[Fundamental Changes in the Treatment of Lung Cancer]. / Klimawandel in der thorakalen Onkologie.

In recent years, the diagnosis and medical treatment of lung cancer patients has been changed profoundly. Still being a deadly disease for most patients, new developments in treatment approaches and therapy selection lead to significantly extended duration of disease control and overall survival. This development is evident not only in medical issues but also comprises various political and organisational aspects. These aspects will be briefly characterised and discussed in the following.

[Updated Recommendation for Treatment of Metastatic Non-Small Cell Lung Cancer]. / Aktualisierte Therapieempfehlung metastasiertes nicht kleinzelliges Lungenkarzinom.

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decisionmaking. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.

[Rebiopsy for Patients with Lung Cancer - Joint Opinion from both the Endoscopic and Thoracic Oncology Sections of the German Society of Pneumology (DGP)]. / Empfehlung der Sektionen 2 und 11 der DGP zur Rebiopsie bei Lungenkarzinomen.

Performing rebiopsies for primary lung cancer and/or their metastases is becoming more and more prominent in daily practice, as the therapeutical spectrum increases and some newer strategies are dependent on immunohistochemical and/or molecular factors. In general, nearly all recurrent lesions or metastases can be reached. However, frequently invasive procedures are necessary with the need to carefully weigh risks and benefits of rebiopsies for the patient in each case. In this review indications for recurrent and progressive disease as well as risks are discussed and alternatives to rebiopsies are shown. This work is the joint opinion from both the endoscopic and thoracic oncology sections of the German Society of Pneumology (DGP).

[Therapy of Metastatic Non-small Cell Lung Cancer]. / Therapieempfehlung für das metastasierte nicht-kleinzellige Lungenkarzinom.

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study.

BACKGROUND: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. PATIENTS AND METHODS: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. RESULTS: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). CONCLUSION: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb.

Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.

The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.

Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload.

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30 mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20 mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6 mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69 years who were treated with DFX for a median duration of 354 days. Mean daily dose of DFX was 19 mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447 ng/mL and decreased to 1,685 ng/mL (reduction by 31 %) at end of study (p = 0.01). In 7 (13 %) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8 mg/g dry tissue weight (± 8.3 mg/g dry tissue weight) at study entry to 10,8 mg/g dry tissue weight (± 10.4 mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52 %) did not complete the 12 month study period most commonly due to AEs in 28 % (n = 15) and abnormal laboratory values in 7 % (n = 4), respectively. The most common adverse events (≥ 10 % of all patients) with suspected drug relationship were diarrhea (n = 25, 46 %), nausea (n = 13, 24 %), upper abdominal pain (n = 8, 15 %), serum creatinine increase (n = 16, 30 %) and rash (n = 5, 9 %). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61 %). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11 %). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.

[Tapentadol prolonged release for severe chronic pain. Results of a non-interventional study involving general practitioners and internists]. / Tapentadol retard bei starken chronischen Schmerzen. Ergebnisse einer nicht-interventionellen Studie bei Allgemeinmedizinern und Internisten.

STUDY OBJECTIVE: This prospective, non-interventional study involving general practitioners and internists in Germany investigated the administration of tapentadol prolonged release (Palexia retard) for the treatment of severe chronic pain in routineclinical practice over a 3-month observation period. METHODS: Collected data included tapentadol PR dosage, previous and concomitant analgesic treatment, pain intensity, sleep and quality of life parameters, and tolerability of tapentadol PR. Effectiveness was analyzed for 3134 patients; additionally, a subgroup analysis was performed in 1331 patients with WHO III pretreatment. RESULTS: A total of 97.8% of all patients received analgesic long-term pretreatment, 42.5% of those strong opioids. Switching to tapentadol PR resulted in a mean pain reduction of 3.9 points from 7.0 +/- 1.5 at baseline to 3.1 +/- 1.8 at end of observation (NRS-11, 11-point pain scale; descriptive p value < or = 0.001); 72.1% of patients experienced a clinically relevant pain relief of > or = 50% at end of observation. A total of 89.4% of the patients attained either their intended pain reduction and/or an additional individual treatment goal at end of observation; both were established at start of tapentadol PR treatment. This was accompanied by a significant decrease in pain-related impairments of daily activities and an improvement in quality of life (descriptive p value < or = 0.001) with an overall good tolerability of tapentadol PR. In particular, good effectiveness of tapentadol PR treatment was reported for various pain indications in patients who had already previously been treated with strong opioids. A clinically relevant pain reduction > or = 50% was achieved in 67.2% of these patients. CONCLUSIONS: Tapentadol PR can be considered an alternative therapy to classical opioids for the treatment of severe chronic pain. Particularly for severe chronic pain requiring long-term medication, a reduction of common opioid side-effects with tapentadol PR therapy could contribute to better patient compliance.

Isolation and basic characterization of a beta-glucosidase from a strain of Lactobacillus brevis isolated from a malolactic starter culture.

AIMS: To study glycosidase activities of a Lactobacillus brevis strain and to isolate an intracellular beta-glucosidase from this strain. METHODS AND RESULTS: Lactic acid bacteria (LAB) isolated from a commercially available starter culture preparation for malolactic fermentation were tested for beta-glycosidase activities. A strain of Lact. brevis showing high intracellular beta-D-glucosidase, beta-D-xylosidase and alpha-L-arabinosidase activities was selected for purification and characterization of its beta-glucosidase. The pure glucosidase from Lact. brevis has also side activities of xylosidase, arabinosidase and cellobiosidase. It is a homotetramer of 330 kDa and has an isoelectric point at pH 3.5. The K(m) for p-nitrophenyl-beta-D-glucopyranoside and p-nitrophenyl-beta-D-xylopyranoside is 0.22 and 1.14 mmol l(-1), respectively. The beta-glucosidase activity was strongly inhibited by gluconic acid delta-lactone, partially by glucose and gluconate, but not by fructose. Ethanol and methanol were found to increase the activity up to twofold. The free enzyme was stable at pH 7.0 (t(1/2) = 50 day) but not at pH 4.0 (t(1/2) = 4 days). CONCLUSIONS: The beta-glucosidase from Lact. brevis is widely different to that characterized from Lactobacillus casei (Coulon et al. 1998) and Lactobacillus plantarum (Sestelo et al. 2004). The high tolerance to fructose and ethanol, the low inhibitory effect of glucose on the enzyme activity and the good long-term stability could be of great interest for the release of aroma compounds during winemaking. SIGNIFICANCE AND IMPACT OF THE STUDY: Although the release of aroma compounds by LAB has been demonstrated by several authors, little information exists on the responsible enzymes. This study contains the first characterization of an intracellular beta-glucosidase isolated from a wine-related strain of Lact. brevis.

[The impact of viruses in lower respiratory tract infections of the adult. Part II: acute bronchitis, acute exacerbated COPD, pneumonia, and influenza]. / Die Rolle von Viren bei tiefen Atemwegsinfektionen des Erwachsenen. Teil 2: Akute Bronchitis, exazerbierte COPD, Pneumonie und Influenza.

In industrialized countries respiratory tract infections are one of the most common reasons for medical consultations. It is assumed that almost one third of these infections affect the lower respiratory tract (LRTI), e. g. acute bronchitis, acute exacerbation of chronic obstructive pulmonary disease (COPD), community- or hospital-acquired pneumonia and influenza. Due to a lack of sufficient and valid investigations on the epidemiology of respiratory viruses, their impact on the pathogenesis of LRTI has probably been underestimated for a long time. Therefore, there might have been many cases of needless antibiotic treatment, particularly in cases of acute bronchitis or acute exacerbations of COPD, because of an assumed bacteriological aetiology. Following the introduction of diagnostic procedures with increased sensitivity, such as polymerase chain reaction, it is possible to reliably detect respiratory viruses and to illuminate their role in the pathogenesis of LRTI of the adult. We have reviewed the current literature to elucidate the role of viruses in the pathogenesis of LRTI. The first part of this series described frequent viral pathogens, pathogenesis of viral LRTI, and diagnostic procedures. In this 2 (nd) part the aetiological role of viruses in the most frequent forms of LRTI will be highlighted, and the third and last part will provide an overview of therapeutic and preventive options.

[The impact of viruses in lower respiratory tract infections of the adult. Part III: therapy and prevention]. / Die Rolle von Viren bei tiefen Atemwegsinfektionen des Erwachsenen. Teil 3: Therapie und Prävention.

In industrialized countries respiratory tract infections are one of the most common reasons for medical consultations. It is assumed that almost one third of these infections include the lower respiratory tract (LRTI), e. g. acute bronchitis, acute exacerbation of chronic obstructive pulmonary disease (COPD), community- or hospital-acquired pneumonia and influenza. Due to a lack of sufficient and valid investigations to prove the presence of respiratory viruses their impact in the pathogenesis of lower respiratory tract infection has probably been underestimated for a long time. Therefore, there might have been many cases of unnecessary antibiotic treatment, especially in cases of acute bronchitis or acute exacerbations of COPD, because of an assumed bacteriological cause. With the introduction of more sensitive investigational procedures, such as polymerase chain reaction, it is possible to sufficiently prove respiratory viruses and therefore illuminate their role in the pathogenesis of lower respiratory tract infections of the adult. We have reviewed the current literature on the impact of viruses in lower respiratory tract infections to elucidate the role of viruses in the pathogenesis of lower respiratory tract infections. The preceding parts of this series provided an introduction to the frequently found viruses, pathogenesis, and diagnostic procedures (part I) as well as common viral infections of the lower respiratory tract (part II). The present 3 (rd) part deals with therapy for and prevention of viral LRTI.

Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome.

BACKGROUND: Williams syndrome (WS) and autism spectrum disorder (ASD) are neurodevelopmental disorders that demonstrate overlapping genetic associations, dichotomous sociobehavioral phenotypes, and dichotomous pathological differences in neuronal distribution in key social brain areas, including the prefrontal cortex and the amygdala. The serotonergic system is critical to many processes underlying neurodevelopment and is additionally an important neuromodulator associated with behavioral variation. The amygdala is heavily innervated by serotonergic projections, suggesting that the serotonergic system is a significant mediator of neuronal activity. Disruptions to the serotonergic system, and atypical structure and function of the amygdala, are implicated in both WS and ASD. METHODS: We quantified the serotonergic axon density in the four major subdivisions of the amygdala in the postmortem brains of individuals diagnosed with ASD and WS and neurotypical (NT) brains. RESULTS: We found opposing directions of change in serotonergic innervation in the two disorders, with ASD displaying an increase in serotonergic axons compared to NT and WS displaying a decrease. Significant differences (p < 0.05) were observed between WS and ASD data sets across multiple amygdala nuclei. LIMITATIONS: This study is limited by the availability of human postmortem tissue. Small sample size is an unavoidable limitation of most postmortem human brain research and particularly postmortem research in rare disorders. CONCLUSIONS: Differential alterations to serotonergic innervation of the amygdala may contribute to differences in sociobehavioral phenotype in WS and ASD. These findings will inform future work identifying targets for future therapeutics in these and other disorders characterized by atypical social behavior.

Glycogen storage disease type II (Pompe disease)--influence of enzyme replacement therapy in adults.

BACKGROUND: Pompe disease (Glycogen storage disorder type II) is an inherited disease because of a lack or reduced activity of the enzyme alpha-1,4-glucosidase (acid maltase). Since 2006, an intravenous enzyme replacement therapy (ERT) with Myozyme (Genzyme Corporation, Cambridge, MA, USA) is available. METHODS: Four adult patients aged between 39 and 68 years received ERT over a period of 6 months. Clinical and functional parameters were registered longitudinally. RESULTS: In three patients, a considerable improvement of symptoms could be noticed, patients with pre-existing respiratory insufficiency seemed to profit most. In all patients, a continuous decrease of initially raised laboratory parameters (creatine kinase, lactic dehydrogenase, transaminases) was striking. CONCLUSIONS: Enzyme replacement therapy seems to be a long-term effective therapy in adult patients with Pompe disease. Whether all patients will profit from an improvement of symptoms or at least a stabilisation of the otherwise progressive disease is currently not definitively clear.

[The impact of viruses in lower respiratory tract infections of the adult. Part I: Pathogenesis, viruses, and diagnostics]. / Die Rolle von Viren bei tiefen Atemwegsinfektionen des Erwachsenen. Teil 1: Erreger, Pathogenese und Diagnostik.

In industrialised countries respiratory tract infections are one of the most common reasons for medical consultations. It is assumed that almost one third of these infections include the lower respiratory tract (LRTI), e. g. acute bronchitis, acute exacerbation of chronic obstructive pulmonary disease (COPD), community- or hospital-acquired pneumonia and influenza. Due to a lack of sufficient and valid investigations on the epidemiology of respiratory viruses, their impact on the pathogenesis of LRTI has probably been underestimated for a long time. Therefore, there might have been many cases of needless antibiotic treatment, particularly in cases of acute bronchitis or acute exacerbations of COPD, because of an assumed bacteriological aetiology. Following the introduction of diagnostic procedures with increased sensitivity, such as polymerase chain reaction, it is possible to reliably detect respiratory viruses and to illuminate their role in the pathogenesis of LRTI of the adult. We have reviewed the current literature to elucidate the role of viruses in the pathogenesis of LRTI. The first part of this series deals with the relevant pathogens, pathogenesis, and diagnostic procedures. In the subsequent 2 parts of this series a review will be given on the most common variants of viral LRTI (part II), and therapeutic and preventive options (part III).

Bilayer microfluidic chip for diffusion-controlled activation of yeast species.

A bilayer microfluidic chip is used, in which multiple laminar streams are generated to define local microenvironments. The bilayer architecture of the microchip separates cell handling and positioning from cell activation by soluble chemicals. Cell activation is diffusion controlled through a porous membrane. By employing time-lapse fluorescence microscopy, gene expression of the enhanced green fluorescent protein (eGFP) in Saccharomyces cerevisiae is studied under various conditions. We demonstrate that the yeast cells remain viable in the microchip for at least 17 h, and that gene expression can be initiated by the supply of the inducer galactose at a spatial precision of a few micrometers.

Evidence for direct projections from the basal nucleus of the amygdala to retrosplenial cortex in the Macaque monkey.

The role of the primate retrosplenial cortex (RSC) in memory processing and spatial navigation has been well established. Recently, processing emotionally salient information has been attributed to the RSC as well. Little anatomical data, however, exist linking the RSC with known emotional processing centers within the brain. The amygdala has been implicated as a substrate for modulating memory for emotionally salient events; yet no study to date has demonstrated that this area has a direct connection in the primate brain. With modern retrograde tracer injections into the RSC and adjacent cortical areas of the monkey (Macaca fascicularis), we demonstrate that there are efferent projections from the basal nucleus of the amygdala to the RSC and area 31. These projections offer anatomical data supporting the hypothesis that the RSC might receive emotionally salient input directly from the amygdala and suggest a role for the RSC as a node within a neural system potentially capable of integrating emotional information for use in memory or other cognitive processes.

Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism.

OBJECTIVE: To assess the efficacy and safety of a novel long-acting im testosterone undecanoate (TU) formulation in comparison with testosterone enanthate (TE). SUBJECTS AND METHODS: An open-label, randomized, prospective clinical trial in 40 hypogonadal men (baseline serum testosterone levels <5 nmol/l), randomly assigned to 250 mg TE/3 weeks (no.=20) or 1000 mg TU im every 6 to 9 weeks for 30 weeks (no.=20). Subsequently, 32/40 men continued the study for another 114 weeks, now receiving TU 1000 mg/12 weeks. RESULTS: TU and TE produced no statistically significant improvements in grip strength over the first 30 weeks, which only occurred after approximately 90 weeks when all subjects received TU. There were no changes in body mass index with TU and TE, neither in the follow-up period when all patients received TU. But ratios of waist to hip circumferences declined in the longer term. Total serum cholesterol, LDL cholesterol, and triglycerides declined over the first 30 weeks, while plasma HDL also declined. Plasma LDL decreased further under long-term TU therapy, while HDL then increased. Hemoglobin and hematocrit values significantly increased over the first 30 weeks in both treatment groups and then no further increase was observed. Levels did not exceed the upper limit of normal. In both treatment groups, serum prostate specific antigen levels rose slightly after 30 weeks, with no further increase over the first 12 months, remaining stable within the normal range. Plasma T before the following TU injection was above the lower limit of reference values. Four injections per year are adequate. CONCLUSIONS: Administration of TU every 12 weeks is at least as safe and efficacious for treatment of hypogonadal men as TE, with a substantially lower frequency of administration. Follow-up over 114 weeks, when all subjects received TU, showed an excellent profile of efficacy and safety.

[Scope and limitations of risk-adjusted evaluation of lethality in community-acquired pneumonia using data collected according to section 21 of the German Hospital Reimbursement Law (Krankenhaus-Entgeltgesetz, KHEntG)]. / Möglichkeiten und Grenzen der risikoadjustierten Bewertung der Letalität bei der ambulant erworbenen Pneumonie mithilfe der section 21-Daten des Krankenhaus-Entgeltgesetzes (KHEntG).

INTRODUCTION: Several institutions are currently evaluating whether it is possible to gather valid, risk-adjusted quality indicators from routine billing data according to section 21 of the German Hospital Reimbursement Law (Krankenhaus-Entgeltgesetz, KHEntG). It is hoped that this method will enable hospitals to obtain quality assurance data in an easy and timely fashion. MATERIALS AND METHODS: For analysis, section 21 data according to KHEntG, quality assurance forms, and patients' medical records of the University Medical Center Ulm were evaluated in comparison to state and federal benchmark data from 2006. RESULTS: With regard to the quality indicator "Lethality in community-acquired pneumonia", it is possible to identify those cases that need to be included in quality assurance analysis by using predefined diagnosis lists. Risk adjustment can likewise be done according to the requirements set forth by the Federal Quality Assurance Office (Bundesgeschäftsstelle Qualitätssicherung, BQS), using only those data routinely collected for billing purposes. The results obtained are comparable to state and federal benchmark data. In addition, the analysis shows that the S3 recommendation to measure breathing rate as part of pneumonia risk assessment is not sufficiently being practiced at the moment. CONCLUSIONS: Risk-adjusted quality indicators can be generated from routine billing data according to section 21 KHEntG. Taking the patients' medical records as a reference, these indicators can even be shown to be more valid than those generated from BQS quality assurance data at the University Medical Center Ulm.

Advances in nonhuman primate models of autism: Integrating neuroscience and behavior.

Given the prevalence and societal impact of autism spectrum disorders (ASD), there is an urgent need to develop innovative preventative strategies and treatments to reduce the alarming number of cases and improve core symptoms for afflicted individuals. Translational efforts between clinical and preclinical research are needed to (i) identify and evaluate putative causes of ASD, (ii) determine the underlying neurobiological mechanisms, (iii) develop and test novel therapeutic approaches and (iv) ultimately translate basic research into safe and effective clinical practices. However, modeling a uniquely human brain disorder, such as ASD, will require sophisticated animal models that capitalize on unique advantages of diverse species including drosophila, zebra fish, mice, rats, and ultimately, species more closely related to humans, such as the nonhuman primate. Here we discuss the unique contributions of the rhesus monkey (Macaca mulatta) model to ongoing efforts to understand the neurobiology of the disorder, focusing on the convergence of brain and behavior outcome measures that parallel features of human ASD.

Protracted dendritic growth in the typically developing human amygdala and increased spine density in young ASD brains.

The amygdala is a medial temporal lobe structure implicated in social and emotional regulation. In typical development (TD), the amygdala continues to increase volumetrically throughout childhood and into adulthood, while other brain structures are stable or decreasing in volume. In autism spectrum disorder (ASD), the amygdala undergoes rapid early growth, making it volumetrically larger in children with ASD compared to TD children. Here we explore: (a) if dendritic arborization in the amygdala follows the pattern of protracted growth in TD and early overgrowth in ASD and (b), if spine density in the amygdala in ASD cases differs from TD from youth to adulthood. The amygdala from 32 postmortem human brains (7-46 years of age) were stained using a Golgi-Kopsch impregnation. Ten principal neurons per case were selected in the lateral nucleus and traced using Neurolucida software in their entirety. We found that both ASD and TD individuals show a similar pattern of increasing dendritic length with age well into adulthood. However, spine density is (a) greater in young ASD cases compared to age-matched TD controls (<18 years old) and (b) decreases in the amygdala as people with ASD age into adulthood, a phenomenon not found in TD. Therefore, by adulthood, there is no observable difference in spine density in the amygdala between ASD and TD age-matched adults (≥18 years old). Our findings highlight the unique growth trajectory of the amygdala and suggest that spine density may contribute to aberrant development and function of the amygdala in children with ASD.