressed genes proved to be a key first step in the identification of essential gene variants associated with preeclampsia. Application of this insight to other populations and related pregnancy-induced syndromes, such as HELLP, and acknowledgment of the features shared between chromosomal loci associated with preeclampsia in different populations provide the rationale for new strategies for the identification of susceptibility genes and for new and more effective diagnostic strategies. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Neuromodulation for the treatment of refractory interstitial cystitis

Interstitial cystitis (IC) is a symptom complex of urinary urgency, frequency and pelvic pain. Multimodality behavioral and phamacologic treatment is often effective in treating IC. Unfortunately, some patients with IC are refractory to standard treatments. Neuromodulation has been shown to be effective in treating voiding dysfunction. Small studies have demonstrated improvement in pelvic pain and IC symptoms during temporary sacral nerve stimulation. This current study demonstrates that patients refractory to traditional therapies for IC can respond well to sacral nerve stimulation and maintain improvement in symptoms after permanent implantation of a neurogenerator. The technique used to place the neurostimulator can impact on the degree of the response and the complication rate. Sacral neurostimulation continues to evolve and should be in the armamentarium available to treat voiding dysfunction.     

A型肉毒素在间质性膀胱炎治疗中的研究进展

间质性膀胱炎（interstitial cystitis,IC）好发生于30-70岁女性,平均43岁,美国妇女的发病率为197／10万,而男性发病率为41／10万。国内尚无明确的流行病学统计资料。间质性膀胱炎严重影响着患者的生活质量,其发病率高,但发病原因和发病机理至今仍未明确。近年来,随着国内外学者对肉毒素进行深入和广泛的研究,提出了A型肉毒素在间质性膀胱炎的新疗法。本文就A型肉毒素在问质性膀胱炎治疗中的研究进展进行综述,临床医师实际工作中参考应用。     

A型肉毒素在间质性膀胱炎治疗中的研究进展

间质性膀胱炎(interstitial cystitis,IC)好发生于30～70岁女性,平均43岁,美国妇女的发病率为197/10万,而男性发病率为41/10万。国内尚无明确的流行病学统计资料。间质性膀胱炎严重影响着患者的生活质量,其发病率高,但发病原因和发病机理至今仍未明确。近年来,随着国内外学者对肉毒素进行深入和广泛的研究,提出了A型肉毒素在间质性膀胱炎的新疗法。本文就A型肉毒素在间质性膀胱炎治疗中的研究进展进行综述,临床医师实际工作中参考应用。     

Interstitial cystitis: characterization and management of an enigmatic urologic syndrome

The enigmatic urologic condition known as interstitial cystitis has an estimated prevalence of 0.01% to 0.50% of the female population. Its etiology is unknown but may involve microbiologic, immunologic, mucosal, neurogenic, and/or other, as yet undefined, agents. There is no gold standard for the diagnosis of interstitial cystitis; rather, it is a diagnosis of exclusion. It is impossible to provide a purely evidence-based treatment strategy, but review of available evidence suggests that conservative supportive therapy (including diet modification); oral treatment with pentosan polysulfate, amitriptyline, hydroxyzine, or cimetidine; and intravesical treatments with heparinoids, dimethyl sulfoxide, alkalized lidocaine, or bacille Calmette-Guérin may be effective in some patients.     

Continuity and change: paradigm shifts in neural induction

The problem of "primary embryonic induction" was one of the first areas of developmental biology to become "molecularized." What had been seen as an intractable series of problems became amenable to the techniques of Northern blotting, ectopic RNA insertion, and in situ hybridization. These molecular analyses showed that some of the fundamental concepts of primary embryonic induction concluded by experimental embryologists were false. First, primary embryonic induction was not primary. The organizer tissue, itself, was the product of a prior induction. Second, the neural fate of cells was not being induced. Rather, the epidermal fate was induced and the neural state was the default, uninduced, fate of ectodermal tissues. Third, primary embryonic induction was not something unique to vertebrates. Rather, the ventral neural cord of insects formed using the same mechanisms as the dorsal neural tube of vertebrates. Fourth, the brain formed in a matter distinctly different from that the spinal cord. Despite these differences, there has been a clear and strong continuity between the experimental embryological tradition and the molecular genetic tradition, and these new results are seen by many contemporary developmental geneticists as strengthening, rather than destroying, the older science.     

Genetics of Parkinson disease: paradigm shifts and future prospects

Parkinson disease is a complex, multifactorial neurodegenerative disease. Although a heritable basis was originally thought unlikely, recent studies have implicated several genes in its pathogenesis, and molecular findings now allow accurate diagnosis and challenge past criteria for defining Parkinson disease. Most importantly, genetic insights provide the rationale for new strategies for prevention or therapy, and have led to animal models of disease in which these strategies can be tested. Neuroprotective therapies can now be designed to slow or halt disease progression in affected subjects and asymptomatic carriers.     

Regime, phase and paradigm shifts: making community ecology the basic science for fisheries

Modern fishery science, which began in 1957 with Beverton and Holt, is ca. 50 years old. At its inception, fishery science was limited by a nineteenth century mechanistic worldview and by computational technology; thus, the relatively simple equations of population ecology became the fundamental ecological science underlying fisheries. The time has come for this to change and for community ecology to become the fundamental ecological science underlying fisheries. This point will be illustrated with two examples. First, when viewed from a community perspective, excess production must be considered in the context of biomass left for predators. We argue that this is a better measure of the effects of fisheries than spawning biomass per recruit. Second, we shall analyse a simple, but still multi-species, model for fishery management that considers the alternatives of harvest regulations, inshore marine protected areas and offshore marine protected areas. Population or community perspectives lead to very different predictions about the efficacy of reserves.     

Psychiatric diagnosis and treatment in the 21st century: paradigm shifts versus incremental integration

Psychiatry has always been characterized by a range of different models of and approaches to mental disorder, which have sometimes brought progress in clinical practice, but have often also been accompanied by critique from within and without the field. Psychiatric nosology has been a particular focus of debate in recent decades; successive editions of the DSM and ICD have strongly influenced both psychiatric practice and research, but have also led to assertions that psychiatry is in crisis, and to advocacy for entirely new paradigms for diagnosis and assessment. When thinking about etiology, many researchers currently refer to a biopsychosocial model, but this approach has received significant critique, being considered by some observers overly eclectic and vague. Despite the development of a range of evidence‐based pharmacotherapies and psychotherapies, current evidence points to both a treatment gap and a research‐practice gap in mental health. In this paper, after considering current clinical practice, we discuss some proposed novel perspectives that have recently achieved particular prominence and may significantly impact psychiatric practice and research in the future: clinical neuroscience and personalized pharmacotherapy; novel statistical approaches to psychiatric nosology, assessment and research; deinstitutionalization and community mental health care; the scale‐up of evidence‐based psychotherapy; digital phenotyping and digital therapies; and global mental health and task‐sharing approaches. We consider the extent to which proposed transitions from current practices to novel approaches reflect hype or hope. Our review indicates that each of the novel perspectives contributes important insights that allow hope for the future, but also that each provides only a partial view, and that any promise of a paradigm shift for the field is not well grounded. We conclude that there have been crucial advances in psychiatric diagnosis and treatment in recent decades; that, despite this important progress, there is considerable need for further improvements in assessment and intervention; and that such improvements will likely not be achieved by any specific paradigm shifts in psychiatric practice and research, but rather by incremental progress and iterative integration.     

An easy method to record slow potential shifts (SPS) in rabbits using the oddball paradigm

Rabbits with chronically implanted Ag-AgCl electrodes over somatosensory and visual cortex were trained to a modified 'oddball' paradigm with visual stimulation. Event related potentials (ERP) and slow potential shifts (SPS) were recorded. By means of a computer controlled stimulator 'frequent' and 'rare' LED flashes were administered to the eyes of the rabbit. If 'rare' stimuli were reinforced by a weak electrical footshock, negative SPS rose steeper and reached significantly higher amplitudes than in 'frequent' conditions without reinforcement. Different kinds of the follow-up of 'frequent' and 'rare' series were tested. Best effects were obtained, if a session was divided into 3 blocks (3 srs. 'frequent'--5 srs. 'rare' reinforced--2 srs. 'frequent' and probability of 'rare' flashes was 20%. Our present data formed a basis for investigations on the neuronal and glial sources of SPS in rabbits.     

CKAP4/p63 is a receptor for the frizzled-8 protein-related antiproliferative factor from interstitial cystitis patients

Antiproliferative factor (APF) is a low molecular weight sialoglycopeptide that is secreted by bladder cells from interstitial cystitis patients and is a potent inhibitor of both normal bladder epithelial and bladder carcinoma cell proliferation. We hypothesized that APF may produce its antiproliferative effects by binding to a transmembrane receptor. This study demonstrates that cytoskeleton-associated protein 4/p63 (CKAP4/p63), a type II transmembrane receptor, binds with high affinity to APF. The antiproliferative activity of APF is effectively inhibited by preincubation with anti-CKAP4/p63-specific antibodies, as well as by short interfering RNA knockdown of CKAP4/p63. Immunofluorescent confocal microscopy showed co-localization of anti-CKAP4/p63 and rhodamine-labeled synthetic APF binding in both cell membrane and perinuclear areas. APF also inhibits the proliferation of HeLa cervical carcinoma cells that are known to express CKAP4/p63. These data indicate that CKAP4/p63 is an important epithelial cell receptor for APF.     

Severe dengue: questioning the paradigm

Severe dengue has been recognised for more than 200 years, but attempts to define, categorize and explain the condition have hotly contested for more than four decades. Resolution of this controversy may provide new insights for the management of patients.     

DSB repair: the yeast paradigm

Genome stability is of primary importance for the survival and proper functioning of all organisms. Double-strand breaks (DSBs) arise spontaneously during growth, or can be created by external insults. In response to even a single DSB, organisms must trigger a series of events to promote repair of the DNA damage in order to survive and restore chromosomal integrity. In doing so, cells must regulate a fine balance between potentially competing DSB repair pathways. These are generally classified as either homologous recombination (HR) or non-homologous end joining (NHEJ). The yeast Saccharomyces cerevisiae is an ideal model organism for studying these repair processes. Indeed, much of what we know today on the mechanisms of repair in eukaryotes come from studies carried out in budding yeast. Many of the proteins involved in the various repair pathways have been isolated and the details of their mode of action are currently being unraveled at the molecular level. In this review, we focus on exciting new work eminating from yeast research that provides fresh insights into the DSB repair process. This recent work supplements and complements the wealth of classical genetic research that has been performed in yeast systems over the years. Given the conservation of the repair mechanisms and genes throughout evolution, these studies have profound implications for other eukaryotic organisms.     

Arthropod segmentation: beyond the Drosophila paradigm

Most of our knowledge about the mechanisms of segmentation in arthropods comes from work on Drosophila melanogaster. In recent years it has become clear that this mechanism is far from universal, and different arthropod groups have distinct modes of segmentation that operate through divergent genetic mechanisms. We review recent data from a range of arthropods, identifying which features of the D. melanogaster segmentation cascade are present in the different groups, and discuss the evolutionary implications of their conserved and divergent aspects. A model is emerging, although slowly, for the way that arthropod segmentation mechanisms have evolved.     

Interstitial cells associated with the deep muscular plexus of the guinea-pig small intestine,with special reference to the interstitial cells of Cajal

Summary Interstitial cells associated with the deep muscular plexus of the guinea-pig small intestine were studied by electron microscopy, and three-dimensional cell models were reconstructed from serial ultrathin sections with a computer graphic system. Three types of cells were recognized. The first type was similar in shape to smooth muscle cells, but did not contain an organized contractile apparatus. Many large gap junctions comprising about 4% of the cell surface were present; they connected cells of the first type to each other, to the second type of cell and to smooth muscle cells of the outer circular layer. The second type of cell had a welldemarcated cell body with long slender processes and was characterized by a large amount of glycogen comprising about 9% of the cell volume. The third type of cell was similar to fibroblasts, and contained well-developed Golgi apparatus and rough endoplasmic retiulum. Some of these fibroblast-like cells (a possible subtype) formed small gap junctions. All three types of cells showed close relationships with nerve varicosities. This cellular network consisting of gap-junction-rich cells, glycogen-rich cells and smooth muscle cells may be involved in the pacemaking activity of intestinal movement.     

Flipping the paradigm on malaria transmission-blocking vaccines

The idea of malaria transmission-blocking vaccines (TBVs) surfaced more than two decades ago. Since then, the research paradigm focused on developing TBVs that target surface antigens of parasite sexual stages. Only recently has an effort emerged that flipped this paradigm, targeting antigens of the parasite's obligate invertebrate vector, the Anopheles mosquito. Here, we review the current state of knowledge of mosquito-based TBVs and discuss the utility of this approach for future vaccine development.