Showing papers by "University of Modena and Reggio Emilia published in 2006"

Inflamm‐aging: An Evolutionary Perspective on Immunosenescence

Abstract: In this paper we extend the “network theory of aging,” and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as “inflamm-aging,” is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.

Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations.

Abstract: Rationale: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial.Objectives: We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation.Methods: We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection.Results: Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% ...

Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells

Abstract: The continuous renewal of human epidermis is sustained by stem cells contained in the epidermal basal layer and in hair follicles. Cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin, mucosal and corneal defects. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epidermolysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient's legs. Engraftment was complete after 8 d. Synthesis and proper assembly of normal levels of functional LAM5 were observed, together with the development of a firmly adherent epidermis that remained stable for the duration of the follow-up (1 year) in the absence of blisters, infections, inflammation or immune response. Retroviral integration site analysis indicated that the regenerated epidermis is maintained by a defined repertoire of transduced stem cells. These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.

Paracetamol: New Vistas of an Old Drug

Abstract: Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB1 receptor agonist, completely prevents the analgesic activity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB1 agonists are being introduced for pain treatment, it comes out that an indirect cannabino-mimetic had been extensively used (and sometimes overused) for more than a century.

Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors

Abstract: Purpose To evaluate whether hormonal receptor (HR) status can influence the prognostic significance of pathologic complete response (pCR). Patients and Methods This retrospective analysis included 1,731 patients with stage I to III noninflammatory breast cancer treated between 1988 and 2005 with primary chemotherapy (PC). Ninety-one percent of patients received anthracycline-based PC, and 66% received additional taxane therapy. pCR was defined as no evidence of invasive tumor in the breast and axillary lymph nodes. Results Median age was 49 years (range, 19 to 83 years). Sixty-seven percent of patients (n = 1,163) had HR-positive tumors. A pCR was observed in 225 (13%) of 1,731 patients; pCR rates were 24% in HR-negative tumors and 8% in HR-positive tumors (P < .001). A significant survival benefit for patients who achieved pCR compared with no pCR was observed regardless of HR status. In the HR-positive group, 5-year overall survival (OS) rates were 96.4% v 84.5% (P = .04) and 5-year progression-free sur...

Serum anti-Mullerian hormone throughout the human menstrual cycle

Abstract: BACKGROUND: The anti-Mullerian hormone (AMH) is a member of the transforming growth factor (TGF) superfamily. In women, AMH serum levels can be almost undetectable at birth, with a subtle increase noted after puberty. Data are lacking with regard to menstrual cycle day-to-day fluctuations. This longitudinal study was designed to investigate the pattern of secretion of AMH throughout the menstrual cycle in regularly cycling women. METHODS: Twelve healthy female subjects aged 18–24 years participated in this study. Blood samples were taken every other day throughout one menstrual cycle. Serum FSH, LH, estradiol (E 2 ), progesterone, inhibin B and AMH levels were assayed by double-antibody radioimmunoassay using commercial kits. RESULTS: Serum AMH in the first days of the menstrual cycle (days -14 to -12) was 3.8 ± 1.2 ng/ml (mean ± SD). No significant changes were observed in serum AMH levels throughout the menstrual cycle. The highest value was 3.9 ± 1.3 ng/ml at day -12 and the lowest value was 3.4 ± 1.1 ng/ml at day 14, and the difference was not significant. CONCLUSION: In this study, we demonstrated that serum AMH levels do not change significantly throughout the menstrual cycle. Hence, AMH exhibits a relatively stable expression during the menstrual cycle, making it an attractive determinant of ovarian activity.

A new self-consistent empirical interatomic potential model for oxides, silicates, and silica-based glasses.

Abstract: A new empirical pairwise potential model for ionic and semi-ionic oxides has been developed. Its transferability and reliability have been demonstrated by testing the potentials toward the prediction of structural and mechanical properties of a wide range of silicates of technological and geological importance. The partial ionic charge model with a Morse function is used, and it allows the modeling of the quenching of melts, silicate glasses, and inorganic crystals at high-pressure and high-temperature conditions. The results obtained by molecular dynamics and free energy calculations are discussed in relation to the prediction of structural and mechanical properties of a series of soda lime silicate glasses.

Electron transport through single Mn12 molecular magnets.

Abstract: We report transport measurements through a single-molecule magnet, the Mn12 derivative [Mn12O12(O2C-C6H4-SAc)16(H2O)4], in a single-molecule transistor geometry. Thiol groups connect the molecule to gold electrodes that are fabricated by electromigration. Striking observations are regions of complete current suppression and excitations of negative differential conductance on the energy scale of the anisotropy barrier of the molecule. Transport calculations, taking into account the high-spin ground state and magnetic excitations of the molecule, reveal a blocking mechanism of the current involving nondegenerate spin multiplets.

Polyphenols, anthocyanins, ascorbic acid, and radical scavenging activity of Rubus, Ribes, and Aronia.

Abstract: Total polyphenols, total anthocyanins, and reduced ascorbic acid were evaluated in berries belonging to the genera Rubus, Ribes, and Aronia by means of spectrophotometric and high-performance liquid chromatography (HPLC) techniques. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of the fruit extracts was tested. Total polyphenols ranged from 140.6 to 888.5 mg/100 g fresh weight (FW), total anthocyanins ranged from 22.0 to 460.5 mg/100 g FW, and reduced ascorbic acid ranged from 12.4 to 153.8 mg/ 100 g FW. The average EC50 values for Aronia melanocarpa, Ribes nigrum, Ribes rubrum, Rubus fruticosus, and Rubus idaeus were 1.8, 2.8, 5.3, 6.4, and 8.2 mg FW, respectively. The results indicate that the fruits tested are good sources of natural antioxidants.

An update on the diagnosis of tuberculosis infection.

Abstract: Targeted testing and treatment of individuals with latent tuberculosis infection at increased risk of progression to active disease is a key element of tuberculosis control. This strategy is limited by the poor specificity of the tuberculin skin test in populations vaccinated with bacille Calmette-Guerin and its low sensitivity in immunosuppressed persons, who are at highest risk of progression. Two blood tests (T-SPOT.TB and QuantiFERON-TB Gold), based on detection of IFN-gamma released by T cells in response to M. tuberculosis-specific antigens, may offer an improvement on the skin test. However, validation is challenging due to the lack of a diagnostic gold standard. This critical appraisal of published evidence summarizes the diagnostic accuracy of the new tests. The blood tests have operational advantages over the skin test because no return visit is required, results are available by the next day, and repeated testing does not cause boosting. Both tests are significantly more specific than the skin test in populations vaccinated with bacille Calmette-Guerin. The data suggest that T-SPOT.TB may be more sensitive than the skin test. Data in groups at high risk of progression to disease are scarce, and more research is needed in these populations, but it is clear that T-SPOT.TB performs better than the skin test in young children and HIV-infected people with active tuberculosis. Incorporation of these tests into programs for targeted testing of latent tuberculosis infection will reduce false-positive and false-negative results inherent in tuberculin testing, equipping clinicians with more accurate tools for tuberculosis control and elimination in the 21st century.

The predictive value of positron emission tomography scanning performed after two courses of standard therapy on treatment outcome in advanced stage Hodgkin's disease

Abstract: BACKGROUND AND OBJECTIVES: We explored the predictive value on therapy outcome of an early evaluation of treatment response by 18F-fluorodeoxyglucose position emission tomography (18F-FDG-PET) scan performed after two courses of conventional standard-dose chemotherapy in advanced-stage Hodgkin's disease. DESIGN AND METHODS: One hundred and eight patients with newly-diagnosed Hodgkin's disease in stage IIA with adverse prognostic factors, or in stage IIB through IVB, were re-staged with FDG-PET after two cycles of ABVD (PET-2). The end-point of the study was the predictive value of PET-2 on 2-year progression-free survival and 2-year failure-free survival. No treatment variation based only on PET-2 results was allowed. RESULTS: Eighty-eight patients attained complete remission (CR) while 20 showed disease progression during therapy or within 6 months after having reached CR; one patient relapsed. PET-2 was positive in 20 patients: 17 progressed during therapy, one relapsed and two remained in CR. By contrast, 85/88 (97%) patients with a negative PET-2 remained in CR; three progressed or relapsed early after the end of the chemotherapy. Thus, the positive predictive value of a PET-2 was 90% and the negative predictive value was 97%. The sensitivity, specificity and overall accuracy of PET-2 were 86%, 98% and 95%, respectively. The 2-year probability of failure-free survival for PET-2 negative and for PET-2 positive patients was 96% and 6%, respectively (log rank test = 116.7, p < 0.01). INTERPRETATION AND CONCLUSIONS: 18F-FDG-PET scan performed after two courses of conventional standard-dose chemotherapy in advanced-stage Hodgkin's disease was able to predict treatment outcome in 103/108 (95%) of the patients.

Anti‐Müllerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool?

Abstract: Anti-Mullerian hormone (AMH) is a dimeric glycoprotein, a member of the transforming growth factor (TGF) superfamily. It is produced exclusively in the gonads and is involved in the regulation of follicular growth and development. In the ovary AMH is produced by the granulosa cells of early developing follicles and seems to be able to inhibit the initiation of primordial follicle growth and FSH-induced follicle growth. As AMH is largely expressed throughout folliculogenesis, from the primary follicular stage towards the antral stage, serum levels of AMH may represent both the quantity and quality of the ovarian follicle pool. Compared to other ovarian tests, AMH seems to be the best marker reflecting the decline of reproductive age. AMH measurement could be useful in the prediction of the menopausal transition. It could also be used to predict poor ovarian response and possibly the prognosis of in vitro fertilization (IVF) cycles. AMH has been shown to be a good surrogate marker for polycystic ovary syndrome (PCOS). Finally, its use as a marker for granulosa cell tumours has been proposed. A clearer understanding of its role in ovarian physiology may help clinicians to find a role for AMH measurement in the field of reproductive medicine.

A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals.

Abstract: Aims The guidelines of the European Society of Cardiology (ESC) define the current standard for the management of syncope, but are still incompletely applied in the clinical setting. Methods and results Prospective systematic evaluation, on strict adherence to the guidelines, of consecutive patients referred for syncope to the emergency departments of 11 general hospitals. In order to maximize the application, a decision-making guideline-based software was used and trained core medical personnel were designated—both locally in each hospital and centrally—to verify adherence to the diagnostic pathway and give advice on its correction. A diagnostic work-up consistent with the guidelines was completed in 465/541 patients (86%). A definite diagnosis was established in 98% (unexplained in 2%): neurally mediated syncope accounted for 66% of diagnosis, orthostatic hypotension 10%, primary arrhythmias 11%, structural cardiac or cardiopulmonary disease 5%, and non-syncopal attacks 6%, respectively. The initial evaluation (consisting of history, physical examination, and standard electrocardiogram) established a diagnosis in 50% of cases. Hospitalization for the management of syncope was appropriate in 25% and was required for other reasons in a further 13% of cases. The median in-hospital stay was 5.5 days (interquartile range, 3–9). Apart from the initial evaluation, a mean of 1.9±1.1 appropriate tests per patient was performed in 193 patients and led to a final diagnosis in 182 of these (94%). Conclusion The results of this study assess the current standard for the management of syncope on the basis of a rigorous adherence to guidelines of the ESC and provide a frame of reference for daily activity when dealing with syncope.

The role of networks of practice, value sharing, and operational proximity in knowledge flows between professional groups

Abstract: This article investigates the process of knowledge sharing between individuals in different professional groups. Through an ethnographic study in a hospital unit, we examine the individuals’ involvement in networks of practice, their sharing of organizational values, and their operational proximity. Recent attention to networks of practice has led to a view of organizations as crossroads of networks; accordingly, boundary relations between different networks of practice are of core relevance to ensure knowledge diffusion in organizations, but empirical evidence is still lacking. Our grounded theory supports the idea that working side-by-side and having common organizational values are important bases for knowledge transfer between professional groups which belong to different networks of practice. Boundary knowledge transfer evokes new kinds of organizational citizenship behaviours. Professionals who initiate the transfer exhibit extra-role behaviours which, in turn, require the recipient to perform extra...

Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1

Abstract: Facioscapulohumeral muscular dystrophy is a human muscle disorder linked to deletions of a repeat unit on chromosome 4 An experiment in which transgenic mice were engineered to overexpress three skeletal muscle genes linked to this deletion shows that overexpression of one of them, FRG1, causes the signs of muscular dystrophy Too much FRG1 leads to abnormal splicing of pre-mRNAs in skeletal muscle Future studies will explore how this leads to abnormal spine curvature and other symptoms And the availability of a mouse model for this type of muscular dystrophy will be of value in evaluating therapeutic strategies Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is not due to a classical mutation within a protein-coding gene1,2 Instead, almost all FSHD patients carry deletions of an integral number of tandem 33-kilobase repeat units, termed D4Z4, located on chromosome 4q35 (ref 3) D4Z4 contains a transcriptional silencer whose deletion leads to inappropriate overexpression in FSHD skeletal muscle of 4q35 genes located upstream of D4Z4 (ref 4) To identify the gene responsible for FSHD pathogenesis, we generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1, FRG2 or ANT1 We find that FRG1 transgenic mice develop a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seem normal FRG1 is a nuclear protein and several lines of evidence suggest it is involved in pre-messenger RNA splicing5,6,7 We find that in muscle of FRG1 transgenic mice and FSHD patients, specific pre-mRNAs undergo aberrant alternative splicing Collectively, our results suggest that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs

Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology.

Abstract: In this article we summarise present knowledge on the role of pro-inflammatory cytokines on chronic inflammation leading to organismal aging, a phenomenon we proposed to call "inflamm-aging". In particular, we review genetic data regarding polymorphisms of genes encoding for cytokines and proteins involved in natural immunity (such as Toll-like Receptors and Heat Shock Proteins) obtained from large population studies including young, old and very old people in good health status or affected by age-related diseases such as Alzheimer's Disease and Type II Diabetes. On the whole, despite some controversial results, the available data are in favour of the hypothesis that pro-inflammatory cytokines play an important role in aging and longevity. Further, we present a possible hypothesis to reconcile energetic dysfunction, including mitochondria, and inflamm-aging. New perspectives for future studies, including phylogenetic studies in animal models and in silico studies on mathematical and bioinformatic models inspired by the systems biology approach, are also proposed.

Tuning anisotropy barriers in a family of tetrairon(III) single-molecule magnets with an S=5 ground state

Abstract: Tetrairon(III) Single-Molecule Magnets (SMMs) with a propeller-like structure exhibit tuneable magnetic anisotropy barriers in both height and shape. The clusters [Fe4(L1)2(dpm)6] (1), [Fe4(L2)2(dpm)6] (2), [Fe4(L3)2(dpm)6].Et2O (3.Et2O), and [Fe4(OEt)3(L4)(dpm)6] (4) have been prepared by reaction of [Fe4(OMe)6(dpm)6] (5) with tripodal ligands R-C(CH2OH)3 (H3L1, R = Me; H3L2, R = CH2Br; H3L3, R = Ph; H3L4, R = tBu; Hdpm = dipivaloylmethane). The iron(III) ions exhibit a centered-triangular topology and are linked by six alkoxo bridges, which propagate antiferromagnetic interactions resulting in an S = 5 ground spin state. Single crystals of 4 reproducibly contain at least two geometric isomers. From high-frequency EPR studies, the axial zero-field splitting parameter (D) is invariably negative, as found in 5 (D = -0.21 cm(-1)) and amounts to -0.445 cm(-1) in 1, -0.432 cm(-1) in 2, -0.42 cm(-1) in 3.Et2O, and -0.27 cm(-1) in 4 (dominant isomer). The anisotropy barrier Ueff determined by AC magnetic susceptibility measurements is Ueff/kB = 17.0 K in 1, 16.6 K in 2, 15.6 K in 3.Et2O, 5.95 K in 4, and 3.5 K in 5. Both |D| and U(eff) are found to increase with increasing helical pitch of the Fe(O2Fe)3 core. The fourth-order longitudinal anisotropy parameter B4(0), which affects the shape of the anisotropy barrier, concomitantly changes from positive in 1 ("compressed parabola") to negative in 5 ("stretched parabola"). With the aid of spin Hamiltonian calculations the observed trends have been attributed to fine modulation of single-ion anisotropies induced by a change of helical pitch.

Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells

Abstract: The use of retroviral vectors in gene therapy has raised safety concerns for the genotoxic risk associated with their uncontrolled insertion into the human genome. We have analyzed the consequences of retroviral transduction in T cells from leukemic patients treated with allogeneic stem cell transplantation and donor lymphocytes genetically modified with a suicide gene (HSV-TK). Retroviral vectors integrate preferentially within or near transcribed regions of the genome, with a preference for sequences around promoters and for genes active in T cells at the time of transduction. Quantitative transcript analysis shows that one fifth of these integrations affect the expression of nearby genes. However, transduced T cell populations maintain remarkably stable gene expression profiles, phenotype, biological functions, and immune repertoire in vivo, with no evidence of clonal selection up to 9 yr after administration. Analysis of integrated proviruses in transduced cells before and after transplantation indicates that integrations interfering with normal T cell function are more likely to lead to clonal ablation than expansion in vivo. Despite the potentially dangerous interactions with the T cell genome, retroviral integration has therefore little consequence on the safety and efficacy of T cell transplantation.

Analysis of reliability and power efficiency in cascode class-E PAs

Abstract: Power efficiency in switched common source class-E amplifiers is usually obtained at the expense of device stress. Device stacking is a viable way to reduce voltage drops across a single device, improving long-term reliability. In this paper, we focus on cascode-based topologies, analyzing the loss mechanisms and giving direction to optimize the design. In particular, a new dissipative mechanism, peculiar of the cascode implementation, is identified and a circuit solution to minimize its effect is proposed. Prototypes, realized in a 0.13-/spl mu/m CMOS technology demonstrate 67% PAE while delivering 23 dBm peak power at 1.7 GHz. Good bandwidth was also realized with greater than 60% PAE over the frequency range of 1.4-2 GHz.

Hyperemesis gravidarum complicated by Wernicke encephalopathy: background, case report, and review of the literature.

Abstract: Wernicke encephalopathy (WE) is a rare but known complication of severe hyperemesis gravidarum caused by thiamine deficiency. This article presents an unusual case that occurred at our institution and reviews the 48 previously published cases of WE in pregnancy. Considering all the 49 cases, the mean (+/-standard deviation) patients' age was 26.7 +/- 4.9 years, the mean gestational age when WE manifested was 14.3 +/- 3.4 weeks, and the mean duration of vomiting and feeding difficulties was 7.7 +/- 2.8 weeks. Wernicke's classic triad (confusion, ocular abnormalities, and ataxia) manifested in only 46.9% (23 of 49) of the patients. Confusion affected 63.3% (31 of 49) of the patients, ocular signs 95.9% (47 of 49) and symptoms 57.1% (28 of 49), and ataxia 81.6% (40 of 49). Deterioration of consciousness affected 53.1% (26 of 49) of the subjects and memory impairment 61.2% (30 of 49). Complete remission of the disease occurred in only 14 of 49 cases. Symptom resolution required months and permanent impairments were common. The overall pregnancy loss rate, directly (spontaneous fetal loss) and indirectly (planned abortion) attributable to WE, was 47.9% (23 of 49). The diagnosis of WE is clinical and can be rapidly confirmed by magnetic resonance imaging. We emphasize the importance of thiamine supplementation to women with prolonged vomiting in pregnancy, especially before intravenous or parenteral nutrition. We also underline the necessity to promptly replace vitamin B1 when neurologic symptoms and/or signs develop in a patient with hyperemesis gravidarum.