Higher melatonin secretion is associated with lower leukocyte and platelet counts in the general elderly population: the HEIJO‐KYO cohort

Circulating white blood cell (WBC) and platelet (PLT) counts are widely available and inexpensive cellular biomarkers of systemic inflammation and have been associated with a risk of cardiovascular disease, cancer, and mortality. Melatonin may reduce systemic inflammation through its direct and indirect antioxidative effect; however, the associations of melatonin secretion with systemic inflammation remain unclear. In this cross‐sectional study on 1088 elderly individuals (mean age, 71.8 years), we measured overnight urinary 6‐sulfatoxymelatonin excretion (UME) and WBC and PLT counts as indices of melatonin secretion and systemic inflammation, respectively. UME was naturally log‐transformed for linear regression models because of skewed distribution (median, 6.8 μg; interquartile range, 4.1–10.6 μg). Univariate models revealed that higher log‐transformed UME levels were significantly associated with lower WBC and PLT counts (P = 0.046 and 0.018). After adjusting for potential confounding factors significantly associated with WBC or PLT counts, higher log‐transformed UME levels were significantly associated with lower WBC and PLT counts (WBC: β, ?0.143; 95% confidence interval, ?0.267 to ?0.020; P = 0.023; PLT: β, ?6.786; 95% confidence interval, ?12.047 to ?1.525; P = 0.012). Furthermore, the adjusted mean differences in WBC and PLT counts between the lowest and highest UME tertile groups were 0.225 × 10⁹/L and 9.480 × 10⁹/L, respectively. In conclusion, melatonin secretion was significantly and inversely associated with WBC and PLT counts in the general elderly population. The associations were independent of several major causes of systemic inflammation, including aging, obesity, smoking, hypertension, diabetes, and physical inactivity.     

A dominantly inherited malformation syndrome with short stature,upper limb anomaly,minor craniofacial anomalies,and absence of TBX5 mutations: Report of a Thai family

We report on a Thai family with dominantly inherited malformation syndrome with upper limb anomalies, short stature, quadricuspid aortic valve, and minor craniofacial anomalies. The affected individuals comprised a mildly affected mother, a moderately affected daughter, and a most severely affected son. The daughter and son had short stature. The craniofacial abnormalities comprised frontal bossing, hypoplastic nasal bones, depressed nasal bridge, and broad nasal alae. The upper limb defects varies among the patients, ranging from radial ray defects in the mother through radial and ulnar ray defects with unilateral humeral hypoplasia in the daughter to radial ray defects with severe oligodactyly and bilateral humeral hypoplasia in the son. All patients in this family had hypoplasia of the shoulder girdle and resembled what is observed in many families with Holt‐Oram syndrome. Moreover, the son showed quadricuspid aortic valve with mild aortic regurgitation. However, the present family did not show any mutation of the TBX5 gene, a disease‐causing gene of Holt‐Oram syndrome. The present family deserves further investigation on other genes that play a role in the development of the upper limbs, particularly of radial rays. © 2002 Wiley‐Liss, Inc.     

Long-term results of first-line sequential high-dose carboplatin, etoposide and ifosfamide chemotherapy with peripheral blood stem cell support for patients with advanced testicular germ cell tumor

OBJECTIVE: Standard chemotherapy shows relatively low long-term survival in patients with poor-risk testicular germ cell tumor (GCT). First-line high-dose chemotherapy (HD-CT) may improve the result. High-dose carboplatin, etoposide, ifosfamide chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) was investigated as first-line chemotherapy in patients with advanced testicular GCT. METHODS: Fifty-five previously untreated testicular GCT patients with Indiana 'advanced disease' criteria received three cycles of bleomycin, etoposide and cisplatin (BEP) followed by one cycle of HD-CT plus PBSCT, if elevated serum tumor markers were observed after three cycles of the BEP regimen. RESULTS: Thirty patients were treated with BEP alone, because the tumor marker(s) declined to normal range. Twenty-five patients received BEP and HD-CT. One patient died of rhabdomyolysis due to HD-CT. Three and six (13% and 25%) out of 24 patients treated with BEP and HD-CT achieved marker-negative and marker-positive partial responses, respectively. The other patients achieved no change. Fifteen (63%) are alive and 14 (58%) are free of disease at a median follow-up time of 54 months. Severe toxicity included treatment-related death (4%). CONCLUSIONS: HD-CT with peripheral stem cell support can be successfully applied in a multicenter setting. HD-CT demonstrated modest anticancer activity for Japanese patients with advanced testicular GCT and was well tolerated. This regimen might be examined for further investigation in randomized trials in first-line chemotherapy for patients with poor-risk testicular GCT.     

Effect of KB-2796, a new diphenylpiperazine Ca antagonist, on voltage-dependent Ca currents and oxidative metabolism in dissociated mammalian CNS neurons

The effects of KB-2796, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine-2HCl, on the low- and high-voltage activated Ca²⁺ currents (LVA and HVA I_Ca, respectively) and on oxidative metabolism were studied in neurons freshly dissociated from rat brain. KB-2796 reduced the peak amplitude of LVA I_Ca in a concentration-dependent manner with a threshold concentration of 10⁻⁷ M when the LVA I_Ca was elicited every 30 s in the external solution with 10 mM Ca²⁺. The concentration for half-maximum inhibition (IC₅₀) was 1.9 × 10⁻⁶M. At 10⁻⁵ M or more of KB-2796, a complete suppression of the LVA I_Ca was observed in the majority of neurons tested. There was no apparent effect on the current-voltage (I-V) relationship and the current kinetics. KB-2796 delayed the reactivation and enhanced the inactivation of the Ca²⁺ channel for LVA I_Ca voltage- and time-dependently, suggesting that KB-2796 preferentially binds to the inactivated Ca²⁺ channel. KB-2796 at a concentration of3.0 × 10⁻⁶M also decreased the peak amplitude of the HVA I_Ca without shifting the I-V relationship. In addition, KB-2796 reduced the oxidative metabolism (the formation of reactive oxygen species) of the neuron in a concentration-dependent manner with a threshold concentration of3 × 10⁻⁶M. It is suggested that the inhibitory action of KB-2796 on the neuronal Ca²⁺ influx and the oxidative metabolism, in combination with a cerebral vasodilatory action, may reduce ischemic brain damage.     

Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia, and high serum creatine phosphokinase level

The neuroleptic malignant syndrome (NMS) is a life-threatening complication of neuroleptic treatment. To elucidate the pathogenesis of NMS, an animal model has been developed. Experimental rabbits treated with haloperidol (1 mg/kg) by intramuscular injection, were studied for the diagnostic symptoms of increased muscle rigidity, elevated body temperature, and high serum creatine phosphokinase (CPK) level. Administration of haloperidol (1 mg/kg) and atropine (0.4 mg/kg), and exposure to high ambient temperature (35°C) induced a significant increase in electromyographic activity with muscle rigidity similar to that observed in patients with NMS. Such rabbits also showed elevated body temperature and serum CPK value. In addition to the similarity of the signs and symptoms, all parameters measured (muscle rigidity, body temperature, and serum CPK level) were normalized by dantrolene treatment. The effectiveness of dantrolene in the experimental animal partially confirms the validity of this animal model for NMS. This experimental animal model for NMS may be useful to elucidate the pathogenesis of NMS.     

Reelin expression is upregulated following ocular tissue injury

Purpose Reelin is important in the guidance of neuronal stem cells in the central nervous system during normal development. We wished to determine whether reelin is expressed in the retina and cornea after injury. Methods Mice underwent laceration of their retina as well as corneal epithelial debridement. The mice were sacrificed at 3 days, and eyes were fixed and stained for reelin expression and reelin messenger ribonucleic acid (mRNA). Results In normal eyes, reelin was expressed only at very low levels in the ganglion cell layer of the retina and the endothelial cell layer of the cornea. In injured eyes, there was marked expression in reelin immunoreactivity in the retina and cornea. Reelin gene expression was seen in the retina and cornea. Conclusions Reelin is expressed during normal retinogenesis. This study shows that reelin is also upregulated following injury to the retina and cornea. The expression of reelin following injury suggests that reelin may play an important role in regulating stem cell trafficking in neuronal and nonneuronal tissues following injury similar to its role in normal organogenesis. For consideration of publication in Graefe’s Archive for Clinical and Experimental Ophthalmology.     

UFT for head and neck cancers: its tissue concentrations and effects on lymphocyte subpopulations

Summary UFT, a combination of the masked compound of 5-fluorouracil (FT-207) and uracil, was given to head and neck cancer patients for 1 week preoperatively and for 8 weeks postoperatively. Drug concentrations were examined in the surgically removed tissues. The concentrations of FT-207, 5-fluorouracil, and uracil were higher in tumor tissues than in normal tissues. The lymphocyte subpopulations were assessed by cytofluorometry with monoclonal antibodies. There was no evidence that adjuvant chemotherapy with UFT specifically suppresses immunocompetent cells. We therefore conclude that further clinical evaluation of adjuvant chemotherapy with UFT would be worthwhile.     

A case of autoimmune hepatitis needed to be differentiated from EBV hepatitis, in that the histology of liver biopsy specimen was useful for diagnosis]

A 10-year-old girl with autoimmune hepatitis (AIH) was reported. She was admitted to our hospital because of cholestasis and elevation of liver enzymes for 2 months. Laboratory examination revealed that EBV-DNA copy number in the PBMNC (peripheral mononuclear cells) was 1.2 x 10(3) copies/microg of DNA, hypergammaglobulinemia, and positive antinuclear antibody, positive anti-smooth muscle antibody. The histology of her liver biopsy specimen revealed interface hepatitis, dense mononuclear cell infiltrates, mild fibrosis, and negative for EBV in situ hybridization assay indicating AIH and not EBV-associated hepatitis. She was treated firstly with methylprednisolone pulses, then will prednisolone p.o.+azathioprine p.o.. Intravenous cyclophosphamide pulse therapy was introduced because of her abnormal immune pathology. All abnormal laboratory parameters improved to normal levels within 2 months, and EBV-DNA copy number in the PBMNC became negative after 4 months. The histology of liver biopsy specimen was useful for the diagnosis of AIH in such a difficult case needed to be differentiated from EBV hepatitis.