Detectability of Neural Tracts and Nuclei in the Brainstem Utilizing 3DAC‐PROPELLER

Despite clinical importance of identifying exact anatomical location of neural tracts and nuclei in the brainstem, no neuroimaging studies have validated the detectability of these structures. The aim of this study was to assess the detectability of the structures using three‐dimensional anisotropy contrast‐periodically rotated overlapping parallel lines with enhanced reconstruction (3DAC‐PROPELLER) imaging. Forty healthy volunteers (21 males, 19 females; 19‐53 years, average 23.4 years) participated in this study. 3DAC‐PROPELLER axial images were obtained with a 3T‐MR system at four levels of the brainstem: the lower midbrain, upper and lower pons, and medulla oblongata. Three experts independently judged whether five tracts (corticospinal tract, medial lemniscus, medial longitudinal fasciculus, central tegmental and spinothalamic tracts) and 10 nuclei (oculomotor and trochlear nuclei, spinal trigeminal, abducens, facial, vestibular, hypoglossal, prepositus, and solitary nuclei, locus ceruleus, superior and inferior olives) on each side could be identified. In total, 240 assessments were made. The five tracts and eight nuclei were identified in all the corresponding assessments, whereas the locus ceruleus and superior olive could not be identified in 3 (1.3%) and 16 (6.7%) assessments, respectively. 3DAC‐PROPELLER seems extremely valuable imaging method for mapping out surgical strategies for brainstem lesions.     

Prediction of human pharmacokinetics for low‐clearance compounds using pharmacokinetic data from chimeric mice with humanized livers

Development of low‐clearance (CL) compounds that are slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CL_int) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro–in vivo extrapolation is widely used to predict human CL, its application has been limited for low‐CL_int compounds because of the low turnover of parent compounds in metabolic stability assays. To address this issue, we focused on chimeric mice with humanized livers (PXB‐mice), which have been increasingly reported to accurately predict human CL in recent years. The predictive accuracy for nine low‐CL_int compounds with no significant turnover in a human hepatocyte assay was investigated using PXB‐mouse methods, such as single‐species allometric scaling (PXB‐SSS) approach and a novel physiologically based scaling (PXB‐PBS) approach that assumes that the CL_int per hepatocyte is equal between humans and PXB‐mice. The percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 89% and 100%, respectively, for both PXB‐SSS and PXB‐PBS approaches. Moreover, the predicted CL was mostly consistent among the methods. Conversely, the percentages of compounds with predicted CL within 2‐ and 3‐fold ranges of the observed CL for low‐CL_int compounds were 50% and 63%, respectively, for multispecies allometric (MA) scaling. Overall, these PXB‐mouse methods were much more accurate than conventional MA scaling approaches, suggesting that PXB‐mice are useful tools for predicting the human CL of low‐CL_int compounds that are slowly metabolized.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

It is important to identify low‐clearance (CL) compounds that are slowly metabolized during the drug discovery process, but the ability of in vitro–in vivo extrapolation to predict human CL decreases as the value of intrinsic CL (CL_int) decreases. Although chimeric mice with humanized livers (PXB‐mice) have been reported to be useful for predicting human CL, their applicability to low‐CL_int compounds with no significant turnover in human hepatocyte assays has not been clarified.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study examined the predictive accuracy of PXB‐mouse methods for low‐CL_int compounds.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In addition to the previously reported single‐species allometric scaling approach, we proposed a novel physiologically based scaling approach. Both methods displayed much greater predictive accuracy for low‐CL_int compounds than conventional multispecies allometric scaling approaches.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The findings should improve the accuracy of human pharmacokinetic prediction and enable efficient and safe first‐in‐human studies.     

IDENTIFICATION OF A UNIVERSAL B CELL EPITOPE ON DNA TOPOISOMERASE I,AN AUTOANTIGEN ASSOCIATED WITH SCLERODERMA

Objective. To investigate the distribution of B cell autoepitopes of human DNA topoisomerase I (topo I), an autoantigen associated with scleroderma. Methods. A complementary DNA clone, T1B, was used to produce recombinant proteins of topo I as β-galactosidase fusion proteins. Immunoreactivity to these fusion proteins was then tested in 35 anti–topo I–positive sera from patients with scleroderma, by immunoblotting, enzyme-linked immunosorbent assay, and double immunodiffusion. Results. One epitope was found to be universally recognized by all sera tested. Thirty-two of the samples recognized multiple antigenic regions, but sera from the remaining 3 patients recognized only this universal epitope, and in longitudinal studies of 1 of these 3 patients, the serum recognized only this epitope for more than 2 years, even though multiple, potent, antigenic regions were found on topo I. Conclusion. Recognition of multiple epitopes in most patients suggests that the topo I molecule itself would drive the autoimmunity on topo I. However, antigen-driven autoimmunity could not explain the production of the monoreactive anti–topo I antibody seen in the 3 patients. We thus hypothesize that there is a process whereby recognition of the universal epitope by cross-reaction develops into antigen-driven autoimmunity.     

Gallbladder function and CCK after gastrectomy

Postgastrectomy cholelithiasis has become a problem and biliary tract dyskinesia has been cited as an etiologic factor. CCK is the most important gut hormone with respect to biliary tract function, so we conducted an experimental study of postgastrectomy gallbladder function and CCK levels which gave the following results: 1. Although postprandial gallbladder contraction for the most part occurred in response to endogenous CCK, another mechanism (the gastro-cholecystic reflex) seemed to be responsible for some of them. 2. The postgastrectomy decrease in postprandial gallbladder contraction appeared to be due to disappearance of this gastro-cholecystic reflex. 3. Gallbladder contraction occurred in association with postprandial CCK secretion following total gastrectomy and Roux-en-Y reconstruction, but the altered food passage route caused changes in the dynamics of CCK secretion, and this is believed to have had an influence on the gallbladder contractile response.     

Prognostic Significance of Immunohistochemically Detected Blood and Lymphatic Vessel Invasion in Colorectal Carcinoma: Its Impact on Prognosis

Background The prognostic significance of blood vessel invasion (BVI) and lymphatic vessel invasion (LVI) is unclear. Because of the absence of specific markers for venous and lymphatic vessels, earlier studies could not reliably distinguish between BVI and LVI. Methods By immunostaining for podoplanin and CD34 antigen, we retrospectively investigated LVI and BVI in 419 tissue specimens of colorectal carcinoma. We performed univariate and multivariate analysis of the clinicopathologic features, frequency of recurrence, and outcome of patients with or without LVI and BVI. Results The use of hematoxylin and eosin (H&E) staining to identify BVI and LVI yielded a false positive rate of 9.1% and false negative rate of 12.6%. The incidence of BVI was significantly higher among tumors with LVI than tumors without LVI (P <.001). In logistic multivariate analysis, only LVI (P < .001) was associated with lymph node metastasis and BVI (P = .015) was associated with distant recurrence. Calculating the prognostic relevance, both two invasion types correlated with decreased survival in univariate analysis (both P <.001). In multivariate analysis, BVI (P =.024), lymph node status (P =.003) and tumor stage (P <.001) remained statistically significant factors for survival. Conclusions Our results suggest that immunohistologic evaluation of BVI and LVI could be useful in colorectal carcinoma indicating the risk of lymph node metastasis and recurrence, thereby contributing to prognostic evaluation.     

Medical management of acute urolithiasis in one American academic emergency room

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To determine the implementation of medical expulsive therapy (MET) for ureterolithiasis in one tertiary‐care emergency room (ER); referral patterns in the surgical and metabolic follow‐up of ureterolithiasis were also assessed.

PATIENTS AND METHODS

In this retrospective review we identified 556 patients with ureterolithiasis in the ER at our centre between 2005 and 2007. Of these, 131 patients met inclusion criteria, including first‐time stone formers and no urological visit within the previous 5 years. ER records were reviewed and telephone interviews conducted to determine if MET was used, if the patient was referred to a urologist, if surgery was ultimately required, and if there was ultimately a metabolic evaluation.

RESULTS

The mean (range) stone size was 4.2 (2–10) mm. Ten patients were admitted directly from the ER and 121 were discharged home. Of the 121 discharged patients, 48 (40%) were prescribed MET. In all, 46 patients received tamsulosin 0.4 mg and two received doxazosin 2 mg; no patient was prescribed steroids. The mean size of passed stones was statistically significantly lower than that of stones that did not pass (P < 0.05). Patients prescribed MET had a 23% chance of needing surgery, vs 32% in those not prescribed MET (P < 0.05). Seventy‐one (61%) patients were followed up by a urologist, 27 (23%) by a primary‐care physician, and eight (7%) had no further follow‐up. Ultimately, 31 (23%) patients had a metabolic evaluation and it was abnormal in 29 (95%).

CONCLUSIONS

In this single‐institution ER experience, 40% of patients with symptomatic ureterolithiasis were treated with MET on discharge from the ER. Our data also show that only patients referred to a urologist received a metabolic evaluation. This is notable given that the vast majority of those evaluated were found to have a correctable abnormality.     

The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats

The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanol-amine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H₂-receptor. Portions of this work were presented at the 75th annual meeting of Japanese Society of Gastroenterology. March 1989 in Yokohama, Japan.