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Rationale: Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%., Patient Concerns: A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened., Diagnoses: Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system., Interventions: Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL., Outcomes: Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient's exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells., Lessons: This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Triphenyltetrazolium chloride (TTC) is one of the most conventional stains to detect infarcted area of the heart in animal experiments. However, its availability and limitations have not been thoroughly discussed in the forensic field. Here, authors stained human hearts with TTC soon after the harvest. Photographs of the samples were analyzed using image analysis software, which evaluated the occupying ratio of the stained area on the surface of each slice. The results showed that the stainability of TTC declines with the length of the postmortem interval (PMI). Specimens reacted well to TTC within 1.5 days after death and then decreased the stainability logarithmically with PMI (y = - 0.294 In (x) + 1.0441; x = PMI, y = TTC-stained area / total myocardial area, R = 0.5673). Samples with old myocardial infarction produced clear TTC contrast; normal tissue is vivid red, and fibrotic myocardium is white discoloration. In acute myocardial infarction cases where death occurred within 9 hours after the attack, however, the detection of infarcted area was very difficult even when PMI was less than 1.5 days. In summary, the TTC method may be useful within 1.5 days after death, but short suffering period before death disturbs its staining efficiency.

Rationale: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD(+)-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion., Objective: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection., Methods and Results: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H(2)O(2) production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose resveratrol., Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.

Background: Overeating and obesity are major health problems in developed countries. Caloric restriction (CR) can counteract the deleterious aspects of obesity-related diseases and prolong lifespan. We have demonstrated that short-term CR improves myocardial ischemic tolerance and increases adiponectin levels. Here, we investigated the specific role of adiponectin in CR-induced cardioprotection., Methods and Results: Adiponectin antisense transgenic (Ad-AS) mice and wild-type (WT) mice were randomly assigned to a group fed ad libitum and a CR group (90% of caloric intake of ad libitum for 3 weeks, then 65% for 2 weeks). Isolated perfused mouse hearts were subjected to 25 minutes of ischemia, followed by 60 minutes of reperfusion. CR increased serum adiponectin levels by 84% in WT mice. Gel filtration analysis of the oligomeric complex distribution showed that CR produced a marked increase in the high-molecular-weight complex of adiponectin in WT mice; in contrast, CR did not change serum adiponectin levels or their oligomeric pattern in Ad-AS mice. CR improved the recovery of left ventricular function after ischemia/reperfusion and limited infarct size in WT mice; these effects were completely abrogated in Ad-AS mice. CR also increased the phosphorylated form of AMP-activated protein kinase and acetyl-CoA carboxylase in WT but not in Ad-AS mice. Recombinant adiponectin restored CR-induced cardioprotection in Ad-AS mice, and inhibition of AMP-activated protein kinase phosphorylation completely abrogated CR-induced cardioprotection in WT mice., Conclusions: The cardioprotective effects of short-term CR are mediated by increased production of adiponectin and the associated activation of AMP-activated protein kinase.

In some herpes zoster patients, pain persists for more than 3 months or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). We have recently reported the association of the human histocompatibility leukocyte antigens (HLA) haplotype, HLA-A*3303-B*4403-DRB1*1302 with PHN patients; however, it has not been determined whether the haplotype is also associated with herpes zoster that did not develop subsequent PHN. To distinguish whether the haplotype is associated with herpes zoster or the development of PHN, we examined if herpes zoster patients without subsequently PHN are also associated with the HLA haplotype or not. Herpes zoster patients were followed up for more than 6 months, and HLA alleles and haplotypes were compared among the PHN patients (n = 52) the herpes zoster patients who did not develop PHN (n = 42) and healthy controls (n = 125). The frequencies of the risk haplotype in the PHN patients, in the healthy controls and in the herpes zoster patients without subsequent PHN were 16.3, 5.2 and 4.8%, respectively. While the frequency of the risk haplotype was significantly higher in the PHN patients than in the healthy controls (P = 0.0006) no difference was observed between the herpes zoster patients without subsequent PHN and the healthy controls. No significant association was found between the duration of symptoms or the site of herpes zoster and the HLA alleles and the haplotype. These results suggest that the HLA-A*3303-B*4403-DRB1*1302 haplotype plays an important role in the development of PHN after herpes zoster, but not in the onset of herpes zoster.

Background: Oncogenic RAS mutants such as v-Ha-RAS activate members of Rac/CDC42-dependent kinases (PAKs) and appear to contribute to the development of more than 30% of all human cancers. PAK1 activation is essential for oncogenic RAS transformation, and several chemical compounds that inhibit Tyr kinases essential for the RAS-induced activation of PAK1 strongly suppress RAS transformation either in cell culture or in vivo (nude mice). Although we have developed a cell-permeable PAK-specific peptide inhibitor called WR-PA18, so far no chemical (metabolically stable) compound has been developed that directly inhibits PAK1 in a highly selective manner. Thus, we have explored such a PAK1 inhibitor(s) among synthetic derivatives of an adenosine triphosphate antagonist., Results: From the naturally occurring adenosine triphosphate antagonist K252a, we have developed two bulky derivatives, called CEP-1347 and KT D606 (a K252a dimer), which selectively inhibit PAKs or mixed-lineage kinases both in vitro and in cell culture and convert v-Ha-RAS-transformed NIH 3T3 cells to flat fibroblasts similar to the parental normal cells. Furthermore, these two K252a analogues suppress the proliferation of v-Ha-RAS transformants, but not the normal cells., Conclusion: These bulky adenosine triphosphate antagonists derived from K252a or related indolocarbazole compounds such as staurosporine would be potentially useful for the treatment of RAS/ PAK1-induced cancers, once their anti-PAK1 activity is significantly potentiated by a few additional chemical modifications at the sugar ring suggested in this paper.

Eccrine syringofibroadenoma is an uncommon benign eccrine tumor, which was first described by Mascaro in 1963. It usually develops on the extremities of elderly persons. We report on a 74-year-old man who presented with a 2-year history of a slowly growing lesion on his face. A detailed histologic and immunohistochemical study was performed on the biopsy material. The tumor consisted of epidermal-derived anastomosing thin epithelial cords embedded in a fibrovascular stroma. The epithelial cords contained ductal and cystic structures lined by luminal cells, which were decorated by antibodies against carcinoembryonic antigen, keratin K19, K8, and K18. Antibody to keratin K6 decorated the luminal walls of the acrosyringia. Antibodies to filaggrin decorated the superficial luminal structures. These results suggest dual acrosyringial and dermal duct differentiation in syringofibroadenoma.

Nearly 10% of Japanese people have pigmented nevi on the soles. Since malignant melanoma also occurs on the plantar area in the Japanese, it would be very valuable to be able to differentiate benign and malignant lesions in the early clinical state. We have investigated the epiluminescence microscopic features of 500 melanocytic nevi on the soles of Japanese people using a dermatoscope and a videomicroscope that can magnify lesions from x 10 to x 200. The results showed that the surface profile of benign melanocytic nevi is mainly classified into five types; that 9% of plantar nevi, however, do not fit into this classification and are categorized as a miscellaneous type; and that the other nonmelanocytic disorders, such as verruca vulgaris and black heel, are easily differentiated by their surface profile. More important, the histological examination showed that atypical nevi, malignant melanoma in situ, and acral lentiginous melanoma are exclusively compartmentalized in the miscellaneous type of surface profile. Our data suggested that epiluminescence microscopy may be a useful method for discrimination of plantar benign and malignant melanocytic lesions.

We saw a patient with a Spitz nevus surrounded by a halo of depigmentation. Although the halo phenomenon is often seen in pigmented melanocytic nevus, an association of this phenomenon with Spitz nevus seems to be rare. Moreover, histopathological findings showed focal lymphoid infiltration in the epidermis of the depigmented halo and marked infiltration in dermal epithelioid nevus cell nests. Thus, it is suggested that identical mechanisms are involved in the destruction of epidermal melanocytes and dermal nevus cells in halo Spitz nevus.

We report a patient who presented with clear cell syringomata concomitant with diabetes mellitus. Also prominent were increased numbers of clear cells within the eccrine glands. This observation of increased numbers of clear cells in eccrine glands of diabetic patients may represent another skin finding that is related to diabetes mellitus.

Functional studies have yet to be undertaken to establish which brain region subserves the parasympathetic regulation of the cerebral circulation. Using 31 anesthetized rats with precluded cervical sympathetic trunks, we therefore attempted to perform chemical stimulation of the greater petrosal nerve (GPN) cell group, which is a subgroup of the superior salivatory nucleus and sends off axons largely to the parasympathetic pterygopalatine ganglion via the GPN component of the facial nerve. The cerebrocortical blood flow was monitored with a laser-Doppler flowmeter. Unilateral stimulation of the GPN cell group by microinjection of L-glutamate reduced the ipsilateral cerebrocortical vascular resistance, maximally by 16.4 +/- 4.1% (mean +/- SD, n = 61). The response was not mediated by the classic muscarinic receptors of the cerebral vessel wall. However, pharmacological blockade of the peripheral parasympathetic ganglia and acute and chronic bilateral removal of the parasympathetic postganglionic fibers originating in the pterygopalatine ganglion abolished the response. The present data thus provide functional evidence that the GPN cell group may constitute a parasympathetic cerebrovasodilator center.

The purpose of this experiment was to determine whether an acute rise in brain perfusion pressure causes hemorrhagic transformation of an infarct without a reopening of the occluded artery. We raised the blood pressure of 22 cats by aortic obstruction 5-24 hours after transorbital middle cerebral artery clipping; hemorrhagic infarcts were induced in 11. Mean arterial blood pressure increased by 57.2 +/- 16.9 mm Hg (mean +/- SD) in the 11 cats with hemorrhagic infarcts and by 40.4 +/- 16.9 mm Hg in the 11 remaining cats with pale brain infarcts (p less than 0.05). Induction of hypertension increased regional cerebral blood flow in the ischemic cortical gray matter more in three cats with hemorrhagic infarcts than in seven with pale infarcts. Our results demonstrate that hemorrhagic transformation of an infarct can be induced by a rapid increase in perfusion pressure to brain tissue already exposed to focal ischemia. We also suggest that the restoration of blood flow through leptomeningeal collaterals plays an important role in the pathogenesis of hemorrhagic infarction in cases without reopening of occluded arteries.

Cerebral lactate, pyruvate and adenosine triphosphate (ATP), and acid-base balance were measured in male and female spontaneously hypertensive rats (SHR) before, and 1, 3 and 5 hours after bilateral carotid occlusion. In male SHR, cerebral lactate and the lactate/pyruvate (L/P) ratio progressively increased after occlusion, while cerebral ATP decreased. In female SHR, an increase in lactate and the L/P ratio was less marked than in male SHR. Cerebral ATP remained unchanged 5 hours after occlusion. These data suggest that bilateral carotid artery occlusion may cause more pronounced ischemic changes in the brain in male SHR than in female SHR, resulting in a greater increase in lactate with a concomitant decrease in ATP in male SHR. Results suggest that female SHR are more resistant to cerebral ischemia following bilateral carotid occlusion than male SHR. Blood pressure and gonads in the susceptibility to cerebral ischemia are discussed.

Brain tissue lactate, pyruvate, and adenosine triphosphate (ATP) were measured 60 min after bilateral carotid ligation in spontaneously hypertensive rats, of which hematocrit (HCT) was varied by exchanging with isovolemic homologous red cells, plasma or whole blood. Supratentorial lactate of the ischemic brain was increased more in high HCT (greater than or equal to 50%) and less in low HCT (30-39%) compared with normal HCT (40-49%). In very low HCT (less than 30%), however, lactate was increased to further extent compared with any other group of HCT (ANOVA p less than 0.0001). Lactate/pyruvate (L/P) ratio of the ischemic brain showed similar changes, namely U-shaped correlation to HCT. In contrast, supratentorial ATP was decreased more markedly in very low HCT, followed by high and normal HCT, and minimally decreased in low HCT, demonstrating an inverse U-shaped relationship to HCT. Mean arterial pressure and arterial acid-base parameters in ischemic animals did not differ among HCT groups. There were no HCT-related changes of brain metabolites in non-ischemic control rats. These findings indicate that cerebral ischemia following carotid ligation is more severe in high HCT but less in low HCT, probably due to hemodynamic effects of HCT changes. When HCT is reduced to below 30%, however, insufficient oxygen supply to the brain or anemic hypoxia may superimpose on ischemia, resulting in more markedly impairment of brain metabolism. The role of HCT as a cause of cerebral ischemia and its severity is discussed.

The relationship between cardiac output (CO) and peripheral resistance (Rp) was examined under the following conditions for coronary perfusion: constant coronary flow perfusion; perfusion with a pressure equal to mean aortic pressure (AoP perfusion); and perfusion with a pressure equal to the mean AoP - 30 mm Hg (AoP - 30 mm Hg perfusion). We also examined the coronary pressure-flow relationship. For these studies, we used paced, isolated, ejecting canine hearts, which were loaded by a hydraulic system that simulated the input impedance of a dog's systemic arterial tree. The CO in the constant coronary flow perfusion continued to increase with the reduction of Rp. The CO in the AoP perfusion became maximal at a slightly subphysiologic Rp, or at an average mean AoP of 65 mm Hg. This mean AoP was closely associated with the lower limit of the autoregulation of coronary blood flow. In the AoP - 30 mm Hg perfusion, the mean AoP at which CO became maximal was 72 mm Hg and the corresponding coronary perfusion pressure appeared to be lower than the lower limit of the perfusion pressure range for coronary flow autoregulation. The Rp value at that point was slightly higher than the physiologic range. We conclude that when coronary perfusion pressure changes with mean AoP, and when left ventricular end-diastolic pressure is fixed, there is a clear optimal Rp at which CO becomes maximal, and this optimal Rp is higher if coronary perfusion pressure is biased from mean AoP to a significant degree.

Cerebral vascular carbon dioxide (CO2) reactivities were compared in normotensive (NTR) and hypertensive (SHR) rats. Cerebral blood flow (CBF) in cortex and thalamus were evaluated before and during one hour of hyperventilation. After one hour of hyperventilation brain lactate, pyruvate, and ATP concentrations were also determined. Significant and similar reductions of CBF due to hyperventilation induce hypocapnia were found in both NTR and SHR groups. In contrast the percent increase in cerebrovascular resistance (CVR) per unit decrease in paCO2 was significant, indicating that hypocapnia induced vasoconstriction is greater in NTR than in SHR groups. During hyperventilation the average value for lactate in the NTR group was 3.98 mM/kg. In contrast it was 3.15 mM/kg in the SHR group, a significant difference (p less than 0.05). When paCO2 fell below 15 mm Hg the cerebral lactate increased strikingly in the NTR group and cortical CVR was reduced suggesting that an accumulation of the ischemic metabolites caused dilatation of the constricted cerebral vessels. In contrast the SHR group disclosed no such changes. The increase CVR characteristic of SHR appeared to diminish the cerebral vasoconstrictive response to hypocapnia. As a result ischemic metabolites in the brain do not increase in this group to the degree that they do in NTR.

WE quantitatively analyzed the effect of graded left anterior descending and septal coronary flow (LAD + septal flow) reduction on left ventricular function with a left ventricular end-diastolic pressure (LVEDP) of 6 mm Hg and 12 mm Hg. We used an isolated, ejecting, canine heart preparation ( n = 8), the coronary flow of which could be controlled independently of the aortic pressure. We kept the other hemodynamic variables - heart rate, left circumflex coronary flow, right coronary flow and aortic input impendance - constant within their normal physiologic range. We considered this reduction in LAD + septal flow to be analogous to that of the most frequent lesion in ischemic heart disease. There was no plateau in the left ventricular work caused by this reduction of the regional coronary flow. Therefore, the plateau commonly reported in previous studies may be partially a result of the compensatory elevation of LVEDP, which is necessary to maintain the left ventricular work.

The influence of ultraviolet B irradiation on the induction of delayed-type hypersensitivity reactions to alloantigens by epidermal cells (EC), on the generation of cytotoxic T lymphocyte activity to alloantigens, and on skin graft rejection was studied. After the skin was irradiated with UVB in vitro, EC were obtained. The EC were injected subcutaneously, and the DTH reaction was compared with that induced by non-UVB-irradiated EC. A reduction in the DTH reaction was observed (from 62% to 99.1%). CTL activity in these mice was assessed after in vitro stimulation. CTL activity in mice sensitized with UVB-irradiated EC was significantly reduced. Furthermore, mice sensitized with UVB-irradiated EC did not reject a subsequent skin allograft in an accelerated fashion, whereas mice sensitized with non-UVB-irradiated EC did. The mechanism(s) of these reactions and the clinical application of the UVB irradiation prior to grafting are discussed.