Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

Imitation strategies in subjects with schizophrenia: a behavioural approach.

Imitation is a basic human ability, present early in life. Previous studies on control subjects and callosotomized patients showed that imitation occurred mainly in mirror-mode in both groups (60% controls, 66% patients) when they imitate without instructions (free sessions). In contrast, when asked to use the same or opposite limb as the model (driven sessions), controls used anatomical mode (93%), callosotomized patients mainly mirror strategy (61%). It has been suggested that callosotomized subjects prefer the mirror mode because of an impaired capacity for mental rotation, likely due to the lack of the corpus callosum (CC). The present research investigated the imitation strategies used by schizophrenic patients, who also could present anomaly in the interhemispheric connections. Fifteen hospitalized patients with diagnosis of schizophrenia participated in the study. They were asked to imitate upper limb intransitive meaningful and meaningless gestures performed by a model in a video. The results were compared with those from 20 healthy individuals. In driven imitation, controls answered in anatomical mode (95% of the responses), versus 63% of patients' responses. In free imitation sessions the answers in anatomical mode decreased to 39% in control subjects and to 46% in schizophrenic patients. In both driven and free imitation, the differences between the two proportions, conditioned to Diagnosis, resulted significantly different. The present data, in line with previous studies on psychotic and neurological patients showing impairments on imitation, suggest that the neural circuitry leading patients to perform differently from controls likely relates with the functional efficiency of the CC.

Imitation Strategies in Callosotomized Patients.

Imitation is a human ability rooted in early life. It allows people to interact with each other by observing and reproducing simple and complex movements alike. Imitation can occur in at least two forms: the rst, de ned as anatomical, seems to be based primarily on the mental construct of the "body schema" because the imitating movement corresponds precisely to the imitated movement in bodily terms, but not in terms of spatial compatibility. For example, a right arm movement of a model is imitated with a right arm movement by a facing imitator in a spatially incompatible fashion. The other form, de ned as specular or mirror-mode, involves a spatially compatible matching between imitated and imitating movements, as when an imitator moves her right arm upon viewing a corresponding left arm movement of a facing model (Chiavarino et al., 2007). In a previous study, healthy subjects showed a slight (61%) preference for the specular mode when freely imitating meaningful and meaningless gestures, whereas they strongly preferred the anatomical mode (93%) when given an intentionally ambiguous instruction such as "use the same (or the opposite) limb as the model" (Pierpaoli et al., 2014). In the present investigation it has been shown that callosotomized patients tended to favour the mirror-mode in both the free (66%) and the instructed condition (61% responses in driven sessions) regardless instructions given by the experimenter. Moreover, present data suggest that the extent of the callosotomy may in uence the patient's performance.

[Nontuberculous mycobacteria]. / Atypische Mykobakterien.

Dermatologically relevant nontuberculous mycobacteria (NTM) include Mycobacterium marinum and Mycobacterium ulcerans and different rapidly growing mycobacteria (RGM). RGM are widely present in the environment and are facultative pathogenic. Diagnostic detection of nontuberculous mycobacteria is frequently challenging. Immune-competent individuals mostly develop localized infections. Immune-suppressed patients may present with severe and disseminated disease. In these cases, rapid initiation of medical treatment is important. Moreover, infections with the more aggressive Mycobacterium ulcerans should be treated early. Due to the risk for the development of inducible antibiotic resistance, antibiotic regimes for NTM infections typically require at least two drugs. Surgical treatment should also be considered. This article discusses clinical presentation, diagnostic workup, and in particular antibiotic treatment options for dermatologically relevant infections caused by NTM.

Two cases of lupus vulgaris in childhood and review of the clinical challenges.

BACKGROUND: Lupus vulgaris (LV) is the most common form of cutaneous tuberculosis (TB) in Europe, nevertheless the overall incidence is low. It constitutes about 1.5% of all extra-pulmonary cases worldwide. A slight raise in TB incidence rates among children was recently registered in Germany, which can be explained by the increased immigration. PATIENTS AND METHODS: We present 2 cases of immigrated children who were diagnosed with Lupus vulagris, both clinically and histopathologically. Although the symptoms and the duration of the skin lesions were very different, both patients had a non-healing skin ulceration.In our cases cultures of the skin biopsy were positive for Mycobacterium tuberculosis and the lesions showed marked improvement in response to antituberculous treatment. In the first patient, it took 6 years between occurrence of skin lesions and final diagnosis. The second patient had an extracutaneous focus, namely abdominal TB. CONCLUSION: We report our experience and emphasize on recent advances in the diagnosis and treatment of paediatric skin TB.

Anatomical or mirror mode imitation? A behavioral approach.

Imitation can occur in at least two forms: one, which can be defined as anatomical, is based primarily on the mental construct of the body schema and allows recognition of correspondences between own body anatomy and that of other individuals. The other form, defined as specular or mirror mode, is most probably based on the allocation of some form of attention to the same region of the environmental space both by model and imitator, and to the objects it contains. This study investigated the behavioral strategy of imitation in normal subjects, to assess whether they carried out task instructions using an anatomical or a mirror perspective. Twenty seven adults were asked to imitate intransitive meaningful and meaningless gestures shown by a model in video clips. Instructions about how to perform them were provided before each trial. Trials were free (intended to produce spontaneous imitation) or driven (intended to produce anatomical imitation); further driven trials were administered to verify participants' knowledge of bodily laterality and were used as control. Performances were interpreted as anatomical or mirror imitation, according to the observation of anatomical or spatial reference frames between stimulus and imitator. The results revealed that in spontaneous imitation the mirror mode was more frequent (61% of responses), in line with previous studies. The novel finding was the prevalence (93% of responses) of anatomical imitation in tasks involving detailed driven instructions.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Assessment of the application of an automated electronic milk analyzer for the enumeration of total bacteria in raw goat milk.

Automated electronic milk analyzers for rapid enumeration of total bacteria counts (TBC) are widely used for raw milk testing by many analytical laboratories worldwide. In Ontario, Canada, Bactoscan flow cytometry (BsnFC; Foss Electric, Hillerød, Denmark) is the official anchor method for TBC in raw cow milk. Penalties are levied at the BsnFC equivalent level of 50,000 cfu/mL, the standard plate count (SPC) regulatory limit. This study was conducted to assess the BsnFC for TBC in raw goat milk, to determine the mathematical relationship between the SPC and BsnFC methods, and to identify probable reasons for the difference in the SPC:BsnFC equivalents for goat and cow milks. Test procedures were conducted according to International Dairy Federation Bulletin guidelines. Approximately 115 farm bulk tank milk samples per month were tested for inhibitor residues, SPC, BsnFC, psychrotrophic bacteria count, composition (fat, protein, lactose, lactose and other solids, and freezing point), and somatic cell count from March 2009 to February 2010. Data analysis of the results for the samples tested indicated that the BsnFC method would be a good alternative to the SPC method, providing accurate and more precise results with a faster turnaround time. Although a linear regression model showed good correlation and prediction, tests for linearity indicated that the relationship was linear only beyond log 4.1 SPC. The logistic growth curve best modeled the relationship between the SPC and BsnFC for the entire sample population. The BsnFC equivalent to the SPC 50,000 cfu/mL regulatory limit was estimated to be 321,000 individual bacteria count (ibc)/mL. This estimate differs considerably from the BsnFC equivalent for cow milk (121,000 ibc/mL). Because of the low frequency of bulk tank milk pickups at goat farms, 78.5% of the samples had their oldest milking in the tank to be 6.5 to 9.0 d old when tested, compared with the cow milk samples, which had their oldest milking at 4 d old when tested. This may be one of the major factors contributing to the larger goat milk BsnFC equivalence. Correlations and interactions between various test results were also discussed to further understand differences between the 2 methods for goat and cow milks.

Cardiac myxoma: clinical presentation, surgical treatment and outcome.

PURPOSE: To analyse the clinical characteristics and patterns of cardiac myxomas and to evaluate the clinical course and surgical treatment results. METHODS: In this retrospective study we evaluated the clinical presentation, diagnostic methods and surgical treatment outcome in all patients (n=17) with cardiac myxoma treated at the Institute of Cardiovascular Diseases of Vojvodina between the 1.1.2006-31.1.2009. RESULTS: Patients with cardiac myxoma constituted 0.52% of all patients having had heart operations for different reasons. The average patient age was 56.59 years and 12 (70.88%) patients were female and 5 (29.12%) male. Left atrial myxomas were by far more frequent (16 patients, 94.11%) than right atrial myxomas (1 patient, 5.88%). The average time of symptom presence was around 12 months while 4 patients (23.53%) were asymptomatic. The most common symptom was dyspnoea (53%) and fatigue (41%). Total extirpation of tumor mass was achieved in all cases. The tumor size ranged from 1.7x1 cm to 9.5x3.3 cm (average of 2x2.86) and histological examination confirmed the diagnosis of cardiac myxoma in every instance. The 30-day mortality after surgical extirpation of atrial myxomas was 0%. CONCLUSION: Cardiac myxoma may mimic a huge variety of other cardiac diseases. Echocardiography plays an important role in diagnosing this disease. Because of relatively low risk, surgical treatment is recommended for most patients with excellent postoperative prognosis.

Seafloor litter from the continental shelf and canyons in French Mediterranean Water: Distribution, typologies and trends.

Seafloor litter has been studied both on the continental shelves (by trawling during 24 years) and in canyons (by ROV) of the French Mediterranean sea Water (FMW). On the continental shelf, mean densities range from 49.63 to 289.01 items/km2. The most abundant categories were plastic, glass/ceramics, metals and textiles. Trend analysis shows a significant increase in plastic quantities during the study period. Plastics accumulate at all depths, with heavier items being found in deeper areas, while the continental slope-break appears as a clean area. The spatial distribution of litter revealed the influence of geomorphologic factors, anthropic activities, shipping route, river inputs. All the canyons are affected by debris but coastal canyons (Ligurian Sea and Corsica) were more impacted than offshore canyons in the Gulf of Lion. The FMW appears to be highly polluted with regard to values found in other areas, but lower than those observed in the Eastern Mediterranean.

Further evidence for the topography and connectivity of the corpus callosum: an FMRI study of patients with partial callosal resection.

BACKGROUND AND PURPOSE: This functional MRI study was designed to describe activated fiber topography and trajectories in the corpus callosum (CC) of six patients carrying different degree of partial callosal resection. METHODS: Patients receiving gustatory, tactile, and visual stimulation according to a block-design protocol were scanned in a 1.5 Tesla magnet. Diffusion tensor imaging (DTI) data were also acquired to visualize spared interhemispheric fibers. RESULTS: Taste stimuli evoked bilateral activation of the primary gustatory area in all patients and foci in the anterior CC, when spared. Tactile stimuli to the hand evoked bilateral foci in the primary somatosensory area in patients with an intact posterior callosal body and only contralateral in the other patients. Callosal foci occurred in the CC body, if spared. In patients with an intact splenium central visual stimulation induced bilateral activation of the primary visual area as well as foci in the splenium itself. CONCLUSION: Present data show that interhemispheric fibers linking sensory areas crossed through the CC at the sites where the different sensory stimuli evoked activation foci, and that topography of callosal foci evoked by sensory stimulation in spared CC portions is consistent with that previously observed in subjects with intact CC.

Ipsilateral cortical connections of primary somatic sensory cortex in rats.

The organization of ipsilateral cortical connections of the rat primary somatic sensory area (SI) was analyzed following small injections of multiple fluorescent tracers in the same case, into two or three SI body representations identified electrophysiologically. Labeling patterns were studied in tangential cortical sections and in flattened reconstructions from coronal sections. The cytochrome oxidase staining in tangential sections served as a control for injection location and to position labeling patterns found within granular portion of SI. The results show that most connections made with SI are reciprocal. Their topographical organization show different degrees of precision in the different areas. Homotypical and heterotypical connections were defined, the latter being more evident within the granular portion of SI. The findings: (1) were consistent with subdividing rat SI into four distinct areas with each having its own pattern of connections, (2) revealed two topographically organized regions in parietal cortex lateral to SI called second somatosensory (SII) and parietal ventral (PV) areas, (3) confirmed a topographical pattern in motor cortex and suggested an organization for connections between SI and an agranular medial field, and (4) demonstrated three more regions in parietal cortex connected to SI: posterior to SI called parietal medial; lateral to PV called parietal rhinal; posterior to SII called parietal lateral. Differences were noted in the distinctions between and within the maps when label distributions were plotted separately from supra- and infragranular layers. These findings agree with previous parcellations of the rat SI (Chapin et al., '87: J. Comp Neurol 263:326-346), squirrel PV and SII (Krubitzer et al., '86: J. Comp Neurol 250:403-430), and the organization of rat corticospinal neurons in many of the same areas (Li et al., '90: Somat Motor Res 7:315-335).

Ipsilateral intracortical connections of physiologically defined cutaneous representations in areas 3b and 1 of macaque monkeys: projections in the vicinity of the central sulcus.

This study examined cortical connections of areas 3b and 1 in 17 macaque monkeys in reference to regional somatotopography. The fluorescent retrograde tracers Fast Blue and Diamidino Yellow and the anterograde tracer Rhodamine Dextran were injected into closely related cutaneously responsive sites in primary somatosensory cortex, e.g., adjacent digits. Supra- and infragranular layers in nearly all studied areas contained labeled pyramidal cells. Labeled infragranular cells predominated at the fringes of a distribution where cells labeled from different tracer injections in the same brain intermixed more. All topographical regions across area 1 have reciprocal connections with areas 4, 3a, 3b, 1, 2, and 5. Intrinsic connections within area 1 and between it and area 2 are greatest; those with area 3b are less. Intrinsic connections within area 3b exceed all other nearby projections from this area which reciprocally connects with areas 3a, 1 and 2. Connections appear topographically organized, including those with poorly mapped regions, like area 5. These connections link representations of neighboring skin and skip map regions that include disjoint dermatomal areas. Connections from adjacent digit representations overlap; however, double-labeled cells were not found. Distal and proximal digit zones mostly interconnect within an area. Intrinsic connections spread further in area 1 than in area 3b, thereby joining more disparate topographical zones than interareal connections, which project more homotopically. The domain over which the map in somatosensory cortical area I (SI) dynamically changes following intracortical microstimulation (Recanzone, Merzenich and Dinse, Cerebral Cortex 2:181-196, 1992) may depend on the range of intrinsic connections observed in this study. The extent of connections between cortical areas was less than expected and this challenges the hypothesis that these connections directly create receptive field enlargements.

Callosal projections from area SII to SI in monkeys: anatomical organization and comparison with association projections.

The present research was aimed at ascertaining in the macaque monkey the reciprocity of the heterotopical callosal connections between SI and SII, with particular regard to the connectivity of the hand representation, and at comparing the topographical and laminar pattern of these callosal connections with those of association connections entertained by these areas. Horseradish peroxidase (HRP) was unilaterally injected into area SI in five monkeys. The sites of HRP delivery included the trunk and the hand zones preliminarily identified by recording multi-unit responses to peripheral stimulation by means of microelectrodes. Anterograde and retrograde labelling was studied in SII of both sides. The results showed the complete reciprocity of the heterotopical callosal connections between SI and SII. In the latter area both callosal axon terminals and neurones were found, which were labelled from either the trunk or the hand zone of contralateral SI. Labelling of callosal axon terminals occurred mainly in layer IV and in the lowermost part of layer III. Labelled callosal neurones were mainly in the lower half of layer III, whereas few occurred in infragranular layers. Topographically, the distribution of callosal terminals and cell bodies duplicated the distribution of association terminals and cell bodies labelled in SII on the side ipsilateral to HRP injection. The laminar pattern of termination of association fibres from SI was similar to that of callosal fibres. However, the distribution of association-projecting neurones in SII showed a striking difference from that of callosal-projecting neurones. Unlike the latter neurones, which were mainly located in supragranular layers, association cell bodies overwhelmingly dwelt in layers V and VI and were less numerous in layers II and III. This laminar pattern of association SII-SI cells corresponds to the "feed-backward" model and fits the laminar pattern of their axon terminations (Friedman: Brain Res. 273: 147-151, '83). The association and callosal inputs and outputs of area SII are discussed in relation to the function of the forward and backward type of reciprocal connections entertained with SI in the ipsilateral hemisphere and to the function of SII in the interhemispheric exchange of somatosensory information.

Cortical areas within the lateral sulcus connected to cutaneous representations in areas 3b and 1: a revised interpretation of the second somatosensory area in macaque monkeys.

Cortical connections between various body representations in areas 3b and 1 and lateral parietal cortex were examined in 18 macaque monkeys. We injected tracers (Fast Blue, Diamidino Yellow, Horseradish Peroxidase, and Rhodamine Dextran), alone or in combination, into closely related cutaneous responsive sites, e.g., adjacent digits. Separated patches of labeling were found across the parietal operculum and insula for all injected locations. On the basis of cytoarchitectural criteria, the labeled regions include the second somatosensory area (SII), retroinsular area (Ri) and granular insula (Ig). Assuming the connections are homotopical from physiologically identified body representations in primary somatosensory cortex, the labeling patterns in SII include complete anterior and posterior body maps. The orientation of the body is erect in the posterior and supine in the anterior SII region. Area 3b has greater density of connections with anterior SII. The maps are mirror images aligned along the distal extremities. The anterior-posterior (A-P) length of the "SII region" exceeds 7 mm; it extends in the coronal plane from the fundus of the lateral sulcus to surface cortex near the anterior tip of the intraparietal sulcus. Two additional topographically organized maps are likely in Ri. These are "worm-like" body maps oriented along the A-P axis and joined at the head representation. Connections with the center of Ig are not somatotopically organized. The diversity of somatosensory areas in lateral parietal cortex revealed by the labeled connections was discussed in reference to prior mapping of SII in monkeys and was compared to reports of multiple areas in this region of cortex in other species.

D-[3H]aspartate retrograde labelling of callosal and association neurones of somatosensory areas I and II of cats.

Experiments were carried out on cats to ascertain whether corticocortical neurones of somatosensory areas I (SI) and II (SII) could be labelled by retrograde axonal transport of D-[3H]aspartate (D-[3H]Asp). This tritiated enantiomer of the amino acid aspartate is (1) taken up selectively by axon terminals of neurones releasing aspartate and/or glutamate as excitatory neurotransmitter, (2) retrogradely transported and accumulated in perikarya, (3) not metabolized, and (4) visualized by autoradiography. A solution of D-[3H]Asp was injected in eight cats in the trunk and forelimb zones of SI (two cats) or in the forelimb zone of SII (six cats). In order to compare the labelling patterns obtained with D-[3H]Asp with those resulting after injection of a nonselective neuronal tracer, horseradish peroxidase (HRP) was delivered mixed with the radioactive tracer in seven of the eight cats. Furthermore, six additional animals received HRP injections in SI (three cats; trunk and forelimb zones) or SII (three cats; forelimb zone). D-[3H]Asp retrograde labelling of perikarya was absent from the ipsilateral thalamus of all cats injected with the radioactive tracer but a dense terminal plexus of anterogradely labelled corticothalamic fibres from SI and SII was observed, overlapping the distribution area of thalamocortical neurones retrogradely labelled with HRP from the same areas. D-[3H]Asp-labelled neurones were present in ipsilateral SII (SII-SI association neurones) in cats injected in SI. In these animals a bundle of radioactive fibres was observed in the rostral portion of the corpus callosum entering the contralateral hemisphere. There, neurones retrogradely labelled with silver grains were present in SI (SI-SI callosal neurones). Association and callosal neurones labelled from SI showed a topographical distribution similar to that of neurones retrogradely labelled with HRP. The laminar patterns of corticocortical neurones labelled with D-[3H]Asp or with HRP were also similar, with one exception. In the inner half of layer II, SII-SI association neurones and SI-SI callosal neurones labelled with the radioactive marker were much less numerous than those labelled with HRP. In cats injected in SII, D-[3H]Asp retrogradely labelled cells were present in ipsilateral SI (SI-SII association neurones). Their topographical and laminar distribution overlapped that of neurones labelled with HRP but, as in cats injected in SI, association neurones labelled with silver grains were unusually rare in the inner layer III.(ABSTRACT TRUNCATED AT 400 WORDS)