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Tension pneumomediastinum is a rare complication of interstitial pneumonia. This case shows computed tomography findings of the Macklin effect, in which air dissection along the bronchovascular interstitium caused by alveolar rupture leads to pneumomediastinum.

Key Clinical Message We report the case of a 25-year-old woman with a pulmonary artery sling who was misdiagnosed as having childhood-onset refractory asthma for approximately 20 years. The use of computed tomography may be useful for diagnosing this rare condition.

Pulmonary arterial hypertension (PAH) secondary to pulmonary Langerhans cell histiocytosis (PLCH) is known to be a relatively common complication and is associated with a poor prognosis. However, the optimal therapeutic approach for these cases remains to be established. A 57-year-old man visited our hospital because of a progressive dry cough. A thoracic computed tomography examination showed a combination of diffuse thick-walled cysts and reticulonodular shadows that were predominant in bilateral upper lobes of the lungs. He was diagnosed as having PLCH based on the results of video-assisted thoracoscopic lung biopsies. During a 3-year clinical course, his condition deteriorated despite smoking cessation. A systemic evaluation demonstrated precapillary PAH caused by PLCH (PAH-PLCH), and treatment with tadalafil, a phosphodiesterase-5 inhibitor, was started. During a 50-month period of treatment with tadalafil, improvements in his dyspnea, 6-min walking distance, and hemodynamics were maintained without either overt hypoxemia or pulmonary edema. We considered that tadalafil therapy may be a useful option in the treatment of patients with PAH-PLCH.

Long-acting βWe examined if genes encoding CYSLTR1, CYSLTR2, PTGER2 or PTGER4 could explain differential responses to salmeterol versus montelukast using the participants of the J-Blossom study. This study included 76 patients with mild-to-moderate asthma. The difference in peak expiratory flow (PEF) (ΔPEF, l/min) after 16 weeks of treatment with salmeterol (ΔPEFsal) versus montelukast (ΔPEFmon) was associated with the genotypes at each of 4 genes. In addition, multivariate analyses were used to identify a gene-gene interaction between ADRB2 gene and each of these 4 genes.Although none of 4 genes were associated with ΔPEFsal-ΔPEFmon in the univariate analyses, multivariate analysis showed that PTGER4 gene, interacting with ADRB2 Gly16Arg, was associated with ΔPEFsal-ΔPEFmon (p=0.0032).Our findings suggested that the interactions between two genetic loci at ADRB2 and PTGER4 is important in determining the differential response to salmeterol versus montelukast in patients with chronic adult asthma.

The tremor rat is an autosomal recessive mutant exhibiting sterility with gonadal hypoplasia in both sexes. The causative mutation tremor (tm) is known as a genomic deletion spanning >200 kb in Chr 10q24. Spermatogenesis associated 22 (Spata22) has been shown to be a vertebrate-specific gene essential for the progression of meiosis through prophase I and completion of chromosome synapsis and meiotic recombination using a mouse repro42 mutant carrying an N-ethyl-N-nitrosourea (ENU)-induced nonsense mutation in Spata22. In this study, we show that Spata22 was identified as the gene responsible for the failure of gametogenesis to progress beyond meiosis I in tm homozygous rats by a transgenic rescue experiment. Meiosis was arrested during prophase I in the mutant testis. Precise mapping of the breakage point revealed that the deleted genomic region spanned approximately 240 kb and comprised at least 13 genes, including Spata22. Rat Spata22 was predominantly expressed in the testis, and its transcription increased with the first wave of spermatogenesis, as seen in the mouse ortholog. These results suggest that Spata22 may play an important role in meiotic prophase I in rats, as seen in mice, and that the tm homozygous rat may be useful for investigating the physiological function of Spata22, as an experimental system for clarifying the effect of a null mutation, and may be an animal model for studying the pathogenesis and treatment of infertility caused by impaired meiosis.

The cerebellar vermis defect (cvd) rat is a mutant characterized by a cerebellar vermis defect and fused cerebellar hemisphere. This mutant rat also exhibits heterotopic dysplastic cerebellum, especially in the cerebello-pontine junctional zone. We focused on the auditory system of the cvd rat. The homozygous cvd rats exhibited bilaterally indistinct ABR (auditory brainstem response) waves or prolongation of latency in each ABR component. The number of the spiral ganglion neurons in the Rosenthal's canal was apparently decreased in the homozygous rats. Present study indicates the homozygous cvd rats had auditory disorders concerned with cerebellar malformation.

Body-tremorous rats were found in a colony of WTC-tm rats and a new coisogenic mutant strain void of the tm mutation was established. Histological analysis revealed that these rat mutants had abnormal vacuoles in the red nucleus of the midbrain, the reticular formation in the brain stem, and the white matter of the cerebellum and spinal cord. Electron microscopic observation showed many irregular myelin-bound vacuoles and degenerated oligodendroglia. Genetic analysis indicated that the presence of the abnormal vacuoles in the central nervous system (CNS) is controlled by a recessive gene named "vacuole formation (vf)" on chromosome (Chr) 8, and that this gene is also involved in the appearance of body tremors. Comparative maps suggested that the mouse and human orthologs would be located on Chr 9 (43-48 cM) and Chr 6 (328-370 cR3000), respectively. Since similar mutations have not been mapped yet around these regions, the authors believe this novel rat mutation will allow the discovery of a new function of these particular genes that is involved in the development and maintenance of the CNS.

Fertility study of taltirelin hydrate, a thyrotropin releasing hormone analogue, was carried out in Wistar rats. Taltirelin hydrate was orally administrated at a dose of 0 (control), 0.15, 1.5, or 15 mg/kg. Male rats were given the drug from 63 days before mating to the day before autopsy (total of 121 days), and female rats were treated from 14 days before mating to day 7 of gestation. The females were sacrificed on day 21 of gestation and pregnancy outcome was determined. In the 15 mg/kg group, wet dog shaking behavior and hyperlocomotion were observed in males and females, and the food consumption was slightly decreased in male rats. These changes induced by taltirelin hydrate were not found in the 0.15 and 1.5 mg/kg groups. No adverse effects of taltirelin hydrate on reproductive function were detected in any groups. In the fetal examination, taltirelin hydrate had no teratogenic, lethal, or growth retardation effects in any groups. These results show that the no-toxic dose levels of taltirelin hydrate are 1.5 mg/kg for general toxicity in parent animals, and 15 mg/kg for reproductive function of parent animals and for development of their fetuses.

Scanning electron microscopic observation of the organ of Corti was conducted in kanamycin (KM)-treated beagle dogs, which were subjected to time lapse recording of auditory brainstem response (ABR). KM was administered subcutaneously 5 times per week to 4 beagle dogs at doses of 250 and 500mg/kg for 3-6 weeks (a total dose of 4, 750 to 7, 000 mg/kg). The animals were subjected to pathological examination when definite changes in ABR appeared. Severity of morphological changes were closely related with the degree of the ABR change and histopathological renal lesion. In the animals with slightly decreased amplitude of wave I of ABR also exhibited only a slight renal lesion. The organ of Corti, however, showed essentially a normal structure in these animals. In the animal manifesting moderate ABR change, renal lesion was moderate and the change of the hair cell in the organ of Corti was slight. The animal with such severe auditory disturbance as flattened ABR waveform showed a severe renal lesion and almost complete damages of the hair cells in the organ of Corti. In the present observation, the characteristics of KM-induced lesion in the organ of Corti in dogs are essentially the same with in other species. In addition, the examination of hearing ability could be done as an item during the course of routine long-term repeated dose study using dogs.

The aim of this study is to report how pregnancy alters hematology and clinical chemistry values in rats. Female and male Sprague-Dawley rats were mated; the day of copulation was designated as Day 0. Hematology and clinical chemistry measurements were conducted on Days 7, 14, 17 and 21 in pregnant rats. Measurements were also conducted in non-pregnant rats. Red blood cells (RBC), hemoglobin (Hb), hematocrit (Ht), total protein and albumin decreased on Days 7, 14, 17 and 21; sodium, chloride and glucose decreased on Days 14, 17 and 21; iron decreased on Days 17 and 21; hemoglobin content of reticulocytes (CHr), calcium, inorganic phosphorus and the albumin/globulin ratio decreased on Day 21; and total cholesterol, phospholipid and high-density lipoprotein cholesterol decreased on Day 14 in pregnant rats compared with non-pregnant rats. Reticulocyte increased on Days 7, 14 and 17; mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophil count and rate increased on Days 14, 17 and 21; platelets, fibrinogen, triglyceride and free fatty acid increased on Days 17 and 21; and activated partial thromboplastin time was prolonged on Days 17 and 21 in pregnant rats compared with non-pregnant rats. The decreased RBC, Hb, Ht, CHr and iron in pregnant rats indicated that they suffered from iron deficiency anemia. These data can be used as background information for effective evaluation in reproductive toxicology studies.

The spontaneously epileptic rat (SER), a mutant homozygous for both zitter and tremor genes, exhibits absence-like seizures and tonic convulsions without external stimulation from 7 to 8 weeks of age. Histopathological studies of the central nervous system revealed the following abnormalities. The 35-day-old SERs which exhibit body tremor, and which have never shown seizures, had marked vacuolation and hypomyelination in the brainstem and cerebellum. The vacuoles were produced by splitting of the myelin sheaths and swelling of the dendrites and were related to primary swelling of the astrocytes. The 2- to 3-month-old SERs with staggering gait and seizures showed focal axonal swelling ('torpedo') and advanced vacuolation in the granular cell layer of the cerebellum in addition to the abnormalities observed at 35 days of age. Degenerative neurons and spheroidal bodies were observed in the substantia nigra and ventral tegmental nucleus. These brain areas are known to be related to tonic convulsions in the several experimental models. The SER is believed to be a useful tool for the investigation of the relationship between the structure and function of the central nervous system in epilepsy. It is probable that the more severe changes in the cerebellum are responsible for the staggering gait.

As a part of the ILSI-HESI Alternative to Carcinogenicity Testing (ACT) program, we performed a 26-week carcinogenetic study of nonmutagenic drug, ampicillin (ABPC) in Tg-rasH2 mice. ABPC was given to Tg-rasH2 mice (0, 350, 1000, 3000 mg/kg, p.o.) and Non-Tg mice (0, 3000 mg/kg, p.o.) daily for 26 weeks. As a positive control, a single dose of MNU was administered once to Tg-rasH2 mice (75 mg/kg, i.p.). In this study, Tg-rasH2 mice did not demonstrate any increases in tumor development in response to ABPC. Thus, ABPC had no carcinogenicity in the 26-week carcinogenesis study in Tg-rasH2 mice or in a 2-year carcinogenesis study in B6C3F1 mice.

The rat zitter ( zi ) mutation induces hypomyelination and vacuolation in the central nervous system (CNS), which result in early-onset tremor and progressive flaccid paresis. By positional cloning, we found a marked decrease in Attractin ( Atrn ) mRNA in the brain of the zi / zi rat and identified zi as an 8-bp deletion at a splice donor site of Atrn. Atrn has been known to play multiple roles in regulating physiological processes that are involved in monocyte–T cell interaction, agouti -related hair pigmentation, and control of energy homeostasis. Rat Atrn gene encoded two isoforms, a secreted and a membrane form, as a result of alternative splicing. The zi mutation at the Atrn locus darkened coat color when introduced into agouti rats, as also described in mahogany ( mg ) mice, carrying the homozygous mutation at the Atrn locus. Transgenic rescue experiments showed that the membrane-type Atrn complemented both neurological alteration and abnormal pigmentation in zi / zi rats, but that the secreted-type Atrn complemented neither mutant phenotype. Furthermore, we discovered that mg mice exhibited hypomyelination and vacuolation in the CNS associated with body tremor. We conclude from these results that the membrane Atrn has a critical role in normal myelination in the CNS and would provide insights into the physiology of myelination as well as the etiology of myelin diseases.

Taltirelin tetrahydrate (TA-0910), novel thyrotropin-releasing hormone (TRH) analogue, was orally administered to dogs as dose levels 0.5, 5, and 50 mg/kg for 13 weeks and 0.15, 1.5 and 15 mg/kg for 52 weeks. Blood concentrations of test substance measured in 52-week study revealed that absorption of TA-0910 was with dose-dependent manner and not changed through the treatment period. These toxicokinetics suggested that there were no alterations on metabolism of TA-0910 with repeated treatment. The animals receiving 5 or 50 mg/kg showed decrease in body weight or suppression of body weight gain, and decrease in food intake (13-week study). As an abnormality in general conditions, vomiting and salivation (5 mg/kg or more, both in 13- and 52-week studies), increase in behavior as water intake (5 mg/kg or more, 13-week study), and hyperlocomotion (50 mg/kg) were observed. Elevating GPT values were noted temporally in the animals treated with 5 mg/kg or more (both in 13- and 52-week studies) without abnormal findings in histopathology. The thyroid weights were increased in treated animals receiving 5 or 50 mg/kg in 13-week study, but no histopathological changes were noted. Electron microscopy revealed dilatation of granular endoplasmic reticulums in follicular cells of thyroid from 50 mg/kg group in 13-week study. It was concluded that no-effect levels of 13- and 52-week studies were 0.5 mg/kg and 1.5 mg/kg, respectively.

Oncogenicity studies of taltirelin tetrahydrate (TA-0910), a new thyrotropin-releasing hormone (TRH) analogue, were carried out on CD-1 mice and CD rats. Groups of 60 male and 60 female CD-1 mice received TA-0910, by oral gavage, at dosages of 5, 15 or 50 mg/kg/day. Treatment continued for a minimum period of 104 weeks. Groups of 55 male and 55 female CD rats received TA-0910, by oral gavage, at dosages of 20, 60 or 200 mg/kg/day. Treatment continued for a minimum period of 90 or 94 weeks for males and females, respectively. Of the treatment-related behavioral changes noted, the majority were considered to be directly related to the known pharmacological activity of the test substance and, as such, to be of questionable direct toxicological significance. In mice, there was no evidence of a treatment-related effect on the incidence of neoplasms. In rats, slightly higher incidences of pituitary adenoma, in males given 60 or 200 mg/kg/day, and thyroid follicular adenoma, in females given 200 mg/kg/day, were noted. However, in neither case was statistical significance attained in pair-wise comparisons, and the incidences were within expectation from background data. There was no evidence of any oncogenic potential of TA-0910 in these studies.

Postnatal development of auditory brainstem response (ABR) in spontaneously epileptic rats (SER; zi/zi, tm/tm), a double mutant, their parent mutants, tremor rats (tm/tm) and zitter rats (zi/zi), and Kyo:Wistar rats (control), was studied by repeated ABR recordings from 2 to 13 weeks of age. In tremor rats and Kyo:Wistar rats at 2 weeks of age, ABR pattern was almost the same and 2 or 3 waves were identified. However, no further development in ABR was observed in tremor rats and prolongation of latency and lowering of amplitude were marked. Only wave I with prolonged latency and lowered amplitude was recognized in zitter rats, SER and SER-N (zitter phenotype without epilepsy; zi/zi, tm/+ or zi/zi, +/+). ABR pattern was almost the same from 2 to 13 weeks of age in them. Electrocochleography revealed delay of N1 latency of compound action potential in SER. Vacuolation was observed in the cochlear nuclei and the brainstem of tremor rats and SER from 3 weeks of age in histopathological examination. The organ of Corti and cochlear nerve of tremor rats and SER exhibited no remarkable histopathological findings. The deafness in SER and its parent mutants was considered to occur as a result of impairment of inner ear, cochlear nerve and brainstem as well.

Initially, morphological and endocrinological features of the thyroid gland are reviewed in view of the recent progress in thyroidology. The second part of this article deals with morphology and hormone measurement in the rat following drug-induced alteration in thyroid function. Single and short-term injection of hypothalamic thyrotropin-releasing hormone (TRH) resulted in an increase in serum TSH concentration but not in thyroid hormone concentration. Electron microscopic observation revealed that augmented TSH stimulation after administration of TRH, induced follicular exocytosis, followed by endocytosis. The increase in colloid droplet counts after TRH-treatment differed between follicles as well as between follicular cells in the same thyroid. Treatment with the antithyroid drug, propylthiouracil (PTU) caused a progressive decrease in serum thyroid hormone levels and an elevation of serum TSH. The earliest morphological changes in follicular cells after short-term administration of PTU were the appearance of subapical vesicles and colloid droplet formation in response to the elevated level of serum TSH. Conversely, prolongation of goitrogen-treatment led to the disappearance of exocytotic and endocytotic vesicles. Substained decrease of serum TSH after thyroxine (T4) treatment led to colloid and thyroglobulin (Tg) accumulation in the follicular lumen and to the disappearance of exocytotic and endocytotic vesicles. In the T4-treated rats hypothalamic stimulation (TRH injection) resulted in a rise in the serum level of TSH, accompanied by apparent colloid droplet formation in the follicular cells.

SD系ラット3例に自然発生した腎臓腫瘍の病理組織学的検索を行った. 腫瘍は管を形成する一層の上皮性細胞と, その周囲に塊状に増殖する未分化な芽種性細胞から成り, 主に膠原線維から成る間質で分画されていた. この組織構築から腫瘍は腎芽腫と判断された. また, これらの上皮性細胞と芽種性細胞には電顕的に本質的な差を認めず, 組織構築が後腎胚種質に類似することと合わせ, 本腫瘍は腎実質上皮性の腫瘍であると考えられた.

In a colony of Kyo: Wistar strain of rats, we found animals with curled whiskers and hair. These rats exhibited tremor when they moved. There were no sex differences in phenotype and behavior, and the affected animals of both sexes were sterile. Among pairs that produced at least one tremulous offspring, 21.8% of the females and 21.7% of the males were affected; these proportions suggest that the anomaly is caused by an autosomal recessive gene. When the presumed heterozygous males were crossed with WAG/Rij females, about half of their female F1 hybrids were heterozygous, and they produced 26.1% (43/165) of the affected offspring when backcrossed to the sires. Again these results suggested that the disorder is caused by an autosomal recessive gene. We tentatively designated the gene as tremor (tm). The main pathological changes were seen in the gonad and central nervous system. The gonads of both sexes were aplastic even in adult animals. Vacuole formation was seen widely in the central nervous system and sometimes exhibited a spongy appearance. After administration of alpha-methyl-p-tyrosine, the norepinephrine content of the cerebellum was high, indicating that some anomalies of catecholamine release were present. The mutation is being maintained by random mating of the littermates of affected animals. Detailed pathological, endocrinological, neuropharmacological, and genetical studies are proceeding.

Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the Atrnmg-3J allele are resistant to diet-induced obesity and also develop abnormal myelination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotropic effects, we further characterized the molecular abnormalities responsible for two additional Atrn alleles, Atrnmg and Atrnmg-L, and examined in parallel the phenotypes of homozygous and compound heterozygous animals. We find that the three alleles have similar effects on pigmentation and neurodegeneration, with a relative severity of Atrnmg-3J > Atrnmg > Atrnmg-L, which also corresponds to the effects of the three alleles on levels of normal Atrn mRNA. Animals homozygous for Atrnmg-3J or Atrnmg, but not Atrnmg-L, show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These results confirm that the mechanism responsible for the neuropathological alteration is a loss—rather than gain—of function, indicate that abnormal body weight in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.