Consumption of a single serving of red raspberries per day reduces metabolic syndrome parameters in high-fat fed mice.

Using an animal model for diet-induced metabolic disease, we have shown previously that the addition of raspberry juice concentrate (RJC) and raspberry puree concentrate (RPC) at a level of 10% of kcal, equivalent to four servings per day, to an obesogenic high-fat, western-style diet (HF) significantly reduced body weight gain, serum resistin levels, and altered the expression of hepatic genes related to lipid metabolism and oxidative stress. This study was designed to examine the effect of a lower level of RJC or RPC consumption, at a level representing a single serving of food per day (2.5% of kcal). For ten weeks, four groups of C57BL/6J mice (n = 8 ea.) were fed: low fat (LF), HF, HF + RJC, or HF + RPC diets. Intake of RJC and RPC decreased final body weight. Hepatic lipid accumulation was significantly decreased in HF + RPC- and HF + RJC-fed mice, compared to HF-fed mice. Further, the relative expression of hepatic genes including Heme oxygenase 1 (Hmox1) and Hormone sensitive lipase (Lipe), were altered by RPC or RJC consumption. In this mouse model of diet-induced metabolic disease, consumption of the equivalent of a single daily serving of either RPC or RJC improved metabolism in mice fed HF diet. We hypothesize that the phytochemicals contained in raspberries, and/or their subsequent metabolites, may be acting to influence gene expression and other regulatory pathways, to produce the metabolic improvements observed in this study.

FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Micropenis and the AR Gene: mutation and CAG repeat-length analysis.

Various mutations of the AR gene and expanded CAG repeats at exon 1 of that gene have been reported in patients with hypospadias or genital ambiguity. However, the role of the AR gene has not been systemically studied in those with isolated micropenis lacking hypospadias or genital ambiguity. We studied 64 Japanese boys with isolated micropenis (age, 0-14 yr; median, 7 yr), whose stretched penile lengths were between -2.5 and -2.0 SD (borderline micropenis) in 31 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD (definite micropenis) in 33 patients (age, 0-14 yr; median, 6 yr). Mutation analysis of the AR gene was performed for exons 1-8 and their flanking introns, except for the CAG and GGC repeat regions at exon 1, by denaturing HPLC and direct sequencing, identifying a substitution of cytosine to thymine at a position -3 in the 3' splice site of intron 1 in a patient with definite micropenis. CAG repeat length at exon 1 was determined by electrophoresis with internal size markers and direct sequencing, revealing no statistically significant difference in the distribution of CAG repeat lengths [median (range) and mean +/- SE: total patients with isolated micropenis, 24 (14-34) and 23.5 +/- 0.38; patients with borderline micropenis, 24 (15-29) and 23.5 +/- 0.53; patients with definite micropenis, 23 (14-34) and 23.5 +/- 0.56; and 100 control males, 23 (16-32) and 23.5 +/- 0.29] or in the frequency of long CAG repeats (percentage of CAG repeats > or =26 and > or =28: total patients with isolated micropenis, 17.2 and 4.7%; patients with borderline micropenis, 19.4 and 6.5%; patients with definite micropenis, 15.2 and 3.0%; and 100 control males, 21.0 and 10.0%). These results suggest that an AR gene mutation is rare and that CAG repeat length is not expanded in children with isolated micropenis.

Evaluation of autonomic nervous system function with spectral analysis of heart rate variability in a case of tetanus.

The autonomic nervous system is affected in a wide variety of neurological disorders. Its dysfunction may play an important role in the clinical course and may result in serious complications, such as cardiac arrest. We report a case of tetanus who presented with severe autonomic nervous system dysfunction which was detected by spectral analysis of heart rate variability monitored over 24 h. This is a semi-quantitative method for evaluation of the status of the autonomic nervous system. In the present case, the analysis revealed profoundly decreased activity of both sympathetic and parasympathetic nervous system modulation of cardiac rhythm. The parasympathetic nervous system activity was more severely impaired than that of the sympathetic nervous system. The relative predominance of the sympathetic nervous system in the present case may have resulted in unopposed sympathetic nervous system hyperactivity manifested in this patient by tachycardia and excessive sweating. We further infer that the documented diminished buffering capacity of the autonomic nervous system may have lead to a sudden cardiac arrest in our case. Thus, spectral analysis of heart rate variability is a non-invasive and sensitive method for evaluating the status of the autonomic nervous system of critically ill patients in the hospital setting.

Regulation of cyclophosphamide-induced eosinophilia in contact sensitivity: functional roles of interleukin-5-producing CD4(+) lymphocytes.

Blood and tissue eosinophilia is obtained when mice pretreated with cyclophosphamide (CY) and sensitized with picryl chloride are challenged on each ear lobe on day 13. To gain important insights into the cellular mechanisms involved in CY-induced eosinophilia in the contact-sensitivity reaction, we examined the cytokine profile expressed in regional lymph node cells and spleen cells. CY pretreatment 2 days before sensitization enhanced expression of IL-4 mRNA in the regional lymph node cells more strongly than expressions of both IL-2 and IFN-gamma mRNA on day 13. Five days after sensitization, spleen cells expressed IL-5 mRNA and produced IL-5 in vitro. Depletion of CD4(+) cells from spleen cells completely abrogated the secretory capacity of IL-5. In vivo blocking of IL-5 on day 3 entirely inhibited spleen, bone marrow, and subsequent blood eosinophilia. When immune lymph node cells prepared on day 13 were stimulated with hapten-modified cells in vitro, the level of IL-4 secreted in the culture supernatant was enhanced by CY pretreatment, but that of IL-2 was not. One important result was that IL-5 was not produced in response to in vitro stimulation, despite the fact that marked eosinophil infiltration in the dermis was observed in vivo. Thus, eosinophilopoiesis was stimulated by IL-5-producing CD4(+) immune T cells that were present in the eosinophil production site, particularly in the spleen before elicitation. In contrast, eosinophil recruitment into the dermis in the efferent phase can be induced without production of IL-5 from lymphocytes.

Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH.

We report a 30-year-old female with adrenal unresponsiveness to ACTH. Her clinical features included no adrenal crisis despite poor drug compliance, poor pubic hair development (Tanner stage 2), well-developed breasts (Tanner stage 5), and regular menstrual cycles. Endocrinological data included blood ACTH 1500 pmol/l, cortisol 18 nmol/l, dehydroepiandrosterone sulphate below 0.26 micromol/l, activated renin 0.37 pmol/l, and aldosterone 3.4 nmol/l. Direct sequencing and allele-specific amplification revealed two novel mutations in the ACTH receptor gene. One was transition from guanine to adenine at nucleotide position 1002, resulting in substitution of aspartate for asparagine at codon 103, and the other was transition from cytosine to thymine at nucleotide 1104, leading to substitution of arginine for tryptophan at codon 137. The present findings lend additional credence to the notions that adrenal androgens play an important role in female pubic hair development and that ovarian development takes place independently of adrenarche.

Pyridoxine-induced photosensitivity and hypophosphatasia.

We describe a case of photosensitivity due to pyridoxine hydrochloride (vitamin B(6)) in a heterozygote of hypophosphatasia. Photopatch tests using pyridoxine hydrochloride and pyridoxal 5'-phosphate, compounds referred to as vitamin B(6), with ultraviolet light A irradiation were positive. Laboratory examination showed low serum alkaline phosphatase. Tissue-nonspecific alkaline phosphatase exon amplification from DNA of the patient's lymphocytes detected deletion 1154-1156 hypophosphatasia mutation, indicating that this patient was diagnosed to be a heterozygote of hypophosphatasia. The seric pyridoxal 5'-phosphate level of this patient with hypophosphatasia was higher than in normals. Furthermore, after oral administration of vitamin B(6) this level increased greatly and long-lastingly, and this might be related to the low level of alkaline phosphatase in this patient. Photosensitivity in this patient may have been caused by abnormal metabolism of vitamin B(6) under the hypophosphatic condition.

Treatment with a gonadotropin-releasing-hormone analog and attainment of full height potential in a male monozygotic twin with gonadotropin-releasing hormone-dependent precocious puberty.

UNLABELLED: We report on a pair of male monozygotic twins, one unaffected and the other affected with gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, and discuss the role of treatment with a GnRH analog in the attainment of full height potential in GnRH-dependent precocious puberty. At 1.6 years of age, the affected twin was studied for tall stature (+3.8 SD), and was diagnosed as having GnRH-dependent precocious puberty due to a hypothalamic hamartoma of the tuber cinereum. He was treated with oral cyproterone acetate (110-170 mg/m(2) daily) from 1.8 through 5. 0 years of age, with oral cyproterone acetate and intranasal buserelin acetate (700-900 microg/m(2) daily) from 5.0 through 7.5 years, and with intranasal buserelin acetate alone (1100- 1400 microg/m(2) daily) from 7.5 through 12.6 years. He attained a final height of 171.0 cm at 14.9 years of age (+0.10 SD) and his twin 170. 0 cm at 15.3 years of age (-0.10 SD), with their target height being 174.5 +/- 9.0 cm. CONCLUSION: This study indicates that GnRH analog treatment may preserve near full height potential in some patients with GnRH-dependent precocious puberty.

Confluent ecchymoses on the lower extremities of a malnourished patient.

Nutritional deficiencies result in many distinctive cutaneous manifestations. Vitamin C deficiency, or scurvy, produces follicular hyperkeratosis, perifollicular hemorrhages, gingival hypertrophy, and bleeding (1). We report here a case of malnutrition who suddenly developed extensive eccymoses on the lower extremities sharing morphological similarities with purpura fulminans. Although the patient did not have the characteristic dermatological features of scurvy, serum levels of vitamins C, K, B12, and E were decreased.

Phylogeny of Japanese papilionid butterflies inferred from nucleotide sequences of the mitochondrial ND5 gene.

Phylogenetic relationships among the Japanese papilionid butterflies were analyzed by comparing 783 nucleotide sequences of the mitochondrial gene encoding NADH dehydrogenase subunit 5 (ND5). Phylogenetic trees of the representative species from each family in the superfamily Papilionoidea revealed that the species of the family Papilionidae and those of all other families formed distinct clusters, with a few species of the family Hesperiidae (Hesperioidea) as an outgroup. In the phylogenetic trees of most Japanese species of the family Papilionidae with Nymphalis xanthomelas (Nymphalidae) as an outgroup, the tribe Parnassiini (Parnassiinae) formed a cluster, and the rest formed the other cluster in which the tribe Zerynthiini (Parnassiinae) and the subfamily Papilioninae formed different subclusters. In the Papilioninae cluster, the tribes Troidini and Graphiini formed a subcluster, and the tribe Papilionini formed the other subcluster. These results generally agree with the traditional classification of the papilionid butterflies based on their morphological characteristics and support the proposed evolutionary genealogy of the butterflies based on their morphology, behavior, and larval host plants, except that the tribes Parnasiini and Zerynthiini (both Parnassiinae) are not in the same cluster.

A spectrum of mutations induced by crotonaldehyde in shuttle vector plasmids propagated in human cells.

A spectrum of crotonaldehyde-induced mutations in the supF gene of the shuttle vector plasmid pMY189 replicated in human fibroblast cells was examined. Base sequence analysis of 104 plasmids with mutations in the supF gene revealed that the majority of the mutations were base substitutions (85%) and the rest were frameshifts (15%). A single base substitution was most frequently found (47%), while 25% had multiple base substitutions and interestingly 13% had tandem (adjacent two) base substitutions. Of the base substitution mutations, 50% were G:C-->T:A transversions and 23% were G:C-->A:T transitions. The mutations were not distributed randomly but were located at several hotspots, most of which were G:C base pairs in 5'-AAGG-3' (or 5'-CCTT-3') sequences. Production of propanodeoxyguanosine adducts may be related to such specificity in the mutation spectrum.

Pneumoperitoneum complicating mechanical ventilation in congenital myotonic dystrophy.

Pneumoperitoneum is known as a disease caused by perforation of the gastrointestinal tract, but it has also been reported as a complication of mechanical ventilation. In a case of congenital myotonic dystrophy (CMyD), mechanical ventilation was performed to treat severe respiratory distress starting at birth, and then pneumomediastinum and pneumoperitoneum developed as complications 5 days after birth. The fact that the pneumoperitoneum improved when the ventilation pressure was reduced and the patient's course was observed, allowed us to rule out gastrointestinal perforation. It appeared that hypoplasia of the diaphragm may have been involved in the progression of pneumomediastinum to pneumoperitoneum in this patient. Mechanical ventilation is performed on many occasions in CMyD, and the development of pneumoperitoneum secondary to pulmonary air leak should always be borne in mind.

Cyclophosphamide-induced blood and tissue eosinophilia in contact sensitivity: mechanism of hapten-induced eosinophil recruitment into the skin.

The mechanism leading to selective production and accumulation of eosinophils in certain allergic skin diseases is unknown. Cyclophosphamide treatment (150 mg/kg) of BALB/c mice 48 h before sensitization with picryl chloride (PCl) resulted in striking blood and tissue eosinophilia, maximal at 13 days. Blood eosinophilia was not induced by the sensitization with oxazolone and 2,4-dinitrofluorobenzene. Challenge with 1 % PCl, but not croton oil caused preferential eosinophil accumulation into the dermis, which was associated with the enhanced expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells. Intravenous administration of anti-VCAM-1 monoclonal antibody abrogated eosinophil infiltration. In this murine model, we examined the role of several cytokines, including chemokines in inducing selective tissue eosinophilia in vivo. Local administration of antibodies against interleukin (IL)-1beta, IL-4, tumor necrosis factor (TNF)-alpha, and RANTES, but not against IL-5 before challenge inhibited hapten-induced eosinophil recruitment. Intradermal injection of recombinant (r)IL-1beta, rIL-4, rTNF-alpha, rRANTES, and rMIP-1alpha induced marked eosinophil accumulation. Nonetheless, intradermal rIL-5 was not a chemoattractant for eosinophils in vivo. Our findings suggest that IL-1beta, IL-4, TNF-alpha, and RANTES contribute to the selective accumulation of eosinophils in contact sensitivity reaction. Although circulating IL-5 can activate eosinophils and prolong their survival, locally secreted IL-5 is not crucial for inducing eosinophil recruitment into the skin.

Three cases of linear lichen planus caused by dental metal compounds.

Three cases of linear lichen planus on the lower extremities unaccompanied by mucous lesions are described. Dental metal compounds were thought to be the precipitating factor in all cases. Skin lesions did not respond to topical steroid ointment or antihistamines. Two cases showed a positive patch test reaction to gold (HAuCl4) and a positive lymphocyte stimulation test to gold compound (Gold sodium thiomalate). One case showed a positive patch test reaction to mercury (HgCl2), but a negative lymphocyte stimulation test. Suspected metal compounds were demonstrated in their dental materials. Removal of gold materials in one case gradually improved the lesions within 6 months with a transient erythematous swelling of the face shortly after removal of the metal. Both of these cases responded to oral disodium chromoglycate therapy. These results suggest that metal compound specific T cells might be responsible for the development of linear lichen planus.

Effect of cardioplegic arrest and reperfusion on coronary reserve and autoregulation.

BACKGROUND: The effects of cardioplegic arrest and reperfusion on the coronary vasculature remain to be characterized. This study was designed to investigate changes in coronary reserve and autoregulation after hypothermic cardioplegic arrest and reperfusion. METHODS: Isolated rabbit hearts were perfused in a retrograde manner with Krebs-Henseleit bicarbonate buffer solution at a pressure of 80 cm H2O. Baseline measurements were performed for (1) coronary flow; (2) vasodilatory response to 5-hydroxytryptamine (10(-7) mol/L) and nitroglycerin (10(-4) mol/L); (3) autoregulatory capacity, quantified as closed-loop gains; and (4) isovolemic left ventricular function. Hearts were then subjected to cardioplegic arrest for 90 minutes. Twenty minutes after reperfusion, measurements were repeated. RESULTS: Coronary flow decreased significantly after reperfusion (6.2 +/- 1.1 versus 5.3 +/- 1.1 mL.min-1.g-1; p < 0.01). The response to 5-hydroxytryptamine as percentage increase of flow decreased significantly after reperfusion (134.0% +/- 12.0% versus 109.1% +/- 6.8%; p < 0.01). However, there was no significant change in the response to nitroglycerin after reperfusion (121.3% +/- 17.6% versus 136.6% +/- 13.3%). The closed-loop gain demonstrated negative values before arrest but became positive after reperfusion, indicating loss of autoregulation after reperfusion. There was no significant change in left ventricular function. CONCLUSIONS: The coronary flow reserve in response to 5-hydroxytryptamine and autoregulation were impaired after cardioplegic arrest and reperfusion, whereas nitroglycerin-induced vasodilatory response and left ventricular function were preserved.

[An approach to the emergency surgery for arch and/or ascending aortic aneurysm].

The outcome of emergency surgery for the aortic arch aneurysm and/or dissecting aneurysm is worse than that of elective surgery. To decide the future strategy of the emergency surgery for these disease, 11 patients with emergency surgery (= group E: 8 for aortic dissection and 3 for rupture of the aortic arch aneurysm, age; 61 +/- 13 SD) were compared with 12 patients who had elective surgery (= group S: 5 for aortic dissection and 7 for aortic arch aneurysm, age; 69 +/- 3 SD). Ascending aorta replacement was performed in 7 cases in group E v.s. 1 in group S, aortic arch replacement in 2 v.s. 5, ascending aorta and aortic arch replacement in 1 v.s. 4 and patch replacement of the aortic wall in 1 v.s. 2, respectively. Selective cerebral perfusion (SCP) upon the cardiopulmonary bypass (CPB) was used in 45% (5/11) in group E. v.s. in 92% (11/12) in group S, p < 0.05. CPB time, aortic clamp time and SCP time were not significantly different between E group and S group. Postoperative cardiac failure, respiratory failure, renal failure, brain injury and infection occurred at insignificant rates between both groups. Thirty-day and 3-year survivorships were 73% in group E, while in group S they were 92% and 75%, respectively. In group E there were 2 cases which had aortic wall injury due to the aortic clamp used during the surgery. We recommend the use of selective cerebral perfusion and open distal anastomosis in emergency surgery for aortic arch aneurysm and/or Stanford type A aortic dissection.

[Surgical treatment for ruptured aneurysm of distal arch or aortic arch: report of three cases].

We experienced three cases of surgery for ruptured aneurysm of the distal aortic arch (2 cases) or aortic arch (1 case). A 59-year-old man who was diagnosed as distal arch aneurysm ruptured to the pericardial cavity underwent graft replacement of the aneurysm and reconstruction of a left subclavian artery under selective cerebral perfusion (SCP). This patient had left hemiplegia postoperatively. A 73-year-old man who was diagnosed as an aneurysm of distal arch and descending aorta ruptured to left pleural cavity underwent graft replacement of the aneurysm and reconstruction of a left subclavian artery under SCP, and died of severe left ventricular failure possibly due to preoperative myocardial ischemia. A 70-year-old man who was diagnosed as a saccular aneurysm of aortic arch ruptured to mediastinum underwent resection of the aneurysm and patch plasty of the aorta under SCP. The postoperative course was uneventful. We discussed the approach to aneurysm, adjunctive method and surgical precedures from standpoint of our ruptured three cases.