Field clusters are commonly misinterpreted as clusters and would require genotyping to rule out misclassification. Clusters are recognized when meningococcal cases of the same phenotypic strain  occur in spatial and temporal proximity. The incidence of such clusters was compared to the incidence that would be expected by chance by using space-time nearest-neighbor analysis of 4,887 confirmed invasive meningococcal cases identified in the 9-year surveillance period 1993–2001 in the Netherlands. Clustering beyond chance only occurred among the closest neighboring cases (comparable to secondary cases) and was small . Neisseria meningitidis, become asymptomatic carriers and are sources for further transmission. The apparently sporadic occurrence of invasive disease reflects invisible transmission chains of circulating strains, since invasive disease develops in only a small proportion of those infected. The precise mechanisms generating clusters or outbreaks puzzle public health workers, epidemiologists, and microbiologists  , time , and conventional phenotypic markers  make a connection likely (field cluster) or when an excess of incidence  is noticed in a retrospectively specified geographic or population area within a chosen period (community outbreak). Field clusters and community outbreaks are rarely seen in the Netherlands, possibly because of underreporting. A group of unrelated cases that occur in temporal and spatial proximity may be misinterpreted as a cluster or outbreak, but these cases would not justify additional public health measures, except perhaps to reassure the public. In a real cluster, cases of the same strain occur in temporal and spatial proximity at a higher frequency than by chance. The objective of our study was to explore the phenomenon of meningococcal clustering in a more objective way by using a nearest-neighbor analysis in space and time that compares the actual occurrence of clusters with their background incidence.N. meningitidis isolates collected by the Netherlands Reference Laboratory for Bacterial Meningitis in the same period. Additionally, reports of field clusters occurring during the same time were collected as reference.We used data collected from two surveillance sources: mandatory reports from January 1993 through May 2001 and reports of laboratory-confirmed N. meningitidis isolated from blood or cerebrospinal fluid (CSF); meningococcal antigen or DNA detected in cerebrospinal fluid by latex agglutination or polymerase chain reaction; or gram-negative diplococci detected in cerebrospinal fluid, blood, or skin biopsy. The following information was available on an individual level: date of birth, gender, initials, postal code, municipality, date of report, date of first symptoms, date of diagnosis, and age at notification.Report data were obtained from the Inspectorate of Health Care. According to the Communicable Disease Act, physicians must report cases of meningococcal disease to their Municipal Public Health Service. The case definition for report includes clinical meningococcal disease in combination with microbiologic confirmation: N. meningitidis from a patient. When two strains have the same phenotypic markers , these are considered to be identical and to belong to one serosubtype. The following information was available for individual patients: date of birth, gender, initials, municipality, date of sample collection, submitting laboratory, date of receipt of strain, date of blood culture, date of lumbar puncture, source of isolate (blood or CSF), serogroup, serotype, and subtype.The reference laboratory collects meningococcal strains from patients with meningitis or septicemia, isolated from blood or CSF. Strains are sent on a voluntary basis to the reference laboratory by all clinical microbiologic laboratories throughout the country. A strain is defined as an isolate of Records between these two sources were linked (case ascertainment) by using SAS version 8.1 . First, records were linked by date of birth, gender, and initials. Records remaining unlinked were then linked by combinations of two variables. The links in the first step were considered correct, while all further links were checked manually for consistency in data fields, spelling mistakes in initials, date of birth, and municipality. In After notification of meningococcal disease, the Municipal Public Health Service considers taking public health measures. Depending on the attentiveness of the communicable disease consultant, field clusters are recognized and reported to the Inspectorate of Health Care, which made this information available for our investigation. Accurate data on actual rifampicin prophylaxis were not available. Field clusters were named after their probable transmission route: family, daycare center, primary school, or swimming pool.nt nearest-neighbors in time of case 1 as the n cases that occur closest (in time) to case 1. Similarly the np nearest-neighbors in place of case 1 are the n cases that occur closest in space to case 1. The distance between cases is defined as the distance in a straight line between the geographic centers of the reported cases . The k cases that are both nt nearest-neighbors in time and np nearest-neighbors in place (intersection of place and time), are now the group of the 1st, 2nd, …, and kth nearest-neighbors . The order  is set in such a way that k = 1 defines the first nearest-neighbor, k = 2 defines the second nearest-neighbor, and so on. A program was written in C to analyze kth nearest-neighborship. This program is available from the authors.Clustering of meningococcal cases is defined as excess occurrence of the same serosubtype in patients, in spatial and temporal proximity. We used patients' residences as "place" and chose the first day of illness as "time." The actual incidence of clustering was compared to the incidence that would be expected by chance, by using space-time nearest-neighbor analysis . To quankth nearest-neighbor is of the same strain, under no clustering as the null hypothesis, by calculating the frequency of having a kth nearest-neighbor of the same strain when the observed strains are randomly assigned to the observed dates and places of actual cases. This shuffling is called random labeling . As most nearest-neighbors are coincidental, little difference was seen in the mean temporal and spatial distance between nearest-neighbors of the same serosubtype (6.1 km [range 0–44 km] and 13.2 days [range 0–63 days]) and those of different serosubtype (7.6 km [range 0–49 km] and 14.3 days [range 0–380 days]). The probability of the second, third, fourth, and fifth nearest-neighbors being of the same serosubtype did not differ significantly from background values . For serogroup B, the excess probability was 3.1%  for the first nearest-neighbor. For serogroup C, the excess probability was 3.5% , and for serogroup W135 no excess probability was found (n = 59). Seven different serosubtypes, accounting for 14%  of all cases, showed significant excess probability : B:1:P1.The Municipal Public Health Services identified 40 field clusters involving 21 different serosubtypes: 11 primary school clusters (range 2–5 cases), 7 daycare center clusters (2–3 cases), 1 swimming pool cluster (4 cases), and 21 household clusters (2–3 cases). The cases all occurred within 21 days from the first case, and 78% (32/41) occurred within 8 days.Six serosubtypes were identified by both methods as serosubtypes with clustering, 15 were identified only in field clusters, and 1 in statistical clustering only. Most field clusters consisted of only two cases (75%); this result is consistent with the results of our statistical approach.Our results suggest that in the context of current public health efforts, clustering of meningococcal disease is rare in the Netherlands and other Western countries. Our nearest-neighbor analysis provided a useful method of assessing the phenomenon of meningococcal clustering by taking random variance into account. Cases of the same serosubtype appeared beyond the expected background rate and were only seen in the first nearest-neighbor, which implies that only secondary cases occur in excess of chance (3.1%). Connections of more than two cases could not be demonstrated beyond chance. Throughout the year, invasive disease appears mostly as isolated cases. This limited clustering may reflect the positive effect of the prophylactic rifampicin policy; however, household field clusters are still reported, which possibly shows the constraints of this prevention policy. This paucity of real secondary cases is consistent with findings from other studies. A Belgian study found 4.4% secondary cases (range 2.0%–5.2%) in 1,913 cases of invasive meningococcal disease from 1971 through 1976 , occur geographically close to each other , and occur mostly in pairs (75%). These findings are consistent with observations in field cluster studies showing that secondary invasive disease most likely occurs nearby, within the next few days. In a Belgian study, 83% of 63 secondary cases occurred within 8 days of identifying the index case . Most cases are found in children, who often spend time in daycare centers, schools, and other places outside the home. Since these places tend to be located in the same area as their homes, this factor likely did not affect our results. The extent of clustering was possibly overestimated because of imprecise geographic coordinates since our statistical method used the center of the municipality or postal code area, but no more precise alternative is available. Since only phenotypic strain typing was conducted  and not the more sensitive porA-genotyping method that would have identified spurious clusters, background rates of clustering may have been overestimated. However, this method is unlikely to have affected the excess probability (3.1%) of clustering, since this rate is probably a result of direct transmission. Our method for calculating background value was chosen to be as realistic as possible; however, our results do not appear to be sensitive to the choice of 6th to 10th nearest-neighbors as a reference. For instance, results from 3rd to 10th nearest-neighbor or 7th to 10th nearest-neighbor, as a reference, were virtually identical.We believe that our low observed incidence of secondary cases partly reflects the general inability to link cases connected by chains of transmission. As disease develops in only a few of the links in a chain of transmission, connected cases are unlikely to be still temporally and spatially close, which obviates detection. Not surprisingly, we found three times as many serosubtypes among reported field clusters (21 serosubtypes) than assessed with nearest-neighborship analysis (7 serosubtypes), which confirms that field clusters may be spurious. Although field clusters have low specificity, their sensitivity is presumably high. Genotyping can identify those clusters brought about by direct transmission; nevertheless, the value of cluster surveillance as a means of prevention is uncertain. Apparent clusters are not valuable to guide additional intervention efforts, since these would prevent few additional cases. Our method of space-time nearest-neighborship analysis provides a sensitive novel approach to the epidemiology of meningococcal disease and possibly even other infectious diseases.


Abdounodus hamdii and Ocepeia daouiensis from the Selandian of Ouled Abdoun Basin, Morocco, both previously only documented by lower teeth. Here, we describe new fossils of Ocepeia, including O.grandis n. sp., and a sub-complete skull of O. daouiensis, the first known before the Eocene for African placentals. O.daouiensis skull displays a remarkable mosaic of autapomophic, ungulate-like and generalized eutherian-like characters. Autapomorphies include striking anthropoid-like characters of the rostrum and dentition. Besides having a basically eutherian-like skull construction, Ocepeia daouiensis is characterized by ungulate-like, and especially paenungulate-like characters of skull and dentition . However, some plesiomorphies such as absence of hypocone exclude Ocepeia from crown Paenungulata. Such a combination of plesiomorphic and derived characters best fits with a stem position of Ocepeia relative to Paenungulata. In our cladistic analyses Ocepeia is included in Afrotheria, but its shared derived characters with paenungulates are not optimized as exclusive synapomorphies. Rather, within Afrotheria Ocepeia is reconstructed as more closely related to insectivore-like afroinsectiphilians  than to paenungulates. This results from conflict with undetected convergences of Paenungulata and Perissodactyla in our cladistic analysis, such as the shared bilophodonty. The selenodont pattern best supports the stem paenungulate position of Ocepeia; that, however, needs further support. The remarkable character mosaic of Ocepeia makes it the first known “transitional fossil” between insectivore-like and ungulate-like afrotherians. In addition, the autapomorphic family Ocepeiidae supports the old – earliest Tertiary or Cretaceous – endemic evolution of placentals in Africa, in contrast to hypotheses rooting afrotherians in Paleogene Laurasian “condylarths”.While key early(iest) fossils were recently discovered for several crown afrotherian mammal orders, basal afrotherians, e.g., early Cenozoic species that comprise sister taxa to Paenungulata, Afroinsectiphilia or Afrotheria, are nearly unknown, especially in Africa. Possible stem condylarth-like relatives of the Paenungulata  include only  The "condylarths" – or archaic ungulates – are the main and most spectacular radiation of the placental mammals at the beginning of the Tertiary, after the demise of the non-avian dinosaurs. This non-monophyletic group includes various ungulate-grade lineages, some of which became extinct more or less quickly by the Eocene, and some other of which succeeded and gave rise to the extant flourishing ungulate orders such as Perissodactyla and Artiodactyla.The fossil record of the “condylarths” is heterogeneous, especially geographically. They are well known in the Early Tertiary of the Laurasian continents such as North America, Asia, and Europe, where they diversified in various lineages, including primitive and modern taxa. North American and European “condylarths” were known since the turn of the late 19th century, and have been the subject of several classical studies In South Tethyan areas, South America has yielded a diversified Paleogene ungulate fauna that illustrates a remarkable endemic radiation , Paris, France.MHNT PAL: Muséum National d'Histoire Naturelle of Toulouse, France, collection of Paleontology.PM: Phosphate of Morocco, localities of the Ouled Abdoun Basin, Morocco.TZT, THR and NTG2: material from localities of respectively Talazit, Adrar Mgorn 1 and N'Tagourt 2, Ouarzazate Basin, Morocco; collection of the University Montpellier II, France.BD, locality of M'Bodione Dadere, Senegal, collections of the University Montpellier II, France.Eomaia, Acristatherium, Asioryctes, Maelestes, Zalambdalestes, cimolestids, zhelestids, etc… (see Primitive and derived states are abbreviated (p) and (d) in the text; they refer with respect to the generalized eutherian condition, except when mentioned . The primitive eutherian condition is represented by Cretaceous taxa such as Permission for field work in the Ouled Abdoun OCP quarries was provided by the Office Chérifien des Phosphates  and the Ministère de l'Energie, des Mines, de l'Eau et de l'Environnement . Field work (prospects and excavations) was only geological and paleontological, and did not involved endangered or protected species.Measurements are provided in millimeters (mm). The stapedial ratio was measured following Segall MNHN.F PM 45 was subjected to X-ray Computed Tomographic (CT) imaging at the AST-RX platform of the MNHN, using a GE Sensing and Inspection Technologies phoenix|x-ray v|tome|x L240-180 CT scanner. We used the microfocus RX source 240 kV/320 W, detector 400×400 mm with a matrix of 2024 pixels (pixel size: 200×200 µm). Scan parameters: Voltage = 95 kV; Current = 515 µA; Exposure: 200 ms; Isotropic voxel size of 0.04900265 mm. Data were reconstructed using datos|x reconstruction software  and then exported into a 16 bits TIFF image stack of 1717 virtual slices in transversal view.We used MIMICS Innovation Suite software  for the analysis, 3D modelisation and measurements on 3D model.Corrections of distortions and reconstructions were also made with the help of the software VG studio Max  and Cinema 4D .http://zoobank.org/”. The LSID for this publication is: urn:lsid:zoobank.org:pub:13D2D3D4-AC74-444E-A943-C069F10294ED. The electronic edition of this work was published in a journal with an ISSN, and has been archived and is available from the following digital repositories: PubMed Central, LOCKSS.The electronic edition of this article conforms to the requirements of the amended International Code of Zoological Nomenclature, and hence the new names contained herein are available under that Code from the electronic edition of this article. This published work and the nomenclatural acts it contains have been registered in ZooBank, the online registration system for the ICZN. The ZooBank LSIDs (Life Science Identifiers) can be resolved and the associated information viewed through any standard web browser by appending the LSID to the prefix “Systematic PaleontologyCohort Placentalia Owen, 1837Supercohort Afrotheria Stanhope, Waddell, Madsen, De Jong, Hedges, Cleven, Kao, Springer, 1998Superorder ?Paenungulata Simpson, 1945incertae sedis (prob. nov.)Order Family Ocepeiidae nov. GheerbrantDiagnosis. That of the type and only known genus.Type genus. Ocepeia Gheerbrant & Sudre, 2001.genera. Ocepeia, only know genus.Included Distribution. Same as the type genus.ZooBank life science identifer (LSID) for family.urn:lsid:zoobank.org:act:5260AD60-6655-49C8-BD6C-D3C7D577A1EF.Ocepeia Gheerbrant & Sudre, 2001Genus Diagnosis (a: autapomorphies).O. grandis): Short and broad rostrum with very robust construction; short frontal with reduced orbito-temporal process; meso- and postero-cranial region elongated, especially the parietal; parietals with two oblique bony ridges diverging anteriorly from the mid part of the sagittal crest; extensive pneumatization of the skull bones, especially of the supraoccipital; middle ear and inner ear  remarkably small; tegmen tympani large and inflated.Skull ; condyle significantly higher than the tooth row; corpus high and transversely inflated.3 and probably I3 vestigial (a). Lower canine stout and anthropoid-like  (a). Postcanine dentition noticeably large relative to the palate extension (megadontia).Dentition: Dental formula: I3, C, P2, M3. Anterior dentition shortened (a), with P1–2 lost (a), no significant diastemata (a), and lower incisors compressed with root wide and short (a). IMolar pattern bunoselenodont and brachydont with well developed labial shearing crests (associated with semi-lunar shearing wear facets). Molars size increasing slightly from M1 to M3.Crown of lower premolars and molars inflated labially (a). 3-4 simple and trenchant.P1-2, but median transversely in M3; paraconid with small mesial crest; protoconid low, close in height to metaconid and paraconid; postmetacristid and metastylid present; mesoconid large; small entoconulid; hypoconid very large, low and broad (a); entoconid with a short but functional entolophid linking the lingual flank of the hypoconid; hypoconulid reduced and lingual in M1–2 and postcristid very long, in relation to the selenodont pattern; short premetacristid; postcristid bearing several cuspules; no labial cingula. M2 wider than M1 and M3; M3 at least as long as M2, with expanded hypoconulid lobe, and with oblique distal root.Lower molars: paraconid bulbous and lingual in MUpper cheek teeth more or less homodont (a): upper premolars extended transversely with well-developed protocone.Upper molars: parastyle and especially mesostyle large; W-like ectoloph linked to the strong mesostyle; small additional stylar cusps and crest present; hypocone absent; conules and accessory conules present; protocone low, mesio-distally expanded with widely divergent crests at apex; protocone lingual flank strongly canted labially; wide protofossa; very small lingual crest/ridge at the base of the paracone; lingual cingulum thin and continuous.Type species. Ocepeia daouiensis Gheerbrant & Sudre, 2001.Included species. O daouiensis; O. grandis n.sp.Locality and age. Paleocene of the Ouled Abdoun Basin, Morocco.Ocepeia daouiensis Gheerbrant & Sudre, 2001-2Age and occurrence. Paleocene of the Ouled Abdoun Basin , Morocco. The new material of this species confirms its Paleocene age. It comes from the same bone bed level located at the base of phosphorite Bed IIa that is dated Selandian Eritherium azzouzorum, Abdounodus hamdii, and Lahimia selloumi.Holotype4, M1.. CPSGM-MA1, fragment of right dentary with PNew referred material. Most specimens from lower dentition of O. daouiensis were reported and described by Gheerbrant et al. 3–4, M1–2); a small individual, possibly a female; Ouled Abdoun basin, quarries of Sidi Chennane, Selandian.MNHN.F PM45, a partial skull broken on the left side (left maxillary and zygomatic arch absent)and bearing the right P1, P3–4, M1–3, the frontal and anteriormost part of the parietal, a fragment of left premaxillary (with a large incisor); probably a large male individual; Ouled Abdoun basin, unknown exact locality, Selandian.MNHN.F PM54, skull rostrum preserving right and left maxillary with CMNHN.F PM58, lower canine; Ouled Abdoun basin, unknown exact locality.1 (reconstructed), P4; Ouled Abdoun basin, unknown exact locality; collection of the Museum of Toulouse.MHNT PAL 2006.0.17 (PM71), fragment of right dentary with M1 (strongly worn), P4, M1–2; Ouled Abdoun, unknown exact locality; collection of the Museum of Toulouse.MHNT PAL 2006.0.16 (PM72), fragment of left dentary with CDiagnosis. See Gheerbrant Ocepeia daouiensis differs mainly from O. grandis n. sp., the only other known species of the genus (see below), by its smaller size.The new material reported here allows the first description of the skull and upper dental morphology of Ocepeia daouiensis. Two partial skulls of Ocepeia daouiensis, MNHN.F PM45 and MNHN.F PM54, are known. They show important differences in size and general robustness related to intraspecific individual variations.3. MNHN.F PM45 belongs to a small individual with low sagittal crest. The preserved teeth  are unworn and it is possible that M3 was still in crypt or just erupting in this specimen, indicating a young individual. However, the sutures are strongly fused and in many cases hardly distinct; together with the low sagittal crest, it might suggest a young adult female.MNHN.F PM45, a relatively complete cranium, is the best preserved specimen. This is the only and best known mammal skull from the Paleocene of Arabo-Africa. It preserves most part of the cranium, except for a small part of left side , the premaxillae, the distal part of the right zygomatic arch  and the right maxillary tuberosity bearing M1, P2–4, M1–3), the anteriormost part of the parietal, the nasal, the frontal, a fragment of left premaxillary (with a large incisor), most of the right maxillary and the palatine, and part of the left maxillary. It belongs to a larger individual than MNHN.F PM45. It is also characterized by a more robust general construction with much stronger sagittal and temporal crests, and a large canine, all features probably related to sexual dimorphism. These characters suggest that MNHN.F PM54 belongs to a large male adult, in contrast to the individual represented by MNHN.F PM45. The lower jaw PM41 fits better in occlusion with MNHN.F PM 54 than with MNHN.F PM45, which might indicate that it also belongs to a male .MNHN.F PM 54 corresponds to most of the rostrum of a cranium preserving the permanent cheek teeth .Our reconstruction of the cranium of N.F PM45 , Fig. S1N.F PM45 . The sizversus the preorbital length. This primate-like robust short and broad snout is autapomorphic in Ocepeia. The short rostrum might be related to the occurrence of enlarged upper incisors, as illustrated by specimen MNHN.F PM 54 for I2. The face (rostrum) is about 1/3 the total length, and the frontal and nasal are short. A short frontal is known is some Paleocene taxa such as Meniscotherium . The most remarkable feature is that the rostrum is short and wide, whereas the cranial region  is elongated. This is illustrated by a noticeably high ratio (82%) of the width of the snout at the canine level Ocepeia daouiensis, that is evidenced by the CT scan sections, is the extensive pneumatization of the bones such as the supraoccipital, the parietal, the basisphenoid, the basioccipital and the periotic. This is most striking for the supraoccipital which is considerably thickened and expanded below the parietal, and which shows extensive diploë . The skull is low and the dorsal profile is long and straight, as in pantolestids and in contrast to the generalized eutherian construction. The sagittal crest is moderate (MNHN.F PM45) to strong (MNHN.F PM 54), but it does not form a high blade-like structure; the nuchal (lambdoid) crests are strong and salient dorsally and laterally.After correction of the post-mortem distortion , the zygomatic arches appear not strong flared laterally  is also elongated. The premaxillary was probably short (see reconstruction). The nasal cavity seen in MNHN.F PM54 is high and wide, as in primitive proboscideans; this is probably a paenungulate trait. The nasals are broadened posteriorly. They do not penetrate deep in the frontals. The naso-frontal suture is transverse; it is located at the level between M1 and M2, as in the generalized eutherian condition. The maxillae are well-developed, with a high processus frontalis as in primitive proboscideans; the maxillo-nasal suture is long. The maxillary tuberosity was small and located close to the anterior rim of the orbit. The frontal is flat; it extends anteriorly from the temporal line, up to about 1 cm in front the maxillary tuberosity (M3 location).The squamosal , in the generalized eutherian condition. A slight bone inflation might indicate the presence of a lacrimal tubercle close to the jugal. The lacrimal has sutures with frontal and nasal dorsally. It is not clear if the lacrimal has a suture with the jugal or with the maxillary along the orbit rim. However, the jugal is narrowed in its anterior extremity (MNHN.F PM 45) as a short and flat bony blade above the zygomatic process of the maxillary. This suggests that the contact between the lacrimal and jugal was either slight or interrupted by a short intermediate extension of the maxillary onto the orbital rim; in other words, the jugal was slightly withdrawn posteriorly. The condition of Ocepeia is not far from that of basal paenungulates such as hyracoids where the lacrimal it is separated from the jugal by a narrow orbital process of the maxillary. The lacrimal foramen is present (MNHN.F PM 54) and located in the orbit above the maxillary foramen of the infraorbital canal. The infraorbital canal extends from the P3 to M2 levels, above the tooth row.The zygomatic process of the maxilla is well-developed laterally and it extends posteriorly on the medial part of the jugal up to the level of the beginning of the sagittal crest. The temporal fossa and zygomatic arches are longer than wide. The lacrimal is broken but its development can be inferred from surrounding preserved bones in MNHN.F PM45. The lacrimal forms the upper rim of the orbit with a large facial process .The postorbital constriction is strong and maximal at the transverse level where the temporal crests meet and unite with the sagittal crest. The parietals are remarkably long, even longer than in Phosphatherium and in Eritherium. It is located not very high above P3, in the primitive eutherian condition. The orbit is noticeably posterior, with its anterior rim located at the level of M2–3, as in Hyopsodus and in contrast to primitive proboscideans (Eritherium: P4) and even hyracoids . The jugal extends below the orbit but does not contact the lacrimal, because of the presence of a short intermediate process of the maxillary. The maxillary participates in the zygomatic apophysis, as a short medial process extending 1,5 cm posteriorly. There is no submaxillary fossa. The zygomatic apophysis diverges low with respect to the dental row. There is a robust (wide) ventral postorbital process of the zygomatic arch, that is made mostly by the jugal; this is reminiscent of primitive proboscideans such as Numidotherium. The jugal extends anteriorly up to the level of M2 parastyle. It forms a high and narrow vertical bony blade. The distal part of the zygomatic arch, broken in MNHN.F PM54, remains unknown in Ocepeia.The skull roof profile is very straight. The nasal and the muzzle are high. The maxilla extends high above the tooth row. The infraorbital foramen is much smaller than in Uchkudukodon nessoviOrycteropusPhosphatherium which has a long suture between the frontal and alisphenoid. Such extended relation of the parietal with at least the alisphenoid and possibly also with the orbitosphenoid is an original construction among the eutherians and the placentals , is not completely preserved, making difficult the identification of bones and their topographic relations. This is especially true of the orbital process of the frontal, the orbital process of the palatine, the orbitosphenoid, and the alisphenoid that is nearly entirely broken. The orbitosphenoid is small and located anteriorly, as in some primitive eutherians such as ls e.g., .f. lacerus anterius), or both. Its large size would agree with a common opening for both the sphenorbital fissure and the optic foramen  as in Phosphatherium; it resembles in shape that of Phosphatherium, but it is located much more anteriorly. According to Cox Phosphatherium.At the base of the orbitosphenoid, five millimeters behind the choana and above it, there is a large semi-lunar and anteriorly oriented opening which might be either the optic foramen or the sphenorbital fissure . The nuchal crests are well-developed and salient posteriorly behind the occiput. However, they are not so expanded posteriorly as in many primitive eutherians such as arctocyonids. The nuchal crests are formed by the supraoccipital which extends anteriorly for a short distance (3–5 mm).The distal part of basicranium is not elevated with respect to the anterior part of the skull (mesocranium), in contrast to Ocepeia daouiensis and indicates this is a megadont mammal. This is related to the herbivorous diet and this is another primate (anthropoid) convergence. Comparison of predictive equations of body mass based on various dental measurement  shows that the teeth are especially enlarged transversely. This derived morphology is well distinctive from many artocyonids such as Tricentes and Arctocyon; it is possibly autapomorphic.The palate is wide. The occlusal surface of the cheek tooth series appears relatively large (e.g. breadth extension) with respect to the palatal area, which emphasizes the prominence of the dentition in f. palatinus majus) is located in front of M2. From this foramen, a well-developed palatine groove extends anteriorly up to the P3 level, similarly to primitive hyraxes; it housed the greater palatine nerve (V2) and blood vessels. The palatines are very short (comparable to the premaxillae) and posterior, in the primitive eutherian condition. They do not extend more anteriorly than M2, in contrast to Eritherium , and to Pleuraspidotherium (P3). They are even slightly more posterior than in Hyopsodus. The choana opens at mid-length level of M3. Its mesial rim is inflated as a lip-like structure indicating the presence of a postpalatine torus . The zygomatic process of the maxilla is well-developed laterally but short. It diverges between mid-length of M2 and M3, and it extends as a thin a bony blade medial to the anterior part of the jugal, and well behind M3. The temporal fossa and zygomatic arches are wide laterally and also long. The zygomatic process of the squamosal does not diverge very posteriorly, but at the level of the basisphenoid-basioccipital suture .The tooth row remains restricted mesially on the skull; it does not extend behind the orbit and the middle skull length. The cheek tooth row is aligned closely parallel to the longitudinal axis. Although broken apart in the known material, the premaxillaries are reconstructed as short and wide, by reference to the occlusion of the lower (anterior) dentition. No palatine fenestra are present in the maxillary. The posterior palatine foramen (Pleuraspidotherium) and widely separated. Consequently, the pterygoid fossa is wide and large, similarly to Meniscotherium. The large development of this fossa, which accommodates the medial pterygoid muscle, is in agreement with the enlarged angle of the dentary in the species. Just behind the pterygoid processes, opens the small foramen ovale within a longitudinal groove at the basis of the pterygoid crest. It is located anterior to the basisphenoid-basioccipital suture and to the postglenoid process, in contrast to Pleuraspidotherium. The pterygoid, basisphenoid and basioccipital are elongated, resulting in the overall long basicranial region of Ocepeia. The basiphenoid is especially long ; it extends posteriorly to the pterygoid process. The basioccipital area is large and long, although wider than long. The presphenoid and vomer are poorly distinct. However, the CT scans suggest that the presphenoid was short, high and pneumatized, and that the vomer is crossed by a large canal.The pterygoid processes are well-developed, very long .The glenoid surface of the squamosal is poorly excavated, more extended transversely than longitudinally and opened anteriorly which makes possible wide antero-posterior movements of the dentary in Meniscotherium and Hyoposodus. The median crest vanishes before joining the occipital condyles, but this is probably related to post-mortem damage. The hypoglossal foramen houses two small openings; it is smaller than the jugular foramen, and it is located more posteriorly from the jugular foramen than in Phosphatherium; it is 2.5 mm anterior to the occipital condyle. This eutherian-like construction differs from advanced proboscideans in which the two foramens tend to fuse. The hypoglossal foramen has an oval shape with a long axis parallel to the petrosal-basioccipital suture. The paroccipital process is low and located very posterior , as in Phosphatherium.The basioccipital is convex with a ventrally salient median keel which is also seen in several other condylarth-like taxa such as The braincase is wide, especially caudally , in contrast for instance to the arctocyonids and phenacodontids.Ocepeia is large and especially long: 1) the pars cochlearis is small and very anterior with a strong rostral tympanic process extending to the level of the anterior margin of the postglenoid process; 2) the pars mastoidea is very long and widely exposed ventrally between posttympanic  and paroccipital processes (both separated from about 10 mm). The enlarged pars mastoidea is a remarkable feature of Ocepeia that is shared with proboscideans. The pars cochlearis and promontorium are ovoid, long, and slightly oblique with respect to the longitudinal axis. The promontorium extends posteriorly to the postglenoid process level, and it is more ventral than the basioccipital. It is inflated and located anteriorly. Its almond shape resembles that of Hyopsodus (p). The promontorium has a smooth surface and it bears a stout ridge that is oblique postero-laterally. This ridge is bounded antero-laterally by a sulcus probably for the internal carotid artery (d). The promontorium sulcus for stapedial artery is absent. The rostral tympanic process of the petrosal is salient anteriorly to the promontorium. The epitympanic wing of the periotic medial to the promontorium is absent (p). The fenestra vestibuli  is very small (area  = 0.312 mm2), and much smaller than the fenestra cochleae. The size of the fenestra vestibuli of Ocepeia daouiensis, and correlatively of its stapes, is well below the regression line for fenestra vestibuli area versus body mass in modern mammals Ocepeia daouiensis is in close proportion to Numidotherium koholensePeriotic –6. Both Phosphatherium and the primitive eutherian or placental condition. The presence of the cochlear canaliculus (aquaeductus cochleae) is evidenced by the CT scan observations. It opens, in the primitive condition, ventro-medially in the jugular fossa, below and more medially than the cochlear fenestra; this differs from Phosphatherium where it is more ventral and anterior. This canal is unusually large in section and its opening is dilated transversely. The stylomastoid foramen for n. faciale (VII) is distinct postero-laterally to the fenestra cochleae. The jugular foramen  is the largest foramen of the basicranium; it is located just behind the promontorium. Its shape is oval with an oblique postero-lateral to antero-medial long axis. The caudal tympanic process of the petrosal is well-developed, which is generalized in eutherians according to McPhee Phosphatherium and Numidotherium.The fenestra cochleae (round window) is located postero-medial to the fenestra vestibuli, in the eutherian state. It is larger than the fenestra vestibuli, but smaller than the jugular foramen. It is vertical and elongated transversely (p), and it faces posteriorly as in Meniscotherium, Mesonyx, anthracotheriids, hippopotamids and cetaceans The tympanohyal is large. The tegmen tympani is remarkably inflated and pneumatized; it forms a large and robust barrel-like bony structure located antero-lateral to the promontorium, and it partially covers the epitympanic recess. An inflated tegmen tympani is a derived feature among Eutheria f. acusticum inferius is posterior and circular, and it shows distinct link with the cochlea  close to f. cochleae. The f. acusticum superius is anterior and elongated (bean-like outline). In dorsal to dorso-lateral view, there is a large opening that extends medially as a canal in the inflated tegmen tympani and that might correspond to the foramen for the ramus superior of the stapedial artery. Its opening is as large as that of the internal acoustic meatus.In dorsal view ; here we report a comparative description of the main morphological traits of the inner ear that are of systematic and phylogenetic values. The number of coils of the cochlea measured following method of West Numidotherium has a smaller number of turns than Ocepeia according to Court Notostylops, but of unknown polarity among eutherians. The secondary bony spiral lamina is present on the basal coil (340 to 360° from f. vestibuli). In several late Cretaceous eutherians NotostylopsOcepeia. The anterior semicircular canal is the larger semicircular canal as in most eutherians. The posterior segment of the lateral semi-circular canal is coalescent with the posterior ampula of the posterior semi-circular canal on a short distance from the vestibule. However, the lateral semi-circular canal separates from the posterior ampula before its ends, and the lumen of both lateral semicircular canal and posterior semicircular canal PSC remains distinct, which indicates that there is no true secondary crus commune. The absence of a secondary crus commune is a generalized condition shared by crown placentals in contrast to stem eutherians that have a secondary crus commune ChambiusNumidotheriumZalambdalestesInner ear , 7. The petrosal , as wellHyopsodus; it is wider than high. The occipital condyles are salient posteriorly, and they join ventrally as in Meniscotherium . The nuchal crest is salient posteriorly all around the occiput; it does not form the peculiar posterior upper expansion seen in many eutherians and primitive placentals such as arctocyonids, pleuraspidotheriids, pantodonts, pantolestids and others. Below the nuchal crest, the occiput appears slightly inclined anteriorly (eutherian trait).The supraoccipital is well-developed. Transverse and longitudinal CT sections show that it is very thickened and pneumatized . It exteThe occipital surface is depressed between the nuchal crest and the condyles. There is a small condylar foramen. The paroccipital process is small. There is no mastoid exposure in the occipital side (amastoid structure).Skull measurements: see .O. daouiensis is described by Gheerbrant et al. O. daouiensis identified here is I1?, I2, I3?, C1, P3, P4, M1, M2, M3, which is identical to lower dental formula. In most of the available material, the teeth are unworn and the degree of wear of all cheek teeth is comparable, suggesting that permanent teeth erupt nearly at the same time , except for the mast molar that is the last tooth to erupt . The enamel is slightly wrinkled.Remark - The lower dentition of 2 . The crown was probably procumbent. It is inferred that this is the larger upper incisor as in early proboscideans such as Numidotherium and Moeritherium.A broken piece of left premaxillary of the specimen MNHN.F PM54 bears an enlarged root belonging to a broken incisor that lacks the crown . The rooO. daouiensisAs in the lower dentition known in 2 by a small diastema. The canine is stout, low, but sharp. The root was inflated and larger than the crown. The crown is convex laterally and concave lingually. It bears a small anterior crest and a longer (higher) distal crest. A faint trace of lingual cingulum is present, but it is much smaller than in the lower canine which is more anthropoid-like in this respect.The canine preserved in MNHN.F PM54 is separated from the I3 is very close to C1.The two first premolars are absent, as in the lower dentition. They are not replaced by a significant diastema in the tooth row: P3 and P4 are sub-molarized with a developed protocone, three roots, and a more or less transverse occlusal outline. As a consequence, the whole cheek dentition is rather homodont.P3-4 was enhanced in Ocepeia. There is no trace of metacone. The protocone is much smaller than the paracone. It bears symmetric and well-developed pre- and post-protocristae that enclose a well delimited protofossa. The preprotocrista joins a very small parastyle; the postprotocrista, well distinct in both P3 and P4, joins the postparacrista. One or more variable cuspules are inflated on the postprotocrista behind the protocone. Their position is reminiscent of the molar metaconule. A small but distinct transverse crest crosses the protofossa in its anterior part and links the internal flank of paracone and protocone. The lingual flank of the protocone is convex. A very slight enamel bulging of the crown below and behind the protocone of P4 suggests trace of postcingulum.The labial cingulum is inflated, especially at anterior and distal ends. Traces of stylar cusps are present, most distinctly as a metastyle, and more variably as a D cusp. The paracone is the main labial cusp: it is large, low and nearly as wide as long. It bears long V-shaped shearing anterior and posterior crests that are underlined by a distinct wear facet. Shearing function with trigonid of occlusal relative teeth P3 and P4 are very similar in morphology, but the former is slightly smaller, less transverse and has a smaller protocone.P1-3 are bunoselenodont, with a W-like (selenodont) ectoloph that is linked to an inflated mesostyle. They lack a hypocone.MThe styles are remarkably well-developed and inflated, and located labial to paracone and metacone. Parastyle and mesostyle are the larger styles, they form inflated cusps on the labial side of the crown. Additional small stylar crests and cuspules are variably present in front of the paracone and metacone . The stylar shelf is present but not so wide. The paracone and metacone are low and linked by a dilambdodont ectoloph that is typically joined to the large mesostyle. The two arms of the centrocrista are united labially just before joining the mesostyle.1 to M3. The protocone is remarkably low and expanded mesio-distally; its crests are widely divergent. Its labial flank is convex. The protofossa is vast, and especially long, and shallow. A very short transverse crest is present at the base of the lingual flank of the paracone. The preprotocrista joins the parastyle below the preparacrista. The postmetacrista joins the base of the postmetacrista below the metacone. The paracingulum is much more developed than the metacingulum. A metaconule is more or less inflated on the postprotocrista where it is salient disto-lingually; it is more developed on M1 than on M2. The metaconule is doubled lingually by a small additional conular cuspule. There is also a small paraconule on the preprotocrista; it is located more labially than the metaconule. The lingual flank of the protocone is strongly canted labially. A more or less distinct trace of continuous lingual cingulum is present on M1–3, around the protocone, but it lacks a hypocone. Three roots are present, including in M3.The preparacrista joins the parastyle; the postmetacrista, well-developed, joins the metastyle. The labial flank of the paracone and metacone is convex. The paracone is larger than the metacone, and more so from MThe selenodont pattern of the ectoloph is functionally underlined by well-developed related semi-lunar shearing facets such as wear facets 3 and 4, 1a and 1b , mean M1 and M2 = 8.5 kg) and are obviously overestimated. This is related to the fact that M1 and, less markedly, M2 are larger in Ocepeia daouiensis relative to modern euungulates on which are based the predictive equations Ocepeia. The overestimation of the body mass based on anterior molars seems to confirm that Ocepeia is a megadont form with large anterior molars (see description).Body mass estimates of Ocepeia daouiensis is in the lower range (2.9 kg) and is close to the estimates based on the length of M1-3 and M3. The relative size of M3 (larger relative to M2 and M1) in Ocepeia daouiensis is closer to that of modern mammals; this might explain why M3 provides more reliable body mass estimates that are close to those based on the length of M1-3 and of the skull. The mean body mass estimate of Ocepeia daouiensis based on the length of M1-3, M3 and the skull is 3.5 kg . It is comparable to extant hyraxes and to Meniscotherium chamense (3.4 kg Body mass estimate based on the skull length of e 3.4 kg  which arTetraclaenodon puercensis “pliciferus” (Torrejonian), of skull size (110 mm) close to that of Ocepeia, give much larger body mass estimation (14 kg) than postcranial measurements (3.2 kg), similarly indicating they are megadont primitive ungulates. The cheek dentition of Ocepeia is actually proportionally much larger with respect to the palate and skull size than in Tetraclaenodon puercensis.Kondrashov & Lucas O. daouiensis, made by 3 of us , is based primarily on the most complete specimen, MNHN.F PM45. However, because this specimen is incomplete and slightly crushed dorso-ventrally, some details of the reconstruction  were completed based on comparison with MNHN.F PM54. However, the reconstruction of the whole skull is not a chimera of the two specimens. It is indeed important to note that specimen MNHN.F PM45 is more distorted than other specimens, and it is a probable female with much more gracile overall morphology and smaller size than MNHN.F PM54. Hence, because of the sexual dimorphism of O. daouiensis, our reconstruction is only partially representative of the species, i.e. it is not representative of male individuals which would appear significantly more robust , as exemplified by MNHN.F PM54.The reconstruction of the skull The lower jaw reconstructed in The reconstruction of the skull was made using the 3D models computed from tomographic data and processing (by FG) with help of programs Mimics Innovation Suite , VG studio Max  and Cinema 4D . The 3D model of the specimen MNHN.F PM45 was segmented following bone sutures, lines of distortion and breaks and best preserved part; segments were re-assembled after correction of distortions in the three main anatomical orientations , by compThe main difficulty in our reconstruction was the plastic distortion of individual bone that could not be retrodeformed; this especially true for the dorso-ventral compression of MNHN.F PM 45 that could not be evaluated precisely, and for which we propose an estimated correction in the The final drawing of the reconstruction was based on the reconstructed 3D digital model , with heOcepeia daouiensis are generalized eutherians traits  and hyopsodontids. The arctocyonids such as Ocepeia is noted with dilambdodont pantodonts such as Haplolambda and Leptolambda. It includes the selenodont molars, but also the absence of hypocone, presence of a continuous lingual cingulum on upper molar, presence of a paraconid on lower molars, overall shape of the dentary with enlarged angle and deep and robust corpus, and short anterior dentition and symphysis. Similar skull features are also noted such as the flat and long skull roof, widely fused orbito-temporal fossa, and the long parietal and sagittal crest. However, Ocepeia and pantodonts differ by both derived and primitive features , indicating well distinct lineages that converged for some features.Interestingly, a dental resemblance of Ocepeia daouiensis are known in semi-aquatic mammals such as pantolestids: the short muzzle, the absence of postorbital process and related widely confluent orbito-temporal fossa, the long and flat skull roof, the skull shape broader than high, the strong and posteriorly salient lambdoid crests. However, many other features of Ocepeia are well distinct from pantolestids, for instance the small infraorbital foramen, the short frontal, the lower jaw morphology and the distinctive dentition.Some skull features of Ocepeia daouiensis are characterized by a remarkable combination of primitive and derived features. The most remarkable derived features are summarized in The skull and dentition of These derived features are of different taxonomic rank value. Few but significant ones are placental traits. They concern mostly the inner ear structure, such as the cochlea with at least two turns. Other derived traits are mostly ungulate-like , or paenungulate-like, or autapomorphic features.OcepeiaPaenungulate traits are much more significant than the phenacodont-like features previously discussed for Ocepeia are autapomorphies. Some of them are striking anthropoid-like convergent traits , and loss of P1-2 without significant diastemata, and also the inflated mandibular corpus.Other derived features of its * in , 7: I1–3Ocepeia grandis n. sp. Gheerbrant–20ZooBank life science identifer (LSID) for species. urn:lsid:zoobank.org:act:1E8AD70F-0465-47BA-B8BA-8D8D2B8C00C9.Etymology. Grandis (Latin), in reference to the large size of the species with respect to the type-species O. daouiensis.Age and occurrence. This Paleocene species comes from a phosphate level located above that of O. daouiensis: Thanetian upper Bone Bed  of Bed IIa of the local phosphate series from the Ouled Abdoun Basin (unknown quarries), Morocco Holotype. MNHN.F PM37, fragment of right dentary bearing C1, P3-4, M1-2 ; MHNT PAL 2006.0.9 ; MNHN.F PM39 , right M1? , and labial part of a left upper premolar .N.F PM34 , fragmen.9 PM70; , right dN.F PM39 –20, fragOther referred material. PM66 .al. PM66 , right dDiagnosis. Species most closely related to O. daouiensis. It differs primarily from O. daouiensis in being 150% larger. Other few and discrete morphological features of Ocepeia grandis n. sp. that differs from O. daouiensis are the conules more developed, the hypoconid and the metacone slightly larger.This species is known only by part of the cheek dentition and of the lower jaw. The upper dentition is poorly known, only by broken isolated teeth that perfectly occlude with associated lower teeth.O. daouiensis. Beside the much larger size, the few and most significant distinct morphological features are mentioned in the diagnosis. The mandibular symphysis was at least partially fused as in O. daouiensis  suggesting a more distinct metacone or metastyle than in O. daouiensis. It also differs from O. daouiensis by the presence of a vertical groove instead of a crest on the anterior flank of the paracone.The few known upper molars of  grandis , 20 are ocristae , and in O. daouiensis (Selandian) and O. grandis (Thanetian) agree with the hypothesis that they belong to a single lineage.Both the evolutionary stage (including in relative size) and the relative age Teeth and lower jaw: see C1-M3 length: PM66: 54.5 mm; MNHN.F PM37: 54 mm; MHNT PAL 2006.0.9 (PM70): 54 mm.P3-M2 length: MNHN.F PM37: 37.4 mm; MHNT PAL 2006.0.9 (PM70): 33.4 mm.O. grandis preserves well the molar series. The best body mass estimate of Ocepeia grandis based on available material (lower dentition) is slightly more than ten kilograms .The new matrix includes 175 characters and 25 taxa that are detailed in Ocepeia among Laurasian and African placental taxa, e.g. to test relationships with Afrotheria versus Laurasiatheria. Our comparisons are extended to the Zhelestidae , Ptolemaia (P. lyonsi and P. grangeri: Ptolemaiida), and Orycteropus afer (Tubulidentata). We rooted our phylogenetic analysis using the generalized eutherian morphotype (“Eutheria” in the matrix) as outgroup; it is represented by primitive, mostly Cretaceous, eutherians such as leptictids, cimolestids, Maelestes, Asioryctes and Acristatherium.With respect to the previously published matrix NamatheriumFor the most inclusive taxa such as Eutheria, Perissodactyla, Hyracoidea, Sirenia, Embrithopoda, Zhelestidae, our comparisons are based not on one particular genus or species, but on the most primitive known taxa  unordered;- 152 features ordered;- 152 features ordered and step matrix for 19 unordered features and 12 other unordered characters coded not reversible;- Partitioned matrix, separating dental and skull features;Ocepeia: matrix with key features weighted .- Constrained analysis to test hypothesis of paenungulate position of Ocepeia.One remarkable point is that nearly all our analyses of the whole matrix result in the recovery of few most parsimonious trees (MPTs), i.e. a single tree or a well resolved consensus tree. In other words, we obtained few MPTs and all with similar topology. This means that there is some coherent signal among the various characters analyzed, i.e., they do not conflict significantly. Lower topological resolution is obtained with partitioned analysis restricted to skull features which indicates that 1) there are some conflicts among the skull features, 2) dental traits provide the stronger phylogenetic signal in our analysis. However, it should be stressed that some of the partitioned analyses restricted to skull morphology recover the clade Paenungulata and a clade corresponding to Afroinsectiphilia minus Macroscelidea  before the state number.There are several recurrent nodes that are shared among all resulting trees from our different analyses. We discuss these successively from the base to the higher part of the trees.Todralestes always has the basalmost position, as sister-group of all other taxa except the eutherian outgroup. It is indeed excluded from placentals, and should be considered as a stem eutherian as for the Zhelestidae Todralestes variabilis remains poorly known (45% of characters unknown in matrix), being documented only by cheek teeth.Protungulatum, and Arctocyonidae have a basal position in the trees that is not fixed relative to each other. However, the Zhelestidae is generally the most basal clade.Zhelestidae, Ocepeia has a basal position in the trees, outside the Paenungulata, “Altungulata” (lophodont ungulates) and “Taxeopoda”. It most frequently belongs to a basal afrotherian clade together with Potamogale, Ptolemaia, Orycteropus, corresponding to the molecular-based clade Afroinsectiphilia minus Macroscelidea, although in some case  it is a more derived branch . Relationships with Afroinsectiphilia afrotherians result from the analysis of the whole matrix and from partitioned analysis restricted to dental features, which indicates that the phylogenetic signal is mostly dental. Bremer support for this node (Afroinsectiphilia and Ocepeia) is rather low. Within Afroinsectiphilia, Ocepeia joins preferentially Potamogale , and Ptolemaia groups with Orycteropus in many of our analyses , that is well supported by 3 exclusive synapomorphies , agrees with the conclusions of Simons & Gingerich Teilhardimys, Macroscelidea, )). This node is supported by 3 exclusive synapomorphies of which the most noticeable are the upper molars with lingual root enlarged and bearing a sulcus, and with developed interloph. Upper molar with incipient lophodonty (89-1) appears at this node or at the next node ).In the higher part of the MPTs obtained in this work, the main clades are stable and robust; in nearly all trees, we recover the following clades:  changes in several trees. In the partitioned analysis restricted to skull features (The relative position of Radinskya) and Paenungulata, that corresponds to the taxon “Altungulata”. This is a very robust node in our analysis . Consequently, it would refute the monophyly of the clades Afrotheria and Laurasiatheria. It is supported especially by the lophodonty  and the enlarged M3 (*49-2). However, the latter feature implies unlikely reversal in Eritherium, and the lophodonty is most likely convergent in Perissodactyla and Paenungulata, as indicated by detailed structural traits (see below).We suggest, following Gheerbrant Phenacolophus, Minchenella, and anthracobunids. Phenacodonts are plesiomorphic with a low stem position and do not help to solve this question in the analysis. Only the partitioned analysis restricted to cranial features  and 9 homoplastic synapomorphies of which the best ones (RI>75) are lower molars with loph transverse (26-2) and with large lingual cusps (28-1), and amastoidy (161-1). The presence of a coronoid foramen, unknown in Ocepeia, was recently evidenced in macroscelideans Ocepeia, as well as the selenodont ectoloph (101-2).The node Paenungulata occurs in all our trees with identical taxonomic content. However, 1) Bremer supports are generally low, except in unordered analysis , the claThe clade Tethytheria is generally recovered at least for the crown groups Sirenia and Proboscidea, but the position of stem taxa such as Embrithopoda, Anthracobunia, Desmostylia is variable, and the Bremer supports are low. Tethytheria is not recovered only in partitioned analysis with step matrix restricted to dental features )) is very stable  and Minchenella (50% of its characters unknown in matrix) which are known only by dental specimens and are among the less known analysed taxa. Actually, it should be emphasized that even the described dental material of PhenacolophusEmbrithopoda. A clade (Hyopsodus and Ocepeia: the former joins the primitive afrotherian clade (afroinsectiphilians), and the latter is more derived as sister group of all other taxa that are characterized by incipient lophodonty. The implied weighting analysis does not change the topology. In this analysis, Ocepeia is by far the most autapomorphic with 6 exclusive autapomorphies and 35 homoplastic traits.Unordered analysis  illustrated our reference topology for our discussion of the relationships of Ocepeia. Ocepeia is the sister group of Potamogale, and both are sister group of the clade , corresponding to the clade Afroinsectiphilia (minus Macroscelidea). Analysis with standard “implied weighting” command provides a single tree that fixes relative position of Protungulatum and Arctocyonidae .Ordered analysis  except in the derived position of Orycteropus that clusters with Proboscidea, probably as the result of the optimization of many features  and Paenungulates (but including Zhelestidae). The position of Ocepeia is surprisingly not resolved in the partitioned ordered analysis restricted to the skull. Similar results are obtained with the TNT “implied weighting” command.The partitioned ordered analysis ; 2) skull features provide an unresolved basal polytomy . Other shared features  )). In these trees Ocepeia is noticeably less autapomophic . Within Paenungulata, Ocepeia has a nested derived position rather than a stem position; it clusters with Orycteropus, both as sister group of Hyracoidea (with good Bremer support). We reject this hypothesis of the derived position of Ocepeia within Paenungulata because it admits unlikely reversal of the hypocone that is typically absent in Ocepeia. This topology implies other noticeable reversals in Ocepeia. A stem position of Ocepeia to Paenungulata would be actually more parsimonious for several features at the node of crown Paenungulata .Constrained analysis for paenungulates relationships of ngulates , 7, 12. ures see , such asOcepeia in the exclusive context of the afrotherian relationships ; in this way we excluded from the analysis putative laurasiatherian ungulates such as Perissodactyla, Radinskya, Phenacodonta, and even Hyopsodus. In all obtained trees, Ocepeia keeps the same outgroup position with respect to Macroscelidea and Paenungulata, in the same clade with Potamogale and Orycteropus (Afroinsectiphilia). This is especially related to the absence of hypocone and lophodonty in Ocepeia.Finally, we analyzed the position of Our cladistic analysis confirms that Ocepeia daouiensis is plesiomorphic among placentals, as was indicated in previous studies of more limited material Ocepeia daouiensis are not optimized in the phylogenetic analysis that excludes it from African and Laurasian “ungulates” (including primitive taxa), but instead relates it to basal afrotherians.As a matter of fact, the several and noticeable ungulate-like features of Todralestes is a stem eutherian, several features indicate unequivocal relationships of Ocepeia with crown placentals. This is especially true of the inner ear morphology , as identified from the CT scan study.Whereas Ocepeia is its relationships with Afrotheria, and especially its basal position within Afrotheria. The primitive morphology of the skull of Ocepeia agrees with its basal position in Afrotheria, and also with the basal position of Afrotheria among placentals.The most striking result of the cladistic analysis of Potamogale, Ptolemaia and Orycteropus, i.e. the clade Afroinsectiphilia minus Macroscelidea, remains poorly supported morphologically. The single identified exclusive synapomorphy with afroinsectiphilian implies an unlikely character transformation in Ocepeia (120-1>3: rostrum very narrow to very wide). Six homoplastic synapomorphies  also support the node, most with low RI (40-60), and of which the best is the loss of P11 . Within basal afrotherians, the reduced postorbital process (148-1) is interpreted as an unambiguous synapomorphy of Ocepeia and Potamogale.However, the relationship with an exclusive clade of basal afrotherians such as Ocepeia with basal afrotherian taxa such as Potamogale is questionable in regard to its many remarkable ungulate-like features, for instance. We interpret the basal afrotherian placement of Ocepeia in our trees as a rather more general phylogenetic signal for its afrotherian relationships. However, our analysis does not recognize a monophyletic clade Afrotheria and, hence, any exclusive afrotherian synapomorphy in the Moroccan genus. This is related to the more general problem that the monophyly of the supercohort Afrotheria remains poorly characterized morphologically on the basis of available fossil and neontological morphological data  that remain unknown in extant and fossil insectivoran-like afrotherians (Afroinsectiphilia). Moreover, the synapomorphies that support in our cladistic analysis a relationship of Ocepeia to insectivoran-like afrotherians (Afroinsectiphilia) are weak (see above).The sister- or stem-group position of Ocepeia outside of the Paenungulata. Even the constrained analysis that clusters Ocepeia with paenungulates results in a hypothesis of nested paenungulate position that is refuted by unlikely implied characters transformations such as a secondary loss of the hypocone.Within Afrotheria, our cladistic analysis places Ocepeia described here evidences a combination of primitive eutherian features, placental traits and ungulate-like traits. The ungulate-grade traits include proto-ungulate-like and paenungulate-like features that are summarized in Ocepeia are the low and bunodont teeth , and the posteriorly projecting broad angular process of the dentary (62-1). The most remarkable paenungulate-like features of Ocepeia are dental traits such as especially the presence of an incipient entolophid . The ancestral condition of several of these traits remains poorly known in several paenungulate orders such as hyracoids , sirenians  and embrithopods .Whatever the cladistic results, the new material of ngulates , but notOcepeia in the trees . The shortest trees .e traits , which iOcepeia and Paenungulata conflict with the shared lophodonty of Paenungulata and Perissodactyla which is interpreted in our parsimony analyses as a synapomorphy for a questionable clade “Altungulata”, and which challenges the monophyly of Afrotheria in our trees. The morphotypic bunodont incipiently lophodont pattern of primitive proboscideans and paenungulates  is well distinct from the advanced lophodont pattern (89-2) of primitive perissodactyls, supporting the probable convergence of Laurasian and African ungulate-like mammals Ocepeia and paenungulates such as the selenodont ectoloph, that is unknown in primitive perissodactyls, this challenges such a clade “Altungulata”, and agrees with the alternative hypothesis of the relationships of Ocepeia and Paenungulata.In fact, the shared traits of Ocepeia best fit with its primitive stem position with respect to Paenungulata. The most noticeable plesiomorphic features that exclude Ocepeia from the crown group of extant paenungulate orders are the presence of paraconid, the absence of hypocone and related absence of bilophodonty, and the large canines. Crown paenungulates also depart by the M3 with two lingual roots (115-1), the molar trigonid compressed with reduced paracristid (29-1), presence of coronoid foramen (61-1), orbit more anterior  and possibly relatedly the tuber maxillae more posterior to orbit (143-1), and a more developed posttympanic process (158-1). Such hypothesis of a stem paenungulate position of Ocepeia would actually be more parsimonious for several features at the nodes of stem and crown Paenungulata.In this hypothesis, the proto-ungulate features of selenodont morphology of the molar ectoloph is a structural landmark of the monophyly of the paenungulates including stem taxa such as Ocepeia, i.e. as a key feature of their ancestral morphotype. The incipient entolophid is another, but more derived, significant shared derived trait. Together with the relationships of Ocepeia with basal afrotherians (afroinsectiphilians) obtained in the parsimony study, this would make it the first known fossil link between insectivore-like and ungulate-like afrotherians.In our view, the Teilhardimys and some primitive afrotherians such as early macroscelideans . The ordered analysis , and Orycteropus is consistently much more autapomorphic.Our cladistic analysis emphasizes the autapomorphic nature of analysis  records analysis . In thisOcepeia are the anthropoid-like traits of the skull face and dentition  is also remarkable; its adaptive significance remains unknown .The most remarkable specialized features of entition , 7, suchOcepeia, and the long evolutionary history of its lineage in Africa.These autapomorphic traits are evidences of the strong endemic nature of Ocepeia daouiensis that is reconstructed  at that time.The new material reported here from the Paleocene (Selandian) of the Ouled Abdoun Basin considerably enhances our knowledge of early afrotherians and African condylarth-like mammals. It enlightens the skull morphology of structed –13 and sOcepeia supports its placental and afrotherian relationship. However, it does not fix its ordinal and supra-ordinal position within Afrotheria. The most parsimonious trees (MPTs) support a relationship of Ocepeia with basal insectivore-like afrotherians , in contrast to its many paenungulate-like traits. These most parsimonious trees involve 1) noticeable parallelisms of Ocepeia and Paenungulata in their ungulate-like traits, 2) a mostly dental relationships of Paenungulata and laurasiatherian ungulates such as Perissodactyla. The Paenungulata - Perissodactyla sister group relationship ( = ”Altungulata”) recovered in our most parsimonious trees is considered here as the result of a convergence obscured by fossil gaps that make relationships of Ocepeia uncertain within Afrotheria. The shared derived features of Ocepeia and paenungulates are not optimized as exclusive synapomorphies because they conflict with undetected convergences, in our most parsimonious trees, of Paenungulata and Perissodactyla such as the bilophodonty. A recent study of the enamel microstructure of PhenacolophusThe cladistic analysis of Ocepeia are much more significant than the few and weak synapomorphies recovered in our MPTs with afroinsectiphilians. The selenodont pattern is one of the most remarkable shared derived features of Ocepeia and paenungulates. However, the skull and dentition of Ocepeia show a much more primitive construction with respect to extant paenungulate orders. This excludes unambiguously Ocepeia from the crown clade Paenungulata that departs for instance in the bilophodont molar pattern. Such a combination of primitive and derived features in Ocepeia actually best fits with its stem position to Paenungulata. The sister-group relationship of Ocepeia to Paenungulata needs however to be further and more formally established, hence our referral with a question mark.Within Afrotheria, the remarkable paenungulate-like features of Ocepeia actually shows a remarkable mosaic of autapomorphic, ungulate-like and plesiomorphic features. In particular, the combination of plesiomorphic eutherian-like and afrotherian-like skull features, and of proto-ungulate and paenungulate-like dental traits, makes Ocepeia the first and best known “transitional fossil” between insectivore-like and ungulate-like afrotherians The family Ocepeiidae is representative of a specialized endemic African lineage characterized by unexpected anthropoid-like features of the dentition and muzzle, and by other skull traits such as elongated meso- and postero-cranial region  and short frontal, and remarkably pneumatized bones . It indicates an old history in Africa, since the very beginning of the Tertiary or earlier. This supports the old endemic evolution of Afrotheria and placentals in Africa, in contrast to hypotheses supposing their origin from Paleogene Laurasian stem “condylarths” such as louisinids and apheliscids Figure S1Ocepeia daouiensis, skull MNHN.F PM45, 3D CT scan model of the original specimen (unretouched).(PDF)Click here for additional data file.Figure S2Ocepeia daouiensis, skull MNHN.F PM45, 3D CT scan model reconstruction. A. dorsal view. B.ventral view. C.lateral view. D. posterior view.(TIF)Click here for additional data file.Table S1Matrix of Ocepeia: Data completeness. We distinguish here absence of data (character marked by a question mark) from unapplicable characters (“-”  =  gaps in TNT); unapplicable characters correspond to features that cannot be homologized. Undocumented and unapplicable features are however processed similarly in TNT. The larger number of unapplicable traits occurs in Orycteropus that is the most specialized taxon compared in our cladistic analyses.(DOC)Click here for additional data file.Table S2Matrix of Ocepeia: 18 uninformative characters .(DOC)Click here for additional data file.Table S3Matrix of Ocepeia: Irreversible characters.(DOC)Click here for additional data file.Table S4Matrix of Ocepeia: Step matrices for 19 characters, all non additive; other transformations for these characters are coded unlikely with a cost of 10 steps instead of one step.(DOC)Click here for additional data file.Text S1Phylogenetic analysis of Ocepeia daouiensis. Part I: Studied characters of Ocepeia daouiensis. Part II: Characters matrix for analysis of Ocepeia daouiensis, characters summary list, taxa analyzed. Part III: TNT analysis, method, cladograms, and diagnose of nodes. Part IV: References.(PDF)Click here for additional data file.Video S1Ocepeia daouiensis, skull MNHN.F PM45, 3D CT scan model of the original specimen (unretouched).(AVI)Click here for additional data file.Video S2Ocepeia daouiensis, skull MNHN.F PM45, 3D CT scan model of the left petrosal. Red: fenestra vestibuli; blue: f. cochleae; green: cochleae canaliculus.(AVI)Click here for additional data file.


The aim of this study was to investigate the effects of thyroid hormone deficiencies in childhood on the elements of coagulation proteins. Consecutive 54 children with hypothyroidism and 55 healthy controls aged 1 month–16 years were enrolled. One year after Na-L-thyroxine treatment, the study parameters were reevaluated. Thyroid function tests, procoagulant and anticoagulant proteins were performed for children with hypothyroidism and healthy controls. Significant decreased results were found in children with hypothyroidism in terms of fibrinogen, TT, and anticoagulant proteins including AT, PC, PS, and fPS. Significant increases were found with respect to APTT, fibrinogen, and TT. In the evaluation of posttreatment changes a statistically significant increase was found in vWF, FVIII, AT, PC, PS, and fPS. A positive correlation was found between fT4 and vWF, FVIII, PC, and PS. We would like to emphasize that the coagulation system especially vWF and FVIII, and particularly the anticoagulant system, should be monitored closely in patients followed up for hypothyroidism. Thyroid hormones should be examined and, if necessary, hormone replacement therapy should be administered in patients followed up for a predisposition to coagulation. Additionally, further studies with larger series are needed to investigate the effects of hypothyroidism on the coagulation system. Previous studies have demonstrated the association between hypothyroidism and cardiovascular disease due to increased atherosclerosis and associated morbidity , 2. EvenThe aim of this study was to investigate the effects of thyroid hormone deficiencies in childhood on the elements of coagulation including procoagulant and anticoagulant proteins.  Consecutive 54 children with hypothyroidism aged 1 month–16 years who presented for the first time to our hospital between 2008 and 2009 and who were diagnosed with the disease were enrolled in the study. The control group consisted of 55 children of the same age who had no chronic diseases and who had presented to the pediatric outpatient clinic for growth, immunization, and development followup or counseling. Data recorded included the chronological age, anthropometric features, presence of concomitant diseases, and medication history of both the patient and control groups. None of the patients had any concomitant disease except for hypothyroidism. Neither the patients nor the controls were on drugs affecting the lipid metabolism and/or homeostasis.The diagnosis of primary hypothyroidism was established by a high serum TSH (>5 mIU/mL) concentration and a low serum-free T4 concentration according to age reference limits. Patients with a high serum TSH concentration and a normal serum free T4 concentration were diagnosed as having subclinical hypothyroidism. Central hypothyroidism was diagnosed by a low free serum T4 concentration and a serum TSH concentration that is not appropriately elevated. All of the patients had hypothyroidism. One year after Na-L-thyroxine treatment, the study parameters were reevaluated patients diagnosed with hypothyroidism. Thyroid function tests were performed . Prothrombin time (PT) international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen, thrombin time (TT), factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, and von Willebrand's factor (vWF), antithrombin (AT), protein C (PC), protein S (PS), free protein S (fPS), antiplasmin (AP), and plasminogen (PL) were investigated.For all tests, venous blood samples were collected from both the patient and control groups in the morning after a 12 hour fasting into vacutainer tubes. The coagulation tests were performed on the calibrated daily using kits each of which was compatible with the device. Statistical analysis of the data was performed using SPSS for Windows 11.5 software package. The distribution of continuous variables was tested for normality with the Shapiro and Wilk test.t-test whereas the significance of the median difference between the hypothyroid and control groups was assessed by the Mann-Whitney U test. Pearson's chi-square test was used to analyze categorical variables. The significance of the mean difference between the hypothyroid group and the control group was assessed using Student's t-test or the Wilcoxon Signed-Rank test was used to assess the presence or absence of a statistically significant change between baseline and final measurements of the patients in the case group. The Dependent P < 0.25 in the univariate analyses were entered in the multivariate regression model and were considered candidate variables. Multivariate linear regression analysis was performed to determine whether the most significant clinical variables identified by the gradual regression analysis maintained their significant effects on the changes of thyroid hormones after adjustment for diagnosis, age, sex, and body mass index SDS values. The regression coefficient and 95% confidence interval were calculated for each variable. As thyroid hormones did not show normal distribution logarithmically converted data were used in the regression analyses. A P value of <0.05 was considered statistically significant. Spearman's correlation test was used to determine the relationship between continuous variables. Multivariate Linear Regression analysis was used to identify the clinical variables most associated with the changes of thyroid hormones. Variables with  The study was conducted on 54 children with hypothyroidism and 55 healthy children. There was no difference between the patient and control groups regarding demographic characteristics such as age, sex, height, weight, body mass index (BMI), height standard deviation score (SDS), weight SDS, and BMI SDS . The comparison of basal thyroid function tests between the patient and control groups showed significantly higher TSH in children with hypothyroidism; however, TT4 and fT4 were found to be low .P < 0.001), whereas TT4 and fT4 levels were found to be significantly increased   . At the diagnosis, unlike healthy control group, significant decreased results were found in children with hypothyroidism in terms of fibrinogen, TT, and anticoagulant proteins including AT, PC, PS, and fPS . However, significant improvement was found with respect to APTT, fibrinogen, and TT in children with hypothyroidism . ConsistP = 0.026 and r = 0.21; P = 0.01 and r = 0.25; P < 0.001 and r = 0.43; P = 0.012, and r = 0.24). Multivariate linear analyses showed a negative correlation between TSH and AT , whereas there was a positive correlation between fT4 and AT . Spearman's correlation test was used to determine the relationship between thyroid function tests and the study variables. A positive correlation was found between fT4 and vWF, FVIII, PC, and PS ( Thyroid hormones affect all systems and metabolic events in the body in different ways. The effects of hypothyroidism on the coagulation system are still controversial. Although various studies have reported a hypercoagulable state, some other studies have found a hypocoagulable state in hypothyroid patients . Previou Most of the data concerning the effects of hypothyroidism on the coagulation system are based on previous studies, particularly on adult patients with severe hypothyroidism , 6–8. In There is a limited number of studies in the literature that examine the coagulation system in children with hypothyroidism. However, to the best of our knowledge, there is only one study evaluating coagulation tests in children . In this Thus, our study is important for examining in detail the coagulation system in these patients. Significant decreased results were found in children with hypothyroidism in terms of fibrinogen, TT, FVIII, and vWF. In the evaluation of post-treatment changes in a statistically significant increase was found in fibrinogen, TT, vWF, and FVIII. Close relationship between thyroid function tests and the study variables were found. A positive correlation was found between fT4 and vWF, FVIII. It has been known that decreases in the activity of anticoagulants AT, PC, PS, and fPS may lead to thromboembolic events. These proteins have also been evaluated within the scope of the relationship between hypothyroidism and hemostasis in previous studies. In a study of 20 hypothyroid patients, Erem et al. . In anot In conclusion, we would like to emphasize that the coagulation system especially vWF and FVIII, and particularly the anticoagulant system, should be monitored closely in patients followed up for hypothyroidism. Thyroid hormones should be examined and, if necessary, hormone replacement therapy should be administered in patients followed up for a predisposition to coagulation. Additionally, further studies with larger series are needed to investigate the effects of hypothyroidism on the coagulation system.


We report the case history of a 75-year-old woman with Parkinson's disease who developed severe cognitive problems after deep brain stimulation (DBS) of the bilateral subthalamic nuclei (STN). After a brief cognitive improvement, the patient gradually deteriorated until she developed full-blown dementia. We discuss the case with respect to the cognitive effects of STN DBS and the possible risk factors of dementia after STN DBS surgery. Parkinson's disease (PD) is a degenerative disorder. Clinical heterogeneity, progressive motor pattern changes, and variations in the course of the disease are well known , 2. The  Although there is no causal treatment for PD, deep brain stimulation (DBS) of the bilateral subthalamic nuclei (STN) has been shown to be surgically safe in well-selected candidates, and subsequent improvements in dopaminergic drug-sensitive symptoms and reductions in drug doses and dyskinesias are well documented. However, the procedure is associated with adverse effects, mainly neurocognitive and neuropsychiatric, and with side effects created by the spread of stimulation to surrounding structures, depending on the precise location of electrodes –9. The mA 61-year-old woman was diagnosed with PD in 1991. She had no family history of PD and she had not been chronically treated for any other medical condition. She worked as a high school teacher until the age of 65. The first symptoms of PD included hyposmia, fatigue, and tremor and rigidity of the left lower extremity (LLE). She was first put on selegiline. In 1994, she started L-dopa treatment, which had an excellent effect on the motor symptoms of PD. In 1995, while the daily dose of L-dopa was 500 mg, the first choreodystonic peak-dose dyskinesias appeared on the LLE. After that, different therapies were prescribed as add-on treatments to the L-dopa, including dopamine agonists , amantadine, and entacapone. These therapies had transient effects in the alleviation of both the motor symptoms of PD and the motor complications.  In 2005, the patient was on a stable antiparkinsonian medication therapy consisting of ropinirole 5 mg tid and L-dopa plus entacapone in alternating doses of 100 mg and 50 mg in six 3-hour intervals starting at 7 am . At that time, the patient suffered either from generalised tremor and rigidity accompanied by severe pain of the whole body or from severe choreodystonic involuntary movements. She stopped leaving her house and was unable to take full care of herself. We examined the patient using the Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT-PD) . At thatx, y, z) were 11.5 mm anteriorly, 3 mm posteriorly, 5 mm caudally from AC-PC midpoint. The position of the electrode was confirmed by postoperative CT scan and X-ray with a stereotactic frame still mounted.Bilateral STN electrodes were implanted in December 2005. The stereotactic procedure was performed using the Leibinger open frame with the Praezis Plus software and the Talairach diagram. We used the standard tungsten microelectrode 291A  with an impedance of 0.5–1.5 MΩ for the intraoperative microrecording and microstimulation. Once the target coordinates were determined, a permanent quadripolar DBS electrode  was implanted. The electrode position was verified by the intraoperative use of fluoroscopy to compare the position of the trajectories of the microrecording electrodes with the definitive trajectory of the quadripolar macroelectrode . The fin No complications were observed at the time of surgery; the patient remained conscious, alert, and cooperative during all stages of the procedure. Nevertheless, on the day after the electrode implantation, a transient somnolence, disorientation in time and space, and retrograde amnesia occurred. This acute confusion regressed within 4 days. The electrode cables were internalized, and a neurostimulation device  was implanted. The patient was released from the hospital. She was rehospitalized one month later in order to start the stimulation. In January 2006, a neuropsychological examination was performed with the stimulation off while the patient was on stable dopaminergic medication. It revealed a moderately intense organic psychosyndrome and a marked dysexecutive syndrome with a major impact on other cognitive functions and instrumental activities of daily living. It manifested symptomatically by decreased psychomotor speed, flexibility, spontaneity, and concentration, as well as attention deficits and disinhibition see . μsec pulse width. The stimulated contacts were 2 and 6, respectively. The patient's motor symptoms of PD and motor complications improved significantly. The Unified Parkinson's Rating Scale  III sub Mild cognitive impairment, with the predominant involvement of the frontal lobes, was reported during neuropsychological testing in June 2006 see , affecti During the summer of 2006, the patient's medical condition again started to gradually deteriorate, with episodes of freezing of gait and postural instability, visual hallucinations, and delusions. The behavioural disturbances were worse in the morning. The patient experienced no tremor. Sometimes she had very mild dyskinesias on the left side, but no motor fluctuations were present. She left the house and got lost repeatedly, and she became partially dependent on the caregiver (her husband). Quetiapine was started at that time with a dose titration up to 75 mg per day; this was later exchanged for clozapine in low doses (50 mg per day). All other medications except L-dopa (550 mg/day) and citalopram (20 mg/day) were withdrawn. Cognitive testing in March 2007 confirmed the cognitive decline, with a Mattis Dementia Rating Scale score of 116 points and an IQ score measured at 90. In addition to dysexecutive syndrome, memory functions, and praxis, visuoconstructive, visuospatial, and other cognitive functions were impaired, including writing and picture drawing.μsec. The MMSE was 14. The patient suffered from hallucinations, delusions, and postural instability with occasional falls. She had severe aphasia and dysarthria with telegraphic slurred speech and moderately severe motor and ideomotor apraxia. She became incontinent, and fully dependent on her husband. She died in April 2010. The probable cause of death was pneumonia. No brain biopsy was performed. In 2008, full-blown dementia was reported, which progressed over time. Memantin (20 mg per day) was introduced, but no visible effect on slowing the dementia course was detected. In December 2008, a marked overall brain atrophy was depicted in brain MRI, including both hippocampi. White matter hyperintensities along the electrode trajectories (possible gliosis) were also visible see . In 2009Our patient suffered from intracranial bleeding as a consequence of the STN electrode implantation. Intracerebral hemorrhages (ICHs) have been known to occur as possible adverse effects of DBS surgery in 1 to 4% of cases, according to literature reports of case studies, large studies, and meta-analyses , 16–21.  Interestingly, our patient partially recovered, but approximately 8 months after the surgery she again started to deteriorate cognitively until full-blown dementia developed within 2.5 years after the DBS surgery. Although the vast literature on cognitive short-term as well as long-term outcomes after bilateral DBS surgery of the STN varies and remains rather controversial, mild to moderate decreases in verbal fluency have been reported as the most common after-effects of the procedure (e.g., –9, 27–32 Conversely, development of dementia has been generally related to the PD progression itself –32. Acco The time from onset of PD to dementia varies considerably , 37. The Another interesting issue that has to be taken into consideration relates to possible gliosis along the electrode trajectories. It has been shown by others  that DBS Finally, we indeed cannot exclude a possibility that the ICH as an adverse event of the STN implantation might not only have caused an acute cognitive and behavioural impairment after the procedure but might also have accelerated the development of dementia in our patient, probably as a result of collapsed brain reserve and disturbed compensatory mechanisms caused by the electrode implantation and IHC. Age was probably the major contributor and risk factor for the intracranial bleeding, postoperative confusion, and later dementia development , 40, 41. Despite many unresolved questions, this has taught us not to include PD patients above 70 years of age for the DBS surgery. In addition, the length of PD duration should also be taken into consideration, and the question remains as to what the best time for considering DBS in PD would be. Further research should focus on potential biological markers such as specific brain imaging techniques and cerebrospinal fluid examination that would better predict the disease prognosis and that might help to better select good candidates for DBS surgery in PD patients.