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T Beck

Publications and source records attributed to T Beck.

At least 37 records · Page 2Linked to original sources

Reduced 11beta-hydroxysteroid dehydrogenase activity in the remaining kidney following nephrectomy.

Intracellular access of steroids to gluco- and mineralocorticoid receptors is regulated by reduced 11beta-hydroxysteroid dehydrogenase (OHSD) 1 and 2. These enzymes convert active 11beta-OH-steroids into inactive 11-keto-steroids. The purpose of the present study was to establish whether the 11beta-OHSD1 and 11beta-OHSD2 are modulated in the remnant kidney 24 h or 14 days after uninephrectomy (UNX) in rats. Overall, 11beta-OHSD activity was analyzed by measuring the ratio of the exogenous 11beta-OH-steroid prednisolone to its 11-keto metabolite prednisone in vivo in kidney tissue using high performance liquid chromatography. To determine which isoenzyme accounts for the changed activity 24 h after UNX, the oxidation and reduction attributable to 11beta-OHSD1 and oxidation to 11beta-OHSD2 were analyzed in total renal extracts and in isolated glomeruli, proximal convoluted tubules (PCT), cortical ascending limbs, and cortical convoluted tubules (CCT). The messenger RNA content of 11beta-OHSD1 and 11beta-OHSD2 was measured by RT-PCR in renal tissues and single segments, using glyceraldehyde-3-phosphate-dehydrogenase as an internal standard. Protein amounts of 11beta-OHSD1 and 11beta-OHSD2 were assessed by Western blot. The prednisolone/prednisone ratio increased 24 h after UNX in 9 out of 10 animals (P < or = 0.0011), and was unchanged 14 days after UNX. 11Beta-OHSD1 oxidation (P < or = 0.032) and reduction activity (P < or = 0.002) declined 24 h after UNX in total extracts. 11Beta-OHSD1 oxidase activity was more than 3 times higher in PCT than in glomeruli, cortical ascending limbs, and CCT, and declined by 50% after UNX (P < or = 0.001). The reductase activity did not change following UNX in PCT. 11Beta-OHSD2 activity was 5-15 times higher in CCT than in the other segments, and decreased significantly after UNX (P < or = 0.008). UNX did not affect messenger RNA and protein levels of both enzymes in total renal extracts. In conclusion, 11beta-OHSD1 and 11beta-OHSD2 are predominantly expressed in PCT and CCT, respectively, and their corresponding oxidative activities decline after UNX. Thus, the access of 11beta-glucocorticosteroids to gluco- and mineralocorticoid receptors in the remaining kidney is facilitated after UNX.

11-beta-Hydroxysteroid Dehydrogenases↗

Moderate exercise during growth in prepubertal boys: changes in bone mass, size, volumetric density, and bone strength: a controlled prospective study.

Cross-sectional studies of elite athletes suggest that growth is an opportune time for exercise to increase areal bone mineral density (BMD). However, as the exercise undertaken by athletes is beyond the reach of most individuals, these studies provide little basis for making recommendations regarding the role of exercise in musculoskeletal health in the community. To determine whether moderate exercise increases bone mass, size, areal, and volumetric BMD, two socioeconomically equivalent schools were randomly allocated to be the source of an exercise group or controls. Twenty boys (mean age 10.4 years, range 8.4-11.8) allocated to 8 months of 30-minute sessions of weight-bearing physical education lessons three times weekly were compared with 20 controls matched for age, standing and sitting height, weight, and baseline areal BMD. Areal BMD, measured using dual-energy X-ray absorptiometry, increased in both groups at all sites, except at the head and arms. The increase in areal BMD in the exercise group was twice that in controls; lumbar spine (0.61 +/- 0.11 vs. 0.26 +/- 0.09%/month), legs (0.76 +/- 0.07 vs. 0.34 +/- 0.08%/month), and total body (0.32 +/- 0.04 vs. 0.17 +/- 0.06%/month) (all p < 0.05). In the exercise group, femoral midshaft cortical thickness increased by 0.97 +/- 0. 32%/month due to a 0.93 +/- 0.33%/month decrease in endocortical (medullary) diameter (both p < 0.05). There was no periosteal expansion so that volumetric BMD increased by 1.14 +/- 0.33%/month, (p < 0.05). Cortical thickness and volumetric BMD did not change in controls. Femoral midshaft section modulus increased by 2.34 +/- 2. 35 cm3 in the exercise group, and 3.04 +/- 1.14 cm3 in controls (p < 0.05). The growing skeleton is sensitive to exercise. Moderate and readily accessible weight-bearing exercise undertaken before puberty may increase femoral volumetric BMD by increasing cortical thickness. Although endocortical apposition may be a less effective means of increasing bone strength than periosteal apposition, both mechanisms will result in higher cortical thickness that is likely to offset bone fragility conferred by menopause-related and age-related endocortical bone resorption.

Age Determination by Skeleton↗

The yeast phosphatidylinositol kinase homolog TOR2 activates RHO1 and RHO2 via the exchange factor ROM2.

The Saccharomyces cerevisiae phosphatidylinositol kinase homolog TOR2 is required for organization of the actin cytoskeleton. Overexpression of RHO1 or RHO2, encoding Rho-like GTPases, or ROM2, encoding a GDP/GTP exchange factor for RHO1 and RHO2, suppresses a tor2 mutation. Deletion of SAC7, a gene originally identified as a suppressor of an actin mutation, also suppresses a tor2 mutation. SAC7 is a novel GTPase-activating protein for RHO1. ROM2 exchange activity is reduced in a tor2 mutant, and overexpression of ROM2 lacking its PH domain can no longer suppress a tor2 mutation. Thus, TOR2 signals to the actin cytoskeleton through a GTPase switch composed of RHO1, RHO2, ROM2, and SAC7. TOR2 activates this switch via ROM2, possibly via the ROM2 PH domain.

Cell Cycle Proteins↗

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE: To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS: A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS: Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION: The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

Acute Disease↗

Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice.

An 18-mer full-phosphorothioate oligonucleotide with sequence antisense to the first six codons of the open reading frame of bcl-2 (G3139) has shown efficacy against the DoHH2 lymphoma implanted in severe combined immunodeficient mice. This study evaluated the pharmacokinetics of 35S-labeled G3139 in female BALB/c mice after single i.v. bolus administration or s.c. infusion for 1 week. After 100 microg i.v. bolus (approximately 5 mg/kg), the radioactivity was rapidly distributed and eliminated, with low blood levels 6 hr after administration. Most of the initial plasma radioactivity was protein bound (98% at 5 min). Tissue to plasma ratios were 87 for kidney, 17 for liver, 5 for spleen, 2.5 for heart and lung and 3.5 for gut. High-performance liquid chromatographic determination of G3139 showed triexponential kinetics, with alpha, beta and gamma half-lives of 5 min, 37 min and 11 hr, respectively. After 106 microg/day s.c. infusion, plasma steady state was reached by day 3, when half of the radioactivity was protein bound and 66 to 86% of the radioactivity was associated with parent drug (0.9 microg/ml). The plasma half-life of elimination for G3139 was 22 hr. Tissue to plasma ratios were similar to those after i.v. bolus administration, but accumulation was observed in all organs including bone marrow, where the levels reached were in the cytotoxic range. G3139 was metabolized to at least three different products, all observed in plasma, liver and kidney. Two metabolites eluted before the parent compound and one after the parent compound. There was greater degradation in the liver 6 hr after i.v. administration than at 24 hr, 48 hr, 3 days and 7 days after s.c. administration. In the kidney, most radioactivity was G3139. All degradation products were found in the urine but only traces of parent drug were eliminated. After both routes of administration, most of the radioactivity was eliminated in the urine and to a lesser extent in the feces. Significantly more radioactivity was excreted in the urine after i.v. bolus, compared with s.c. infusion (33% on day 1 and 55% by day 3 for i.v. vs. 7.2% on day 1 and 12.9% by day 3 for s.c.). These data show that s.c. infusion resulted in less excretion and metabolism of the administered dose.

Animals↗

Proton dosimetry intercomparison.

BACKGROUND AND PURPOSE: Methods for determining absorbed dose in clinical proton beams are based on dosimetry protocols provided by the AAPM and the ECHED. Both groups recommend the use of air-filled ionization chambers calibrated in terms of exposure or air kerma in a 60Co beam when a calorimeter or Faraday cup dosimeter is not available. The set of input data used in the AAPM and the ECHED protocols, especially proton stopping powers and w-value is different. In order to verify inter-institutional uniformity of proton beam calibration, the AAPM and the ECHED recommend periodic dosimetry intercomparisons. In this paper we report the results of an international proton dosimetry intercomparison which was held at Loma Linda University Medical Center. The goal of the intercomparison was two-fold: first, to estimate the consistency of absorbed dose delivered to patients among the participating facilities, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration protocols. MATERIALS AND METHODS: Thirteen institutions participated in an international proton dosimetry intercomparison. The measurements were performed in a 15-cm square field at a depth of 10 cm in both an unmodulated beam (nominal accelerator energy of 250 MeV) and a 6-cm modulated beam (nominal accelerator energy of 155 MeV), and also in a circular field of diameter 2.6 cm at a depth of 1.14 cm in a beam with 2.4 cm modulation (nominal accelerator energy of 100 MeV). RESULTS: The results of the intercomparison have shown that using ionization chambers with 60Co calibration factors traceable to standard laboratories, and institution-specific conversion factors and dose protocols, the absorbed dose specified to the patient would fall within 3% of the mean value. A single measurement using an ionization chamber with a proton chamber factor determined with a Faraday cup calibration differed from the mean by 8%. CONCLUSION: The adoption of a single ionization chamber dosimetry protocol and uniform conversion factors will establish agreement on proton absorbed dose to approximately 1.5%, consistent with that which has been observed in high-energy photon and electron dosimetry.

Calibration↗

Efficacy of antibiotics alone for orthopaedic device related infections.

Treatment of orthopaedic device related infections with antibiotics alone generally has been thought to be inadequate. A rabbit model was used to compare the efficacy of 4 different antibiotic regimens for treating orthopaedic device related infection caused by slime producing Staphylococcus epidermidis. After bacterial inoculation of a hole drilled through the intercondylar notch, a stainless steel screw was placed into the femur. Two weeks later, rabbits were randomized to receive a 2-week course of antibiotics: (1) 9 rabbits received vancomycin alone; (2) 10 rabbits received minocycline alone; (3) 10 rabbits received vancomycin plus rifampin; and (4) 10 rabbits received minocycline plus rifampin. Quantitative bone cultures were performed, and antibiotic levels in serum, bone, and biofilm were determined. Despite high levels of vancomycin in biofilm, infection was never cured by vancomycin alone and was eradicated in only 20% of rabbits that received minocycline alone. The highest cure rate (90%) was achieved with the combination of vancomycin and rifampin, whereas the combination of minocycline and rifampin yielded a cure rate of 70%. These results encourage the clinical evaluation of the combination of vancomycin and rifampin in patients in whom infected orthopaedic device cannot be removed.

Animals↗

Functional cerebral activity during regeneration from entorhinal lesions in the rat.

The consequences of an unilateral electrolytic entorhinal lesion on the functional activity in all major anatomically defined brain regions were evaluated in the rat. The 14C-2 deoxyglucose method served as a tool to quantify alterations of local cerebral glucose utilization (LCGU) ipsilateral and contralateral to the lesion at 4 days, 2 weeks, or 3 months after stereotaxic surgery. Apart from a few minor increases in the contralateral hemisphere, the predominant pattern consisted of reductions in the range of 10-40% in the ipsilateral hemisphere. Ipsilaterally, in extrahippocampal areas, LCGU had regained control levels at 2 weeks postlesion in contrast to hippocampal regions, where reductions were more pronounced than in other brain areas and partially persisted for up to 3 months. Interestingly, the termination zones of entorhinal fibers in the dentate gyrus did not regain control levels within 3 months. We conclude from the data that functional recovery of denervated primary target areas does not occur within 3 months after entorhinal lesions and that altered functional activity may be found beyond the primary target areas predominantly during the acute recovery period after the lesion. The data suggest that sprouting fibers do not reestablish a fully functional neuronal network during the recovery period.

Animals↗

[HIV and pregnancy: risks of transmission and therapeutic possibilities].

In Europe, transmission of HIV-1 during pregnancy occurs in 14% of children born to HIV-infected women. Risk factors for transmission are (1) virus load measured by p-24 antigenemia and HIV RNA level, (2) low CD4+ lymphocyte counts (below 600/microliter, (3) placental membrane inflammation and (4) time interval between membrane rupture and delivery. Breast feeding and vaginal delivery increase the risk of transmission of HIV infection. Antiretroviral therapy with zidovudine (Retrovir) at a dose of 500 mg/day reduces the transmission of HIV infection by two thirds. No malformation of the newborn due to zidovudine has been reported so far, but the possibility of unknown long-term adverse effects on children exposed to zidovudine must be weighed against the benefit of a considerable decrease in HIV transmission. Pregnancy is not associated with a higher rate of progression to AIDS, and HIV infection has no adverse effect on the pregnancy outcome in asymptomatic women.

Anti-HIV Agents↗

[Intrafascial hysterectomy ("CISH" method; cervical intrafascial Semm hysterectomy)--can the risk of cervix stump carcinoma be calculated?].

The incidence of the carcinoma of the cervical stump is reported in the literature between 0.1-3%. The operative treatment as well as the radiation therapy is more difficult and complicated in relation to the cervical malignancy of an "intact" uterus. On the other hand the supracervical uterus-amputation offers advantages versus the classical hysterectomy. So many endoscopic experienced groups prefer this operative technique. SEMM performs an additional stanza of the cervix and corpus in order to remove the cervical adenocells. This procedure was simulated with the help of an in vitro model to answer the question of facultative adenocells in the remaining cervix. 41 uteri and the resected stanzas were histologically examined. Adenocells could be detected in 68.3 % of the cervical hulls. The transformation zone could be resected totally in all cases. Taking into account these results we can conclude, that the combination of the supracervical hysterectomy with a cervix-corpus-stanza could reduce the risk of a cervical stump-carcinoma. Because of remaining adenocells in the cervical hull, this special carcinoma-risk can't be excluded after an interval of at least 20-25 years.

Cell Transformation, Neoplastic↗

Activity of the DNA repair protein O6-methylguanine-DNA methyltransferase in human tumor and corresponding normal tissue.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a main determinant of resistance of cells towards the cytostatic effect of N-nitrosoureas. Here we report the activity of MGMT in different types of human tumors. Colorectal tumors showed the highest mean of MGMT activity (481 +/- 258 fmol/mg protein) followed by ovarian tumors (437 +/- 291 fmol/mg), breast (306 +/- 204 fmol/mg), testicular (299 +/- 179 fmol/mg), and brain tumors (55 +/- 44 fmol/mg). Only in breast and brain tumors were MGMT-deficient samples found, with a frequency of 3 and 5%, respectively. No significant difference in mean MGMT activity was observed between breast tumors of grading I, II, and III. For brain tumors there was a tendency of MGMT to decline with increasing grading. Breast and colorectal carcinomas were compared with the corresponding normal tissue obtained from the same patient. The data showed for 11 out of 12 pairs of breast tissue and for 13 out of 15 pairs of colorectal tissue that MGMT activity in the tumor was equal to or, more frequently, higher than the activity found in the corresponding normal tissue. Thus, it appears that in these groups of tumors, increase of MGMT activity during tumor formation and progression is the rule rather than the exception.

Brain Neoplasms↗

[Minimal invasive surgery--future prospects].

Future developments of MIS will strongly depend on economic conditions in the managed care system. There are clear indications for benign diseases but in malignant tumors well defined oncologic standards are mandatory to maintain.

Equipment Design↗

Chiral compounds as indicators of inherited metabolic disease. Simultaneous stereodifferentiation of lactic-, 2-hydroxyglutaric- and glyceric acid by enantioselective cGC.

Urinary organic acid analysis is a vital diagnostic tool in the investigation of patients with suspected inborn errors of metabolism. Recent descriptions of diseases producing abnormal chiral metabolites have provided the need for individual enantiomer analysis. In this paper the isolation and simultaneous stereodifferentiation of lactic, glyceric and 2-hydroxyglutaric acids using capillary gas chromatography on heptakis (2,3-di-O-methyl-6-O-tert.butyldimethylsilyl)-beta-cyclodextrin as the chiral stationary phase is described. The diagnostic potential of this method is demonstrated by the analysis of urine samples from two patients with D-2-hydroxyglutaric aciduria and a dog with D-glyceric aciduria. Due to the lack of specific clinical symptoms in these diseases, enantiomeric analysis is vital for diagnosis enabling prompt therapeutic intervention.

Animals↗

Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma.

In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short survival. These data prompted us to perform a clinical trial with a murine anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of this putatively deleterious factor in these patients. Ten MM patients with extramedullary involvement frequently were treated with anti-IL-6 MoAb. The MoAb was administered intravenously to 9 patients; 1 patient with malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of treatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tumor mass. However, none of the patients studied achieved remission or improved outcome as judged by standard clinical criteria. Of major interest, objective antiproliferative effects were associated with complete inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patients was associated with a higher IL-6 production and inability of the MoAb to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopenia and mild neutropenia. The generation of human antibodies to Fc fragment of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can suppress the proliferation of myeloma cells and underscore the biologic role of IL-6 for myeloma growth in vivo. Furthermore, suppression of CRP and worsening of neutropenia/thrombocytopenia both indicate that IL-6 is critically involved in acute-phase responses and granulopoiesis/thrombopoiesis.

Acute-Phase Reaction↗

Usefulness of immunohistochemical staining for p53 in the prognosis of breast carcinomas: correlations with established prognosis parameters and with the proliferation marker, MIB-1.

Mutations of the p53 gene often result in the overexpression of p53 protein. Previous studies have suggested that the function of p53 and its mutant protein forms may be linked with the disease course of patients with a breast carcinoma. In the present study, we tested 462 primary breast carcinomas for the presence of p53 antigen using immunohistochemical methods employing antibodies against the clone, DO-1. These tumors were also immunohistochemically stained using the monoclonal antibody, MIB-1, in order to demonstrate the presence of Ki67. Comparison of the presence of p53 with other prognostic parameters revealed highly significant negative correlations with estrogen- and progesterone-receptor status (P < 0.001 and P = 0.001, respectively) as well as positive correlations with both the presence of MIB-1 (P < 0.001) and the histological grading (P = 0.008). The presence of p53 was not correlated with tumor stage and node status. Evaluation of the findings for all 462 tumors as well as for node-positive and -negative subgroups revealed less favorable findings for overall survival and the disease-free period for both p53-positive tumors (for total group, overall survival, P = 0.0002, disease-free period, P = 0.02; for node-positive group, overall survival, P = 0.0004, disease-free period, P = 0.1045) and breast carcinomas with higher proportions of cell nuclei positive for MIB-1 (total, overall survival, P = 0.0026, disease-free period, P = 0.0022; node-positive, overall survival, P = 0.021, disease-free period, P = 0.0882). We were able to demonstrate that p53 expression in breast carcinomas means a significantly worse prognosis for grade II tumors (overall survival, P = 0.0002; disease-free period, P = 0.0116), for overall survival in the case of estrogen-receptor-positive tumors (P = 0.014), and for tumors showing increased proliferation activity (overall survival, P = 0.0477).

Antibodies, Monoclonal↗

[Hormone receptor determination in breast carcinoma tissue. Comparison of recent immunohistologic techniques with biochemical receptor testing].

For evaluation of the hormone receptor status in breast cancer tissues two methods are mainly used: immunohistochemical detection by monoclonal antibodies on frozen sections (ER-ICA, PgR-ICA) and the biochemical radioligand-binding assay (DCC) of fresh tissue. Using new antibodies makes it possible to evaluate the estrogen and progesterone receptor status in formalin-fixed and paraffin-embedded tissue. In the present retrospective study, tissues from 223 primary breast carcinomas or breast carcinoma recurrences were re-evaluated with the three methods mentioned above and the results were compared. We used antibody 1D5.26 reacting with the estrogen receptor and mPR1 specific for the progesterone receptor in paraffin-embedded tissue. The agreement of positive and negative cases between these two immunohistochemical procedures was 97.8% for the estrogen receptor and 85.7% for the progesterone receptor. Comparison of immunohistochemistry on paraffin-embedded tissue and biochemical evaluation showed an agreement of 74.7% for the estrogen receptor and 68.7% for the progesterone receptor. These results are comparable to the correspondence between ER-ICA and PgR-ICA and the DCC method. This study proves that the prognostically and therapeutically important hormone receptors can be reliably determined in formalin-fixed and paraffin-embedded tissues. These results are not only important for the evaluation of hormone receptors of a small breast carcinoma that is not found in the frozen section, but for the considerable difference in costs among the different methods.

Antibodies, Monoclonal↗

Local cerebral glucose utilization in perfusion-fixed rat brains.

Local cerebral glucose utilization (LCGU) was measured in 75 cortical areas and nuclei of adult, 3-4-month-old Wistar rats, using the [14C]2-deoxyglucose (2-DG) technique. Measurement of total brain radioactivity content was not significantly different in unfixed material compared to fixed brain tissue. Values of LCGU derived from fresh, unfixed material were compared with values obtained from rats fixed by perfusion 45 min after the [14C]2-DG bolus injection with phosphate-buffered 3.3% paraformaldehyde at room temperature. In the fixed material, the mean LCGU of all brain regions was significantly increased by about 25% compared with the unfixed specimen due to tissue shrinkage of 7.2% in the fixed brains. Shrinkage leading to a higher volume density of [14C]2-deoxyglucose-6-phosphate in brain tissue results in a higher grain density in the respective autoradiographs. The wash-out of blood-borne [14C]2-DG is negligible except for blood-rich structures like the pineal gland and the choroid plexus.

Animals↗