Trade-offs direct the evolution of coloration in Galápagos land snails.

Increasingly, multiple selective factors are recognized as jointly contributing to the evolution of morphology. What is not clear is how these forces vary across communities to promote morphological diversification among related species. In this study of Galápagos endemic snails (genus Naesiotus), we test several hypotheses of colour evolution. We observe mockingbirds (genus Mimus) predating live snails and find that avian predation selects against conspicuous shells. The evolutionary outcome of this selection is a diversity of shell colours across snails of the archipelago, each closely matching local backgrounds. We also find that snails more regularly exposed to the hot, equatorial sun reflect more light than shells of species from shadier habitats, suggesting a role for thermoregulatory constraints directing colour evolution. The signature of thermoregulatory selection is most clear in comparatively young communities (on the youngest islands), while the signature of selection from predators is most evident in older communities (on the older islands). Together, our findings point to a scenario of shifting selective forces along island ontogeny and community maturity that lead to the distribution of snail coloration we observe in Galápagos. Complex selective regimes such as these may have more responsibility for morphological diversity than is currently recognized.

Roux-en-Y Gastric Bypass Reversal for Severe Malnutrition and Cirrhosis.

BACKGROUND: Severe post-operative malnutrition (SM) is a dreaded complication after gastric bypass often related to the short bowel syndrome consecutive limb length mismeasurement or intestinal resections. Patients with rapid weight loss or malnutrition can experience liver failure with cirrhosis and require liver transplantation (LT). Malnutrition can constitute a contraindication to LT since it negatively impacts on postoperative morbidity. RYGB reversal is an effective option to consider when nutritional support has failed. We describe the performance of a RYGB reversal in a pre-LT setting. MATERIAL AND METHODS: A 36-year-old patient with morbid obesity (weight, 140 kg; BMI, 50.1 kg/m2) underwent a RYGB 9 years ago. She presented with 85 kg weight loss (i.e., 60.7% total body weight loss) associated with SM and hepatocellular insufficiency. LT was considered but contraindicated because of SM. An intensive nutritional support was attempted but failed and the RYGB reversal was recommended. RESULTS: Laparoscopic exploration revealed ascites, cirrhosis, and splenomegaly. The whole small bowel measurement revealed a short gut. Alimentary, biliary, and common channel limb lengths were 250 cm, 150 cm, and 30 cm long. The alimentary limb was stapled off the gastric pouch and the gastrojejunostomy was resected. After resection of the gastrojejunostomy, linear stappled gastro-gastrostomy and jéjuno-jejunostomy were performed to restore the normal anatomy. At 1 year, malnutrition was resolved and the cirrhosis was stabilized. CONCLUSION: Reversal to normal anatomy appeared effective and safe in this setting but must be considered only after failure of intensive medical management. Careful bowel measurement is mandatory to prevent patients from this complication.

Batesian mimics influence the evolution of conspicuousness in an aposematic salamander.

Conspicuousness, or having high contrast relative to the surrounding background, is a common feature of unpalatable species. Several hypotheses have been proposed to explain the occurrence of conspicuousness, and while most involve the role of conspicuousness as a direct signal of unpalatability to potential predators, one hypothesis suggests that exaggerated conspicuousness may evolve in unpalatable species to reduce predator confusion with palatable species (potential Batesian mimics). This hypothesis of antagonistic coevolution between palatable and unpalatable species hinges on the 'cost of conspicuousness', in which conspicuousness increases the likelihood of predation more in palatable species than in unpalatable species. Under this mimicry scenario, four patterns are expected: (i) mimics will more closely resemble local models than models from other localities, (ii) there will be a positive relationship between mimic and model conspicuousness, (iii) models will be more conspicuous in the presence of mimics, and (iv) when models and mimics differ in conspicuousness, mimics will be less conspicuous than models. We tested these predictions in the salamander mimicry system involving Notophthalmus viridescens (model) and one colour morph of Plethodon cinereus (mimic). All predictions were supported, indicating that selection for Batesian mimicry not only influences the evolution of mimics, but also the evolution of the models they resemble. These findings indicate that mimicry plays a large role in the evolution of model warning signals, particularly influencing the evolution of conspicuousness.

The disease burden of hepatitis B, influenza, measles and salmonellosis in Germany: first results of the burden of communicable diseases in Europe study.

Setting priorities in the field of infectious diseases requires evidence-based and robust baseline estimates of disease burden. Therefore, the European Centre for Disease Prevention and Control initiated the Burden of Communicable Diseases in Europe (BCoDE) project. The project uses an incidence- and pathogen-based approach to measure the impact of both acute illness and sequelae of infectious diseases expressed in disability-adjusted life years (DALYs). This study presents first estimates of disease burden for four pathogens in Germany. The number of reported incident cases adjusted for underestimation served as model input. For the study period 2005-2007, the average disease burden was estimated at 33 116 DALYs/year for influenza virus, 19 115 DALYs/year for Salmonella spp., 8708 DALYs/year for hepatitis B virus and 740 DALYs/year for measles virus. This methodology highlights the importance of sequelae, particularly for hepatitis B and salmonellosis, because if omitted, the burden would have been underestimated by 98% and 56%, respectively.

Esophagojejunostomy after total gastrectomy for caustic injuries.

The objective of the study was to compare outcomes of emergency esophagogastrectomy (EGT) and total gastrectomy with immediate esophagojejunostomy (EJ) in patients with full-thickness caustic necrosis of the stomach and mild esophageal injuries. After caustic ingestion, optimal management of the esophageal remnant following removal of the necrotic stomach remains a matter of debate. Between 1987 and 2012, 26 patients (men 38%, median age 44 years) with isolated transmural gastric necrosis underwent EGT (n = 14) or EJ (n = 12). Early and long-term outcomes of both groups were compared. The groups were similar regarding age (P = 0.66), gender (0.24), and severity of esophageal involvement. Functional success was defined as nutritional autonomy after removal of the jejunostomy and tracheotomy tubes. Emergency morbidity (67% vs. 64%, P = 0.80), mortality (17% vs. 7%, P = 0.58), and reoperation rates (25% vs.14%, P = 0.63) were similar after EJ and EGT. One patient (8%) experienced EJ leakage. One patient in the EJ group and 13 patients in the EGT group underwent esophageal reconstruction (P < 0.0001). Aggregate in hospital length of stay was significantly longer in patients who underwent EGT (median 83 [33-201] vs. 36 [10-82] days, P = 0.001). Functional success after EJ and EGT was similar (90% vs.69%, P = 0.34). Immediate EJ can be safely performed after total gastrectomy for caustic injuries and reduces the need of further esophageal reconstruction.

Clinical signs, therapy and zoonotic risk of pet guinea pigs with dermatophytosis.

Systematic studies about pet guinea pigs with dermatophytosis are rare. The aim of this study was to evaluate clinical signs, therapy and zoonotic risk of pet guinea pigs with dermatophytosis. Questionnaires from both owners (n = 74) of pet guinea pigs with dermatophytosis and their veterinarians (n = 101) were analysed regarding clinical signs, therapy and data pertinent to zoonotic potential. Trichophyton (T.) mentagrophytes was found in 97% of cases. In the weeks preceding the onset of the clinical signs, a new guinea pig joined the household in 43% of cases. One third of the affected guinea pigs had lived in the household for less than 3 months. Predominant clinical signs were alopecia (83%), scaling (73%) and crusting (70%). The most commonly affected body site was the head (75%). In approximately one quarter of the cases humans showed clinical signs of dermatophytosis, in half the households, only children were affected. Skin lesions were seen most often on the face, the neck and the arms. Pet guinea pigs carrying dermatophytes must be considered a serious zoonotic risk for their owners, especially for children. A major risk factor for dermatophytosis seems to be a recent acquisition of a new guinea pig.

Dermatophytes in pet Guinea pigs and rabbits.

PROBLEM ADDRESSED: The frequency of dermatophytes in pet Guinea pigs and rabbits. OBJECTIVES: To determine the frequency and types of dermatophytes in pet Guinea pigs and rabbits. METHODS AND APPROACH: First, 2153 samples collected from pet Guinea pigs (n=1132) and rabbits (n=1021) with suspected dermatophytosis and submitted to three different laboratories for fungal culture were analysed. Subsequently, healthy Guinea pigs and rabbits, animals with skin lesions and with noncutaneous diseases were examined prospectively for dermatophytes. RESULTS: Trichophyton (T.) mentagrophytes was the most common fungal species isolated (91.6% and 72.3% of positive cultures from Guinea pigs (n=431) and rabbits (n=83), respectively). Animals with positive fungal culture did not show any gender predisposition, but affected animals were younger than those with negative fungal culture (P<0.0001) or than healthy animals of the prospective part of the study. Dermatophytes were isolated from 14/164 healthy Guinea pigs and 0/140 healthy rabbits. In addition, fungal cultures of Guinea pigs with skin lesions (n=26) and other diseases (n=25) were positive in 7.7% and 8.0% respectively. Samples collected from 17 rabbits with skin lesions and 32 rabbits with noncutaneous disease were all negative in culture. CONCLUSIONS: T. mentagrophytes is the most common dermatophyte in pet Guinea pigs and rabbits, asymptomatic carriers are regularly seen in Guinea pigs, but not in rabbits.

The WST survival assay: an easy and reliable method to screen radiation-sensitive individuals.

An easy, fast and reliable method was developed to screen hundreds of Epstein-Barr virus-transformed cell lines (lymphoblastoid cell lines, LCLs) for radiation sensitivity that were generated from lymphocytes isolated from young lung cancer patients. The WST-1 test explores the metabolic activity of the mitochondria as an indicator for the vital status of cells. Cell proliferation as well as indirect cell death can be quantified by this method on a large scale in microtiter plates. Cell survival was measured at 24- and 48-h post-irradiation with 10 Gy ((137)Cs source) by the WST-1 assay and Trypan blue staining. To set up the experimental screening conditions and to establish a positive and a negative control, an ATM-mutated cell line from a radiation-sensitive ATM patient and an ATM proficient cell line from a healthy brother were compared. An optimal differentiation between the two cell lines was demonstrated for 10 Gy and 24- and 48-h cell growth after irradiation. Upon screening 120 LCLs of young lung cancer patients under these conditions, 5 of them were found to be radiation sensitive to a high degree of statistical significance. The results have been confirmed by a second laboratory by means of Trypan blue testing. The WST-1 test represents an efficient and reliable method by means of screening for radiation-sensitive cell lines.

Factors associated with being underweight, overweight and obese among ever-married non-pregnant urban women in Bangladesh.

UNLABELLED: Extremes of body mass index (BMI), viz. underweight, overweight and obese categories, are associated with a variety of adverse health outcomes such as diabetes mellitus, cardiovascular diseases, low birth weight, poor quality of life and higher mortality. In Bangladesh, the prevalence of underweightness is very high with an increasing trend of overweightness and obesity. This is a serious public health concern as it indicates a dual burden of disease. The present study assessed the associations of being underweight, overweight and obese with socioeconomic, demographical and migration variables among ever-married non-pregnant urban Bangladeshi women aged 13-49 years. METHODS: The data was extracted from the Bangladesh Demographic and Health Survey 2004. Bivariable, factor and multinomial logistic regression analyses were performed in this study. RESULTS: The prevalence of being underweight, overweight and obese among ever-married non-pregnant urban women in Bangladesh was 25.2 percent, 15.7 percent and 3.9 percent, respectively. Age, education, region of residence, marital status, current use of contraception and type of occupation were significantly associated with BMI categories. Adjusted multinomial logistic regression analysis indicated that women with a high socioeconomic status were significantly negatively associated with being underweight (odds ratio [OR] 0.55, 95 percent confidence interval [CI] 0.48-0.63) but positively associated with being overweight (OR 1.70, 95 percent CI 1.48-1.96) and obese (OR 2.48, 95 percent CI 1.89-3.26), as compared to the women with normal BMI. In contrast, women who migrated from rural to urban areas showed a significantly positive association with being underweight (OR 1.15, 95 percent CI 1.04-1.27) but negative associations with being overweight (OR 0.80, 95 percent CI 0.71-0.89) and obese (OR 0.75, 95 percent CI 0.62-0.92), when compared with women who did not migrate. CONCLUSION: Suitable interventions based on further studies are needed to reduce the prevalence of being underweight and overweight among ever-married non-pregnant urban women in Bangladesh. Factors, viz. socioeconomic status, rural-urban migration and education, should be considered while developing interventional strategies to reduce the prevalence of extreme BMIs among women living in urban areas of Bangladesh.

Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins.

Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.

[Autoimmune pancreatitis mimicking an intra-ductal papillary mucinous neoplasm of the pancreas: an original case]. / Pancréatite auto-immune mimant une tumeur intracanalaire papillaire et mucineuse : une observation originale et trompeuse.

In recent years, autoimmune pancreatitis (AIP) has been increasingly recognized. It can be associated with diabetes mellitus and other systemic autoimmune diseases, or with bile ducts lesions, which are also responsive to steroid therapy as pancreatic lesions. We report the case of a 34-year-old man with a history of a first acute pancreatitis, attributed to an intraductal papillary-mucinous neoplasm of the pancreas (IPMN) with segmental involvement of the main pancreatic duct. A spleno-pancreatectomy was performed, and pathological examination of the specimen diagnosed autoimmune pancreatitis. A treatment with corticosteroids was carried out. To our knowledge, this is the first reported case of AIP mimicking IPMN of the main pancreatic duct.

Associations between obesity and developmental functioning in pre-school children: a population-based study.

OBJECTIVE: To examine associations between obesity and impairment in developmental functioning in a general population sample of pre-school children. METHOD: Standardized medical examinations were conducted in nine consecutive cohorts of male and female children (n=9415) aged between 4.4 and 8.6 years (mean=6.0, s.d.=0.37) residing in the Lower Bavaria region of Germany. Tests designed to assess performance in subdivisions representing four broad developmental domains, namely, motor development, speech development, cognitive development and psycho-social development, were completed by all participants. RESULTS: Boys had significantly higher rates of impairment than girls. The prevalence of obesity in boys was 2.4%, whereas in girls it was 4.3% (chi (2)=21.51, P< 0.01). After controlling for age, gender, year of recruitment and other potential covariates, the prevalence of impairment in gross motor skills was higher among obese male children than normal-weight male children (adjusted odds ratio=1.76, 95% confidence interval (CI)=1.02, 3.01, P< 0.05), whereas the prevalence of impairment in the ability to focus attention was higher in obese female children than normal-weight female children (adjusted odds ratio=1.86, 95% CI=1.00, 3.44, P< 0.05). CONCLUSIONS: The findings suggest that gender-specific associations between obesity and impairment in specific aspects of developmental functioning may be evident in younger children.

Clinical risk factors and prognostic significance of local recurrence in cutaneous melanoma.

BACKGROUND: True local recurrence (LR) means clinically detectable regrowth of parts of the tumour which were not completely excised. In the literature the term 'LR' has been used in a vague and inconsistent manner that may include satellite and in-transit metastasis. OBJECTIVE: The aim of this study was to establish clinical, histological and surgical risk factors for the manifestation of LR and to evaluate the prognostic significance of LR. STUDY DESIGN: Data from 3960 Stage I and II melanoma patients who visited the melanoma clinic of the Department of Dermatology at the University of Tuebingen from 1980 to 1999 were documented in a prospective manner. A retrospective comparative analysis of patients with and without LR was performed. RESULTS: Of all patients 1.4% had a LR as a first recurrence and 1.7% had a LR in the course of the follow-up period. LR were most frequent after previous clinical or histological misdiagnosis and inadequate therapy. In the univariate analysis significant risk factors for LR-free survival were age, tumour surface area, locality, tumour thickness, level of invasion, histological type, associated naevus, surgery (one step vs. multiple steps) and compliance with recommended excision margins. In the multivarate analysis the factors locality (P < 0.0001), tumour thickness (P = 0.0086) and compliance with recommendations on excision margins (P = 0.014) were significant independent risk factors for the manifestation of LR. The overall survival of patients with LR as first progression did not significantly differ from the overall survival of the other patients with melanoma (P = 0.60). CONCLUSION: True LR is a rare event for which tumour locality, tumour thickness and surgery are independent risk factors. The occurrence of LR might not impair the prognosis of melanoma patients. However, in the published literature numerous definitions of 'LR', including lymphogenic metastasis, complicate comparison.

Remarkable response to rituximab in a patient with atypical CD20(++) mantle cell lymphoma of the bone marrow leading to severe pancytopenia.

Rituximab, a chimeric monoclonal antibody which binds to the CD20 antigen, has been reported in several studies to induce remissions in low- and high-grade non-Hodgkin's lymphoma without causing myelosuppression. We report here a case of a 68-year-old female patient with an atypical mantle cell lymphoma infiltrating only the bone marrow without leukemic involvement or any other nodal or extranodal manifestations. Progressive severe pancytopenia due to the diffuse bone marrow infiltration led to life-threatening infections following oral chlorambucil treatment. No response to chlorambucil was noted. The patient attained a complete remission after salvage therapy with four weekly infusions of single-agent rituximab at a standard dose of 375 mg/m(2). Thus, anti-CD20 antibody may be the treatment of choice for patients with CD20(+) B-non-Hodgkin's lymphoma who cannot tolerate chemotherapy due to high risk of infectious complications as a result of severe pancytopenia.

Reliability of non-invasively acquired human genomic DNA as a substrate for real-time PCR-assisted analysis of genetic polymorphisms.

Molecular epidemiological studies require high numbers of participants. The combination of an non-invasive access to human DNA with a rapid genotyping analysis, e.g. by use of LightCycler assisted real-time polymerase chain reaction (PCR), can be helpful in conducting such trials. The aim of our study was to define, for the first time, the use of LightCycler technology in analysis of non-invasively derived DNA. DNA extracted from blood, mouthwash and buccal cytobrush samples from 100 volunteers was analyzed for the genotypes of cytochrome P450 CYP1B1, and glutathione S-transferases GSTT1, GSTM1 and GSTP1. The median amounts of DNA isolated from blood, mouthwash and buccal cytobrush samples were 95, 11 and 8 microg, respectively. While genotyping for CYP1B1 codon 432 polymorphism and GSTP1 codon 105 polymorphism resulted in a complete correspondence for all three modes of sampling, the identification of individuals with null-genotype for GSTT1 or GSTM1 failed in some cases due to atypical courses of the corresponding melting curves, leading to high false-positive rates in the group of non-invasively derived samples. Thus, the results presented here call for caution in using LightCycler assisted real-time PCR in non-invasively collected samples, at least when appropriate control strategies are not implemented.

Occurrence of sarcoidosis subsequent to chemotherapy for non-Hodgkin's lymphoma: report of two cases.

Sarcoidosis-lymphoma syndrome is a well-established syndrome where sarcoidosis is followed by the development of a lymphoproliferative disease such as non-Hodgkin's lymphoma (NHL). Here we report two patients with NHL who developed sarcoidosis subsequent to the diagnosis of lymphoproliferative disease. In both cases, chemotherapeutic treatment had already been initiated or was completed when sarcoidosis occurred. In these patients, sarcoidosis may have been triggered by immunologic aberrations induced by antineoplastic therapy or as a consequence of an underlying immunologic disturbance associated with the lymphoma. When a suspected relapse of lymphoma presents with signs and symptoms compatible with sarcoidosis, this rare immunologic disorder has to be ruled out by careful clinical and histopathologic analysis to prevent mistreatment.

Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion.

Thalidomide (Thal) is a drug with anti-angiogenic properties. To explore whether the effect of Thal on angiogenesis is associated with a reduction of angiogenic cytokine levels in progressive multiple myeloma (MM), plasma levels of basic fibroblast growth factor, vascular endothelial growth factor, interleukin 6, tumour necrosis factor-alpha and hepatocyte growth factor (HGF) were measured in 51 patients at 0, 3 and 6 months of Thal therapy. After 6 months of treatment, 26 patients were considered to be responsive to Thal therapy, including 17 minimal responses, eight partial responses and one complete response. Only HGF (decreasing, P = 0.02) in the group of responsive patients showed a statistically significant change over a period of 6 months. Because HGF levels are known to correlate to MM tumour burden, we conclude that the mechanism of action of Thal in MM is not caused by a specific inhibition of angiogenic cytokine secretion.

High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma.

The aim of this study was to define prognostic factors that might be predictive for response to thalidomide (Thal) in progressive multiple myeloma (n = 54). We examined the concentration of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), two potent heparin-binding mediators of angiogenesis in peripheral blood (PB; PB-VEGF and PB-bFGF) and bone marrow (BM; BM-VEGF and BM-bFGF), in combination with well-characterized predictors for response and survival to chemotherapy. After a median follow-up time of 15 months (range, 0.3-20), 29 patients (pts.) showed at least a minimal response to Thal therapy, whereas 25 pts. were nonresponsive. As shown by univariate analysis, responsive pts. had statistically significant higher concentrations of PB-bFGF (P = 0.009) and beta2-microglobulin (P = 0.03) before therapy, as well as lower hemoglobin (P = 0.008) and albumin (P = 0.02) levels, whereas no statistically significant difference was found for PB-VEGF (P = 0.93). When a multiple logistic regression analysis was performed, PB-bFGF was the only statistically significant predictor for response to therapy (P = 0.01). None of these variables was associated with a prolonged progression-free survival. In conclusion, our findings indicate that high pretreatment plasma bFGF levels in pts. with progressive multiple myeloma are associated with unfavorable parameters of response and survival but nevertheless predict for response to Thal therapy.

Search for x-ray induced acceleration of the decay of the 31-yr isomer of (178)Hf using synchrotron radiation.

Enhanced decay of the 31-yr isomer of (178)Hf induced by x-ray irradiation has been reported previously. Here we describe an attempt to reproduce this result with an intense "white" x-ray beam from the Advanced Photon Source. No induced decay was observed. The upper limits for the energy-integrated cross sections for such a process, over the range of energies of 20--60 keV x rays, are less than 2 x 10(-27) cm(2) keV, below the previously reported values by more than 5 orders of magnitude; at 8 keV the limit is 5 x 10(-26) cm(2) keV.

Conformational switch and role of phosphorylation in PAK activation.

p21-activated protein kinases (PAKs) are involved in signal transduction processes initiating a variety of biological responses. They become activated by interaction with Rho-type small GTP-binding proteins Rac and Cdc42 in the GTP-bound conformation, thereby relieving the inhibition of the regulatory domain (RD) on the catalytic domain (CD). Here we report on the mechanism of activation and show that proteolytic digestion of PAK produces a heterodimeric RD-CD complex consisting of a regulatory fragment (residues 57 to 200) and a catalytic fragment (residues 201 to 491), which is active in the absence of Cdc42. Cdc42-GppNHp binds with low affinity (K(d) 0.6 microM) to intact kinase, whereas the affinity to the isolated regulatory fragment is much higher (K(d) 18 nM), suggesting that the difference in binding energy is used for the conformational change leading to activation. The full-length kinase, the isolated RD, and surprisingly also their complexes with Cdc42 behave as dimers on a gel filtration column. Cdc42-GppNHp interaction with the RD-CD complex is also of low affinity and does not dissociate the RD from the CD. After autophosphorylation of the kinase domain, Cdc42 binds with high (14 nM) affinity and dissociates the RD-CD complex. Assuming that the RD-CD complex mimics the interaction in native PAK, this indicates that the small G protein may not simply release the RD from the CD. It acts in a more subtle allosteric control mechanism to induce autophosphorylation, which in turn induces the release of the RD and thus full activation.