Gods, Graves, and Scholars. William Hastings. The Cain Mutiny. I Hate Thursday. Arthur Koenig. The Diary of a Writer. The World of Don Camillo. Russell Cosper di Lampedusa. Bruce Woodford. The Melodramatists. John Vickery. The Little World of Don Camillo by Giovanni Guareschi, 071, available at Book Depository with free delivery worldwide.

Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis Ludwig Kappos, M.D., Ernst-Wilhelm Radue, M.D., Paul O'Connor, M.D., Chris Polman, M.D., Reinhard Hohlfeld, M.D., Peter Calabresi, M.D., Krzysztof Selmaj, M.D., Catherine Agoropoulou, Ph.D., Malgorzata Leyk, Ph.D., Lixin Zhang-Auberson, M.D., Ph.D., and Pascale Burtin, M.D., Ph.D., for the FREEDOMS Study Group N Engl J Med 2010; 362:387-401 DOI: 10.1056/NEJMoa0909494. Methods In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing–remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point).

Results A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P. Figure 1 Enrollment, Randomization, and Follow-up of Study Patients. Among the 292 patients who were assessed for eligibility but were not enrolled, some were excluded for more than one reason. For one patient receiving 1.25 mg of fingolimod daily who completed the study while receiving the study drug, the status was incorrectly recorded by the investigator as having discontinued the study while still receiving the study drug. Patients who discontinued the study drug include those who discontinued the study; the correct status is shown here. Figure 2 Study End Points, According to Study Group.

Panel A shows Kaplan–Meier estimates for the time to a first relapse, and Panel B shows Kaplan–Meier estimates for the time to disability progression, confirmed after 3 months, as measured with the Expanded Disability Status Scale (EDSS). Panel C shows the proportions of patients free from gadolinium-enhancing lesions and the mean (±SD) number of gadolinium-enhancing lesions at baseline and at 6, 12, and 24 months. Data on gadolinium-enhancing lesions were available for 416 patients assigned to receive placebo, 424 assigned to receive 1.25 mg of fingolimod, and 424 assigned to receive 0.5 mg of fingolimod, respectively, at baseline; 373, 388, and 403, respectively, at 6 months; 356, 376, and 394, respectively, at 12 months; and 332, 343, and 369, respectively, at 24 months. The P values for the proportions were obtained with the use of a logistic-regression model, with adjustment for study group, country, and number of lesions at baseline.

Fingolimod (FTY720) is an oral sphingosine-1-phosphate–receptor modulator that is currently being evaluated for the treatment of multiple sclerosis. There is evidence that fingolimod acts by preventing lymphocyte egress from lymph nodes. This leads to a reduced infiltration of potentially autoaggressive lymphocytes into the central nervous system.

Preclinical findings also suggest that fingolimod may promote neuroprotective and reparative processes within the central nervous system through modulation of sphingosine-1-phosphate receptors expressed on neural cells. A 6-month, phase 2, placebo-controlled study and its open-label extension study showed sustained suppression, for up to 5 years, of both relapse and inflammatory activity in patients receiving fingolimod. Furthermore, in a recently completed, 12-month, phase 3 study involving patients with relapsing–remitting multiple sclerosis (TRANSFORMS [Trial Assessing Injectable Interferon vs. FTY720 Oral in RRMS]; ClinicalTrials.gov number, NCT00340834), reported elsewhere in this issue of the Journal, fingolimod reduced the relapse rate and disease activity as measured with the use of magnetic resonance imaging (MRI), as compared with a once-weekly, intramuscular injection of interferon beta-1a at a dose of 30 μg. In our phase 3, double-blind, placebo-controlled study, called FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), we investigated the effects of daily fingolimod treatment for 24 months on the relapse rate, disability progression, and MRI measures of inflammation, burden of disease, and tissue destruction in patients with relapsing–remitting multiple sclerosis.

Study Oversight Steering-committee members (listed in the, available with the full text of this article at NEJM.org) collaborated with the sponsor, Novartis Pharma, to develop the protocol and monitor the ongoing study. Data were collected by the investigators and analyzed by the sponsor.

All the authors had access to the data, participated in the data analysis and interpretation, and wrote the manuscript. All authors vouch for the accuracy and completeness of the data and the statistical analysis. All authors participated in the writing of the manuscript and approved the final manuscript before submitting it for publication. Patients Key eligibility criteria were an age of 18 to 55 years; a diagnosis of multiple sclerosis, according to the revised McDonald criteria; a relapsing–remitting course; one or more documented relapses in the previous year or two or more in the previous 2 years; and a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS; which ranges from 0 to 10, with higher scores indicating greater disability). Key exclusion criteria were relapse or corticosteroid treatment within 30 days before randomization, active infection, macular edema, diabetes mellitus, immune suppression (drug- or disease-induced), or clinically significant systemic disease.

Interferon-beta or glatiramer acetate therapy had to have been stopped 3 or more months before randomization. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by each site's institutional review board; patients gave written informed consent before any study-related procedures were performed. Study Design and Randomization Patients were randomly assigned, in a 1:1:1 ratio, to receive oral fingolimod capsules in a dose of 0.5 mg or 1.25 mg or matching placebo, once daily for 24 months. Randomization was performed centrally, with the use of a validated system and stratification according to site, with a block size of six within each site. Study Procedures and End Points Clinical assessments were performed at screening and at randomization (baseline), and study visits, including safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomization.

The EDSS score was determined every 3 months, and the MSFC z score every 6 months. Standardized MRI scans were obtained at the screening visit and at 6, 12, and 24 months and were analyzed centrally at the Multiple Sclerosis–MRI Evaluation Center at the University Hospital in Basel, Switzerland. The primary end point was the annualized relapse rate, defined as the number of confirmed relapses per year.

Relapses were verified by the examining neurologist within 7 days after the onset of symptoms. To constitute a confirmed relapse, the symptoms must have been accompanied by an increase of at least half a point in the EDSS score, of one point in each of two EDSS functional-system scores, or of two points in one EDSS functional-system score (excluding scores for the bowel–bladder or cerebral functional systems). The key secondary end point was the time to confirmed disability progression, defined as an increase of one point in the EDSS score (or half a point if the baseline EDSS score was equal to 5.5), confirmed after 3 months, with an absence of relapse at the time of assessment and with all EDSS scores measured during that time meeting the criteria for disability progression. Statistical Analysis For the primary end point, on the basis of data from a phase 2 study of fingolimod, the expected annualized relapse rate was 0.7 for the group receiving placebo and 0.42 for the group receiving 1.25 mg of fingolimod, with a common standard deviation of 1.06. We calculated that a sample of 1250 patients would provide 95% statistical power to detect a relative reduction of 40% or more in the annualized relapse rate with fingolimod as compared with placebo, after 24 months. With this sample size, using a log-rank test and a two-sided α level of 0.05 (assuming a study-discontinuation rate of 25% ), we calculated that the study would have a statistical power of more than 90% to detect an absolute difference between the two groups of 12% in the proportion of patients with disability progression (confirmed after 3 months) at month 24, which was expected to be approximately 30% in the placebo group. Both the intention-to-treat population and the safety population included all patients who had undergone randomization.

The study tested two null hypotheses: that there were no differences in the annualized relapse rate between the group receiving fingolimod at a dose of 1.25 mg and the group receiving placebo or between the group receiving fingolimod at a dose of 0.5 mg and the group receiving placebo. The aggregate annualized relapse rate was estimated by means of a negative binomial regression model with adjustment for study group, country, number of relapses within 2 years before baseline, and EDSS score at baseline. The time to relapse or progression was estimated with the use of the Kaplan–Meier method.

The times to disability progression (confirmed after 3 or 6 months) were compared in the main analysis by means of the log-rank test and in the supportive analysis by means of a Cox proportional-hazards model with adjustment for study group, country, baseline EDSS score, and age. To control for a type I statistical error, a prospectively planned, hierarchical testing procedure was used to compare fingolimod with placebo regarding the primary and key secondary end points, in the following order: the annualized relapse rate, first in association with 1.25 mg of fingolimod and next in association with 0.5 mg of fingolimod, and then the time to disability progression (confirmed after 3 months), first with 1.25 mg of fingolimod and next with 0.5 mg of fingolimod. Each test was performed with a significance level of 0.05. However, the next test was performed only when the preceding test was statistically significant. Missing data were not imputed.

Safety analyses were summarized by means of descriptive statistics; inferential significance testing was not performed. Statistical details for other end points are provided in the. Study Population From January 2006 through August 2007, a total of 1272 patients were randomly assigned to a study group ( Figure 1 Enrollment, Randomization, and Follow-up of Study Patients. Among the 292 patients who were assessed for eligibility but were not enrolled, some were excluded for more than one reason. For one patient receiving 1.25 mg of fingolimod daily who completed the study while receiving the study drug, the status was incorrectly recorded by the investigator as having discontinued the study while still receiving the study drug.

Patients who discontinued the study drug include those who discontinued the study; the correct status is shown here. ) at 138 centers in 22 countries (see the for a list of the centers and principal investigators). Baseline characteristics were similar across the three study groups ( Table 1 Baseline Characteristics of the Patients, According to Study Group. In total, 1033 patients (81.2%) completed the 24-month study, with 945 (74.3%) still receiving the assigned study drug. The study drug was discontinued in proportionately fewer patients in the group receiving 0.5 mg of fingolimod (18.8%) than in the group receiving 1.25 mg of fingolimod (30.5%) or in the placebo group (27.5%).

Reasons for study-drug discontinuation are listed in. Relapse The aggregate annualized relapse rate (the primary end point) was lower with fingolimod at a dose of 0.5 mg (0.18) and fingolimod at a dose of 1.25 mg (0.16) than with placebo (0.40), representing relative reductions of 54% and 60%, respectively, in the annualized relapse rate ( ). As compared with placebo, both doses of fingolimod reduced the annualized relapse rate among patients who had not previously received disease-modifying treatment as well as among those who had been treated previously (P. Disability The time to disability progression, with confirmation either after 3 months (the key secondary end point) or after 6 months, was longer with both fingolimod doses than with placebo ( and ). Fingolimod reduced the risk of disability progression, confirmed after 3 months, over the 24-month study period (hazard ratios, 0.68 for the 1.25-mg dose and 0.70 for the 0.5-mg dose).

The cumulative probability of disability progression (confirmed after 3 months) was 17.7% for 0.5 mg of fingolimod, 16.6% for 1.25 mg of fingolimod, and 24.1% for placebo. Regarding disability progression that was confirmed after 6 months, the risk was also reduced with fingolimod over the 24-month study period (hazard ratio, 0.60 with the 1.25-mg dose and 0.63 for the 0.5-mg dose), and the cumulative probability of progression was 12.5% for 0.5 mg of fingolimod, 11.5% for 1.25 mg of fingolimod, and 19.0% for placebo. During the study period, the EDSS scores and MSFC z scores remained stable or improved slightly in the fingolimod groups and worsened in the placebo group ( ). MRI-Related End Points Patients in either fingolimod group had significantly fewer gadolinium-enhancing lesions than those in the placebo group at 6, 12, and 24 months, as well as fewer new or enlarged lesions on T 2-weighted MRI scans at 24 months ( ). Proportionately more patients in the fingolimod groups than in the placebo group were also free from gadolinium-enhancing or new or enlarging lesions at these time points ( and ). The median volume of lesions on T 2-weighted scans decreased between baseline and month 24 with fingolimod but increased with placebo. During the 24-month study period, changes in the volume of hypointense lesions on T 1-weighted scans favored both doses of fingolimod over placebo ( ).

In addition, reductions in brain volume were smaller with fingolimod. Adverse Events Similar proportions of patients (93 to 94%) in the three study groups were reported to have adverse events ( Table 3 Adverse Events in the Safety Population, According to Study Group. ); the events were mild to moderate in severity in 82% of patients receiving 0.5 mg of fingolimod, 77% of those receiving 1.25 mg of fingolimod, and 77% of those receiving placebo. Adverse events that led to discontinuation of the study medication (including abnormal laboratory-test results) were more common with fingolimod at a dose of 1.25 mg (occurring in 14.2% of patients) than with fingolimod at a dose of 0.5 mg (occurring in 7.5%) or with placebo (occurring in 7.7%). Serious adverse events were reported for 10.1% of patients receiving 0.5 mg of fingolimod, 11.9% of those receiving 1.25 mg of fingolimod, and 13.4% of those receiving placebo. The most common serious adverse events, each reported for eight patients, were bradycardia, multiple sclerosis relapse, and basal-cell carcinoma. All other serious adverse events occurred in four or fewer patients (.

Infections The overall incidence of infection was similar in the fingolimod and placebo groups (69 to 72%); serious infections occurred in 1.6 to 2.6% of patients. Urinary tract infection was the only serious infection reported in more than one patient (reported in two patients in the group receiving 0.5 mg of fingolimod). Herpesvirus infections were reported in similar proportions of patients across the three study groups ( ). Of these infections, herpes zoster was reported in seven patients receiving 0.5 mg of fingolimod, three receiving 1.25 mg of fingolimod, and four receiving placebo.

Two cases of herpesvirus infection were classified as serious adverse events: one case of genital herpes (in a patient receiving 1.25 mg of fingolimod) and one case of herpes simplex labialis (in a patient receiving 0.5 mg of fingolimod). Lower respiratory tract infections (including bronchitis and pneumonia) were more common with fingolimod than with placebo (occurring in 41 patients [9.6%] receiving 0.5 mg of fingolimod and 49 patients [11.4%] receiving 1.25 mg of fingolimod vs. 25 patients [6.0%] receiving placebo). Cardiovascular Events Transient, dose-related decreases in the heart rate occurred after the first dose of fingolimod was administered, a finding that is consistent with previous clinical experience. Heart-rate decreases started 2 hours after receipt of the first dose, reaching the nadir after 4 to 5 hours, with attenuation beginning at 6 hours. The maximal reduction in the mean resting pulse rate, as compared with the baseline value, was 8 beats per minute 5 hours after the first dose of 0.5 mg of fingolimod and 10 beats per minute 4 hours after the first dose of 1.25 mg of fingolimod. Bradycardia (including the seven cases classified as serious adverse events) was reported in 9 patients receiving 0.5 mg of fingolimod, 14 receiving 1.25 mg of fingolimod, and 3 receiving placebo ( ).

The majority of these events in the fingolimod groups occurred during the monitoring period after the first dose was administered (in 8 and 12 patients receiving 0.5 mg and 1.25 mg of fingolimod, respectively). Of these, six events were symptomatic (characterized by dizziness, chest discomfort, or palpitations) and all resolved with 24 hours; two patients received treatment for bradycardia. First- and second-degree atrioventricular block was infrequently reported as an adverse event ( ). However, electrocardiography performed on day 1 revealed first-degree atrioventricular block in 20 patients receiving 0.5 mg of fingolimod, in 37 receiving 1.25 mg of fingolimod, and in 6 receiving placebo.

Second-degree atrioventricular block (also known as Mobitz I periodicity) was identified on electrocardiography on day 1 in one patient receiving 0.5 mg of fingolimod and in four patients receiving 1.25 mg of fingolimod. Second-degree atrioventricular block was symptomatic in one patient (in the 1.25-mg group), who had shortness of breath and palpitations ( ). No clinically notable effect on heart rate or atrioventricular conduction was seen with continued use of fingolimod.

Starting during month 2, the mean systolic and diastolic blood pressures obtained while the patient was seated increased from the baseline values; at month 24, they had increased by 1.9 and 0.7 mm Hg, respectively, with 0.5 mg of fingolimod and by 3.6 and 2.1 mm Hg, respectively, with 1.25 mg of fingolimod and had decreased by 0.4 and 0.5 mm Hg, respectively, in the placebo group. Laboratory Abnormalities At 1 month, peripheral-blood lymphocyte counts were reduced from the baseline counts by an average of 73% with 0.5 mg of fingolimod and 76% with 1.25 mg of fingolimod, remaining stable thereafter (see the ). These were not reported as adverse events by the investigators, who remained unaware of the actual values unless they dropped to less than 0.2×10 9 per liter. Increases in the alanine aminotransferase level to three times the upper limit of the normal range or more were more frequent in the fingolimod groups (reported in 8.5% of patients in the 0.5-mg group and 12.5% in the 1.25-mg group) than in the placebo group (1.7%) and occurred predominantly in men. One patient receiving 0.5 mg of fingolimod had an increase in the alanine aminotransferase level to more than 10 times the upper limit of the normal range.

Elevated liver-enzyme levels returned to normal in all patients, even in the few who continued the study treatment. In all three groups, bilirubin levels remained stable, with no clinically relevant changes during the study. Discussion This 2-year study showed that as compared with placebo, both doses of fingolimod tested reduced the annualized relapse rate. Disability progression was also significantly reduced in patients receiving fingolimod as compared with those receiving placebo. These clinical findings are supported by the results regarding the MRI end points and are in line with the results of a 6-month, placebo-controlled, phase 2 study and a 1-year, phase 3 study comparing fingolimod with an active drug (intramuscular interferon beta-1a) (TRANSFORMS).

The 30% reduction in the rate of reduction of brain volume in this study — detected as early as 6 months after initiation of the study drug and also seen over a 12-month period in TRANSFORMS — is an interesting corollary to the clinical findings. It remains to be established whether this effect is due to the reduction in inflammatory activity or reflects direct interactions between the drug and sphingosine-1-phosphate receptors on neural cells, as suggested by studies in animals and by in vitro observations. This study also provides important 2-year, placebo-controlled information about the safety of fingolimod.

As medications used to treat multiple sclerosis become increasingly potent, attention to safety findings is paramount. Possible concerns include infections, cardiovascular effects, macular edema, and elevated liver-enzyme levels. The safety profile warrants further longer-term assessment.

As expected on the basis of its mechanism of action, fingolimod treatment led to a reduction in circulating lymphocytes of approximately 70% in the present study. The overall incidence of infection was similar across the three study groups, with the exception of lower respiratory tract infections, which were more common with fingolimod than with placebo.

Although similar proportions of patients in the three groups had herpesvirus infections, reactivation of latent herpes remains a potential risk with immunomodulatory therapy; two fatal herpes infections occurred in TRANSFORMS with the 1.25-mg dose of fingolimod. Cardiovascular effects of fingolimod included slowing of the heart rate and atrioventricular conduction block at the time of the first dose. These effects appear to be dose-dependent and specifically related to the binding of the drug to sphingosine-1-phosphate receptors in cardiac tissue. Interactions with sphingosine-1-phosphate receptors in smooth muscle may account for the mild increase in blood pressure seen during long-term treatment. The long-term relevance of this finding is unclear.

Fingolimod was infrequently associated with macular edema, which resolved with discontinuation of the drug. The frequency of this complication and possible implications during long-term use are not known.

Elevations in liver-enzyme levels were common findings in this study and in earlier studies. These elevated values resolved after fingolimod was discontinued. Our findings do not suggest an increased risk of cancer with the use of fingolimod. However, further long-term observation is necessary, since the risk of cancer is potentially increased by the use of any immunomodulatory agent. In conclusion, oral fingolimod as compared with placebo had superior efficacy in this 24-month study involving patients with relapsing–remitting multiple sclerosis. Rates of relapse, progression of clinical disability, and MRI evidence of inflammatory lesion activity and tissue destruction were all significantly reduced with the use of fingolimod. The two doses of fingolimod had similar efficacy, and adverse events may be less frequent with the 0.5-mg dose than with the 1.25-mg dose.

Thorough observation and long-term follow-up are necessary for a more informed assessment of the benefits and risks of this new treatment option for relapsing multiple sclerosis. References • 1 Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

J Biol Chem 2002;277:7 • 2 Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004;427:355-360 • 3 Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002;296:346-349 • 4 Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-1517 • 5 Bartholomaus I, Kawakami N, Odoardi F, et al.

Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 2009;462:94-98 • 6 Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007;115:84-105 • 7 Brinkmann V.

FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009;158:1173-1182 • 8 Jackson SJ, Baker D, Giovannoni G. Fingolimod enhances myelin basic protein expression and modulates cytokine production following an interferon-gamma mediated insult in the whole brain aggregate cell culture system. Neurology 2009;72:Suppl 3:A377-8 • 9 Miron VE, Jung CG, Kim HJ, Kennedy TE, Soliven B, Antel JP. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008;63:61-71 • 10 Foster CA, Howard LM, Schweitzer A.

At first glance, because the engaging fascination of history overshadows the actual reference to geometry, the focus of The Italian Piazza Transformed does not immediately seem to be the relationships between mathematics and architecture. I must therefore apologize to the author for the delay in suggesting her work for the book review section of the Nexus Network Journal, when the editor asked for my collaboration. The book was still lying on my desk, among those waiting for a second careful reading, when I realized that it indeed deserved a presentation to our readership, because of its subtle approach to the study of the form while inquiring into the design of public spaces as a proper and innovative feature of Italian cities in the Communal Age, that is, the era of the independent comune, city-states, from the twelfth to the fifteenth century (Fig. Fig. 1 Book cover, The Italian Piazza Transformed The book deals with the two main squares in Parma, that of the Cathedral ( duomo) complex and that of the City Hall ( municipio), and asserts that their regular shapes act as the first statements of a new urban concept of the communal age, in which geometry is used as a claim for power, imposing order on the irregular fabric of the medieval city. The European city exists because of the public space, and the book focuses precisely on the importance of the public space in the formation of the modern city, which emerged in the Middle Ages when the comuni declared a political role for themselves and autonomy for secular cities in the quarrel between the two most powerful institutions, the Church and the Holy Roman Empire. Areli Marina is Assistant Professor of Architectural History, Art History, and Medieval Studies at the University of Illinois, Urbana-Champaign. Because she knows Italy’s cities and language well, she is able to access directly original ancient literature and archival documents, even those of the twelfth and thirteenth centuries, when a new urban culture was reviving the splendor of Rome and reinventing public space.

She is able to grasp the great importance that “voids” have in the life of Italian cities and her thesis focuses on the space in between buildings, rather than on the architecture itself. The original character of this particular approach to the city lies in the reading of the piazza as a network of voids that defines the urban character, rather than reading it as a mere cluster of buildings. In her introduction she stresses the differences between her approach and that of earlier studies, explaining the reasons for the absolute significance of the examples she studied. According to Marina, Parma is the first city in Italy where the local rulers applied a new urban design strategy to assert their power, anticipating the Tuscan cities by a century, and acting as a model for the market towns of the thirteenth and fourteenth centuries.

This explains why the research, which deals with a single provincial town, will surely become an fundamental reference for the knowledge of the Italian city and its transformation after the collapse of the Roman Empire, when the pressure of the peculiar dichotomy of power existing in Italy in the Middle Ages would define and influence urban life, echoing in local culture until quite recently. In fact, the tug of war between the two modern folk characters created by Giovannino Guareschi, Don Camillo and Peppone, illustrates the endemic stress between secular and religious power that shaped the city and continued to animate the people during the age of the Cold War. Marina introduces the book by quoting the Etymologies by Isidore of Seville, beginning with the statement that the word city means both the buildings ( urbs) and the citizens’ social network ( civitas). This dichotomy encapsulates the medieval understanding of the city, and Marina demonstrates how the two squares in Parma are the panoptical declaration of urban identity. She bases her thesis on the interwoven testimonies of documents and monuments, identifying pieces of evidence in the surviving architecture and in the survey of urban sites. • the physical evidence of the sites; • contemporary literature about Parma history and architecture; • historical representations of the city; • secondary literature about local and northern Italy political and visual culture.

The study of these materials enabled Marina to reconstruct the conditions of the piazza’s foundations and to see the design concept with “period eyes”. The first step in the analysis regarded the urban space, reconstructing the historical events and facts of the building, shaping the original perimeter and further transformations, with special attention to the relationships between buildings and site.

The second step was the reconstruction of the city of Parma (the urbs) in the Middle Ages. The third step was identifying the patrons, the historical events and the successive military and political leaders. Finally, the last step was a consideration of the cultural environment and the education of the city elite. The final topic is the struggle for authority in the Communal Age, when the city (the civitas) declared its independence from the two leaders fighting for power, namely the Pope and the Emperor.

The book is divided in two parts, each of which is subdivided in two chapters. Part I, “The production of Order”, is the pleasant story of the construction and description of the two squares. Pa Vei Arbeidsbok Pdf Printer. Карточные Игры Паук Играть Онлайн. Piazza del Duomo grew first, starting with the building of the Baptistery, which shaped the urban space between the Bishop’s Palace and the Cathedral.

The first chapter explains how the particular site and the shape of the octagonal Baptistery demonstrate the existence of a clear “political” design behind the aim to impose a geometrical pattern on the square. Later, the increasing strength of the citizens’ secular authority lead to the creation of the Piazza del Comune: a new, larger square which was arranged on the site of the earlier Roman forum.

The second chapter addresses the foundation and the growth of this secular compound, whose design pursued the concept of order in the global perception of urban space, by the imposition of a quality standard on the square and on citizens’ behaviour. Part II, “The Piazza and Public Life”, investigates the Legislation of Order that made the building of the Piazza del Comune possible. Piazza del Comune was intended to testify to the secular city’s social order in the urban decorum, granted by laws and city officers. The enactment of Statuti, statutes, underlined and extended what was symbolised in the abstract by the space’s geometrical form. The last chapter closes by stressing the importance and significance of the Roman heritage in the culture of the Middle Ages, finding evidence in the splendour of the architecture and in the expression of civic spirit through civic space. Fig. 2 Extracts from Areli Marina’s figs. 33, 34, 47 and 98, schemes that show the use of proportional systems based on the doubling of a square module in the elevation of the Baptistery of Parma, and how the same criterion relates the squares that define the plans of the two squares The first appendix, “On Measurement, Module and Geometry in Medieval Parma”, is a synthesis explaining why there is a lack of scientific evidence necessary to state a final interpretation of the metric “measure” in terms of numbers. For this reviewer, this Appendix was fundamental for understanding why Marina, who is so precise in her analysis, describes (geo)metric relations in reference to approximate measurements expressed in metres, and limits herself to looking for individual geometric relationships without seeking an overarching solution that would be confirmed by round measurements.

In the case of the Duomo, the unit of measurement of reference is the Roman foot, which in Parma is the dimension of the bricks used in the square. Since as part of my own research I personally had carried out a survey, I am quite familiar with the measurements, and I was surprised by the author’s use of this approximation, in part because when my team and I had undertaken our survey, one of our goals was to find the modular matrix of the square. Reading the Appendix, which ably summarises the history of local units of measure, which in Italy, as we know, vary according to period and location, I understood the reason behind Marina’s decision. In essence, she renounced a metric reading because there is no way to be certain of the unit of measure used in the Middle Ages, since the Roman foot does not appear to have any relation to the foot used in the Renaissance, and cannot in any case be considered “stable”. With elegance, Areli Marina adds an important piece to the puzzle, confirming the importance of a careful survey of the urban space and her consideration of the architectural survey as a matter of knowledge more than a technical procedure for measurement. The Italian Piazza Transformed is a book, which is indeed worth reading.

It was awarded the 2013 Howard R. Marraro prize for the best work in Italian Catholic history from the American Catholic Historical Association.