Rocuronium priming for tracheal intubation in COVID-19 patients.

Priming doses of non-depolarising neuromuscular blocking drugs given before administration of anaesthetic agents have been used to hasten the onset of neuromuscular blockade. In the settings of coronavirus disease 2019 (COVID-19), this could be used to reduce the apnoeic, and potentially aerosol-generating, window. To our knowledge, we report the first cases of tracheal intubation with rocuronium for COVID-19 using the priming principle. Both patients needed their tracheas intubated for severe hypoxia using a rapid sequence induction technique with a priming dose of rocuronium. Despite adequate pre-oxygenation a sudden, unexpected fall in arterial oxygen saturations was observed in both patients after administration of a priming dose of 2 mg of rocuronium. Clinicians should consider this possible risk associated with priming doses of neuromuscular blocking drugs in the management of patients with respiratory failure due to COVID-19.

Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non-autoimmune diabetes mellitus without history of neonatal diabetes.

AIMS: Abnormalities in the imprinted locus on chromosome 6q24 are the most common causes of transient neonatal diabetes mellitus (6q24-related transient neonatal diabetes). 6q24-Related transient neonatal diabetes is characterized by the patient being small-for-gestational age, diabetes mellitus at birth, spontaneous remission within the first few months and frequent recurrence of diabetes after childhood. However, it is not clear whether individuals with 6q24 abnormalities invariably develop transient neonatal diabetes. This study explored the possibility that 6q24 abnormalities might cause early-onset, non-autoimmune diabetes without transient neonatal diabetes. METHODS: The 6q24 imprinted locus was screened for abnormalities in 113 Japanese patients with early-onset, non-obese, non-autoimmune diabetes mellitus who tested negative for mutations in the common maturation-onset diabetes of the young (MODY) genes and without a history of transient neonatal diabetes. Positive patients were further analysed by combined loss of heterozygosity / comparative genomic hybridization analysis and by microsatellite analysis. Detailed clinical data were collected through the medical records of the treating hospitals. RESULTS: Three patients with paternal uniparental isodisomy of chromosome 6q24 were identified. None presented with hyperglycaemia in the neonatal period. Characteristically, these patients were born small-for-gestational age, representing 27.2% of the 11 patients whose birth weight standard deviation score (SDS) for gestational age was below -2.0. CONCLUSIONS: Abnormalities in the imprinted locus on chromosome 6q24 do not necessarily cause transient neonatal diabetes. Non-penetrant 6q24-related diabetes could be an underestimated cause of early-onset, non-autoimmune diabetes in patients who are not obese and born small-for-gestational age.

Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients.

AIMS: To investigate the molecular and clinical characteristics of the largest series of Japanese patients with glucokinase maturity-onset diabetes of the young (GCK-MODY), and to find any features specific to Asian people. METHODS: We enrolled 78 Japanese patients with GCK-MODY from 41 families (55 probands diagnosed at the age of 0-14 years and their 23 adult family members). Mutations were identified by direct sequencing or multiplex ligation-dependent probe amplification of all exons of the GCK gene. Detailed clinical and laboratory data were collected on the probands using questionnaires, which were sent to the treating physicians.　Data on current clinical status and HbA1c levels were also collected from adult patients. RESULTS: A total of 35 different mutations were identified, of which seven were novel. Fasting blood glucose and HbA1c levels of the probands were ≤9.3 mmol/l and ≤56 mmol/mol (7.3%), respectively, and there was considerable variation in their BMI percentiles (0.4-96.2). In total, 25% of the probands had elevated homeostatic assessment of insulin resistance values, and 58.3% of these had evidence of concomitant Type 2 diabetes in their family. The HbA1c levels for adults were slightly higher, up to 61 mmol/mol (7.8%). The incidence of microvascular complications was low. Out of these 78 people with GCK-MODY and 40 additional family members with hyperglycaemia whose genetic status was unknown, only one had diabetic nephropathy. CONCLUSIONS: The molecular and clinical features of GCK-MODY in Japanese people are similar to those of other ethnic populations; however, making a diagnosis of GCK-MODY was more challenging in patients with signs of insulin resistance.

Significant correlations between the flow volume of patent ductus venosus and early neonatal liver function: possible involvement of patent ductus venosus in postnatal liver function.

BACKGROUND: The biochemical features of portosystemic venous shunt with high flow volume are hypergalactosaemia, hyperammonaemia, prolonged blood coagulation time, and raised serum bile acid concentration. The ductus venosus remains open with shunt flow in most neonates for a certain period after birth. However, the effects of blood flow through the ductus venosus on neonatal liver function remain unclear. OBJECTIVE: To elucidate the effect of patency of the ductus venosus on liver function in early neonates. METHODS: Subjects were divided into three groups by gestational age (group I, 29-32 weeks; group II, 33-36 weeks; group III, 37-41 weeks). The shunt flow volume through the ductus venosus was examined serially using ultrasonography, and correlations between flow volume and liver function in the respective groups were calculated during the first week after birth. RESULTS: Group I had a higher flow volume and later functional closure than the other two groups. Plasma ammonia and serum total bile acid concentrations correlated with flow volume in groups I and II, and blood galactose and galactose 1-phosphate concentrations correlated significantly with flow volume in group III. Percentage hepaplastin also correlated significantly with flow volume in all groups, but plasma vitamin K concentration did not in any group. CONCLUSIONS: Patent ductus venosus has a considerable effect on crucial liver functions such as ammonia detoxification, blood coagulation, and regulation of serum total bile acid concentration in early neonates.

Historical trends of PCDD/Fs and CO-PCBs in a sediment core collected in Sendai Bay, Japan.

The vertical distribution of dioxins in a sediment core was investigated to elucidate historical trends of dioxins discharged into Sendai Bay, Japan. The dioxin concentration was 410 pg/g dry weight (dw) in sediments deposited in the mid-1930s and 3870 pg/g dw in those deposited in the mid-1980s. Dioxin fluxes increased from the mid-1930s and then reached a maximum in the mid-1980s. 1,3,6,8-TeCDD+1,3,7,9-TeCDD, OCDD, and Co-PCB concentrations were 110, 140, and 26 pg/g dw, respectively, in mid-1930s sediments, and reached maximums of 1800, 1100, and 200 pg/g dw, respectively, in mid-1980s sediments. Shipments to Miyagi Prefecture of CNP and PCP products, the major sources of 1,3,6,8-TeCDD+1,3,7,9-TeCDD and OCDD, were highest in 1975 (4700t) and 1970 (3100t), respectively; and in Japan, the amount of PCBs, the major source of Co-PCB congeners, used was highest (11,100t) in 1970. Thus, the period for which the maximum concentrations of 1,3,6,8+1,3,7,9-TeCDD, OCDD, and Co-PCBs were measured in the sediment core (mid-1980s) did not correspond to the time of maximum use of CNP, PCP, or PCB products, but lagged behind by more than 10 years. We attributed this time lag to the time required for the movement of dioxins from Miyagi Prefecture to Sendai Bay.

Two cases with transient lipoprotein lipase (LPL) activity impairment: evidence for the possible involvement of an LPL inhibitor.

UNLABELLED: Two independent severe hypertriglyceridemic infants with transiently impaired lipoprotein lipase (LPL) activity were observed and the causes were explored. Both infants were female, born prematurely with low birth weight and developed hypertriglyceridemia (Fredrickson type V hyperlipidemia: high VLDL and low LDL/HDL) a few months after birth. While mass levels of their post-heparin plasma LPL and apoprotein C-II (apo C-II), a physiological activator of LPL, were normal, their post-heparin plasma LPL activities were remarkably impaired. Both of their mothers' post-heparin plasma LPL activities were slightly or moderately impaired as well, without a decrease in the LPL mass level. No mutations in the genes for LPL and apo C-II were detected in either patient. In an in vitro study with their serum at onset, we could not detect any distinct circulating inhibitors for LPL. There was no data supporting infection or autoimmune diseases, which might have an impact on LPL activity, during the follow-up period. Levels of their plasma triglyceride (TG) and total cholesterol (TC) were decreased quickly by a dietary intervention with medium-chain triglyceride (MCT) milk and kept normal even after stopping the intervention at around age 1 year. However, their low post-heparin LPL activity persisted and returned to normal at around age 2 years. Their low HDL cholesterol levels persisted even after recovery of the TG and TC levels, although lecithin:cholesterol acyltransferase (LCAT) and cholesterol-ester-transfer protein (CETP), two key enzymes of HDL metabolism, were normal throughout the course. The exact reasons why their post-heparin LPL activities were impaired for a certain period and why their HDL cholesterol levels have remained low are still unclear. CONCLUSION: Transiently impaired LPL activity with no defect in LPL enzyme induced severe hypertriglyceridemia in infants. The transient occurrence of inhibitor(s) for LPL was proposed.

Intramucosal naevus with pseudoepitheliomatous hyperplasia in the gingiva: a case report.

This article describes the unusual case of an intraoral pigmented naevus with pseudoepitheliomatous hyperplasia of the gingiva. A 62-year-old man presented with an almost coal-black pigmented and partly white, spotted, dome-shaped swelling on the lingual gingiva of the mandible. Histologically, the lesion consisted of clusters of round-shaped naevus cells containing melanin granules, reactive with both S-100 immunohistochemical stain and Masson-Fontana silver stain, and pseudoinvasive squamous nests, reactive with cytokeratin. The pathogenesis of the present lesion and problems encountered in its differential diagnosis are discussed.

Circulating matrix metalloproteinases and their inhibitors in patients with Kawasaki disease.

BACKGROUND: Accelerated matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) and/or the quantitative imbalance between MMP and tissue inhibitor of MMP (TIMP) have been implicated in several pathological conditions. MMP and TIMP may also be involved in the destruction of the coronary arterial wall and the resultant coronary arterial lesions in Kawasaki disease. METHODS AND RESULTS: Plasma levels of MMPs, neutrophil elastase, and TIMPs were measured by enzyme-linked immunoassay in 57 patients with Kawasaki disease and no coronary arterial lesions (group 1) and in 8 patients with Kawasaki disease and coronary arterial lesions (group 2). Blood samples were obtained before and after intravenous gamma globulin therapy and in the convalescent stage. Levels of MMPs, neutrophil elastase, and TIMPs were significantly higher in Kawasaki disease patients before gamma globulin therapy than in 18 age-matched afebrile control subjects and 17 age-matched febrile disease control subjects (P<0.01). More importantly, the pre-gamma globulin MMP9 level and MMP9/TIMP2 ratio and post-gamma globulin MMP3 level and MMP3/TIMP1 ratio were significantly higher in group 2 than in group 1 patients (P<0.05). Although MMP levels in febrile disease controls were significantly higher than those of afebrile controls, the MMP/TIMP ratios of febrile disease controls and afebrile controls were comparable. CONCLUSIONS: These data suggest that patients with Kawasaki disease and high levels of MMP and/or MMP/TIMP are susceptible to coronary arterial lesions. Studies of the effects of MMP inhibitors on coronary outcome may provide evidence that MMP is a viable therapeutic target for the prevention of coronary arterial lesions due to Kawasaki disease.

Diverse biological activities of moxa extract and smoke.

Diverse biological activities of moxa extracts and smoke (gas phase) were investigated. Moxa was extracted with hot water (Fr. I), or ethanol (Fr. II), or extracted with hot water after ethanol wash (Fr. III) and then lyophilized to obtain the dried powders. Moxa smoke (containing a lot of gaseous components obtained by burning Moxa) (Fr. IV) was collected into phosphate-buffered saline and quantified spectrophotometrically. These extracts and Moxa smoke showed comparable cytotoxic activity against human oral tumor cell lines (HSC-2, HSG). Human gingival fibroblasts (HGF) were more resistant to any Moxa fractions. Neither of the extracts showed anti-HIV activity. Pretreatment of mice with Fr. I significantly reduced the lethal effect of E. coli infection. All extracts produced radicals under alkaline condition, with a maximum intensity at pH 10.5, and enhanced the radical intensity of sodium ascorbate. It was unexpected that these extracts show significant O2- scavenging activities. These data suggest the medicinal efficacy of Moxa extracts and smoke.

Successful living-donor liver transplantation from an asymptomatic carrier mother in ornithine transcarbamylase deficiency.

A liver transplantation from an asymptomatic mother, who was a carrier of ornithine transcarbamylase deficiency, to her daughter, who had severe manifestation, was successfully performed. One-year monitoring of plasma amino acid and urinary orotate/orotidine levels revealed no abnormality in the urea cycle in either subject.

The influences of molar intrusion on the inferior alveolar neurovascular bundle and root using the skeletal anchorage system in dogs.

The skeletal anchorage system (SAS) was developed as intraoral rigid anchors for open-bite correction by intrusion of molars. Since the application of SAS is a new modality in orthodontic treatment, the influences of radical molar intrusion on the root and the inferior alveolar neurovascular bundle were unknown. The purpose of this research is to verify the effect of molar intrusion on the neurovascular bundle, the level of osseointegration of bone screws, and root resorption. The results of this study showed mandibular molars were intruded 3.4 mm on the average over 7 months in dogs. The miniplates were well stabilized with osseointegrated bone screws and the peri-implant soft tissues showed slight inflammatory changes. Neither nerves nor blood vessels were damaged. Root resorption was observed but was repaired with new cementum. We concluded that the SAS utilizing transmucosal titanium miniplates as an immovable orthodontic anchorage could provide a new modality for molar intrusions without serious iatrogenic problems.

Effects of ketamine on formalin-induced activity in the spinal dorsal horn of spinal cord-transected cats: differences in response to intravenous ketamine administered before and after formalin.

BACKGROUND: Although formalin has been widely used as an algesic substance in rodent studies, the unique biphasic effect seen in rats is not present in humans. Humans, like cats, have a monophasic behavioral response to formalin injection. Electrophysiologically, spinal dorsal horn neurons in cats also have what could be considered a monophasic response after the initial burst of activity following formalin injection. Although several studies of the effects of ketamine on formalin responses have been carried out in rodents, we are unaware of similar studies in cats. We hypothesize that such species differences may explain observed differences in preemptive analgesic effects. Therefore, we examined the effects of ketamine on activity of spinal wide dynamic range (WDR) neurons evoked by formalin injection in cats. METHODS: We investigated in cats the effect of ketamine on the activity of WDR neurons in the spinal dorsal horn that was evoked by formalin. In addition, we studied the effects of pre- and post-administration of ketamine on the maintained phase of the formalin response. Each dose was a subanesthetic, anesthetic or high anesthetic dose (3.0 mg x kg(-1), 10 mg x kg(-1), and 30 mg x kg(-1)). RESULTS: Intravenously administered ketamine produced a dose-dependent depression of evoked activity that was significantly greater when the drug was administered before formalin. CONCLUSION: In spite of the species differences in responses to formalin, there still appears to be a clear preemptive effect of ketamine in the cat. Species differences may not explain apparent differences between human and animal preemptive analgesia.

[The anesthetic management for elective or emergent cesarean section in patients with intracranial arteriovenous malformation].

Subarachnoid hemorrhage secondary to ruptured intracranial arteriovenous malformation (AVM) during pregnancy, although rare, is a grave complication. We experienced 3 patients with AVM for cesarean section. Case 1: A 24-year-old woman suffered sudden vomiting and headache during the 22nd week of her first pregnancy. She was diagnosed as having the intracranial hemorrhage due to AVM. Because the patient was bleeding again at 29th week of pregnancy, emergency operation was performed. Her neurological symptom improved. Cesarean section was performed under general anesthesia at 34th week of pregnancy. Case 2: A 42-year-old woman of her first pregnancy had past history of subarachnoid hemorrhage due to AVM at the ages of 23, 28, 29 and 36. The malformation was not corrected surgically. Her neurological status was normal. Cesarean section was performed under spinal anesthesia. Case 3: A 29-year-old woman suffered sudden hemiplegia, vomiting and headache during the 40th week of her first pregnancy. She was diagnosed as having intracranial hemorrhage. Cesarean section immediately followed by the removal of an intra cranial hematoma under general anesthesia. Better perinatal outcome is expected when AVM rerupture is prevented by first performing cesarean section.

Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity.

The antihyperalgesic properties of the opiate antidiarrheal agent loperamide (ADL 2-1294) were investigated in a variety of inflammatory pain models in rodents. Loperamide exhibited potent affinity and selectivity for the cloned micro (Ki = 3 nM) compared with the delta (Ki = 48 nM) and kappa (Ki = 1156 nM) human opioid receptors. Loperamide potently stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding (EC50 = 56 nM), and inhibited forskolin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary cells transfected with the human mu opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee joint resulted in potent antinociception to knee compression that was antagonized by naloxone, whereas injection into the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood pressure. Loperamide potently inhibited late-phase formalin-induced flinching after intrapaw injection (A50 = 6 microgram) but was ineffective against early-phase flinching or after injection into the paw contralateral to the formalin-treated paw. Local injection of loperamide also produced antinociception against Freund's adjuvant- (ED50 = 21 microgram) or tape stripping- (ED50 = 71 microgram) induced hyperalgesia as demonstrated by increased paw pressure thresholds in the inflamed paw. In all animal models examined, the potency of loperamide after local administration was comparable to or better than that of morphine. Loperamide has potential therapeutic use as a peripherally selective opiate antihyperalgesic agent that lacks many of the side effects generally associated with administration of centrally acting opiates.

Skeletal anchorage system for open-bite correction.

A skeletal anchorage system was developed for tooth movements. It consists of a titanium miniplate that is temporarily implanted in the maxilla or the mandible as an immobile anchorage. In this article, we introduce the skeletal anchorage system to intrude the lower molars in open-bite malocclusion and evaluate the results of treatment in two severe open-bite cases that underwent orthodontic treatment with the system. Titanium miniplates were fixed at the buccal cortical bone around the apical regions of the lower first and second molars on both the right and left sides. Elastic threads were used as a source of orthodontic force to reduce excessive molar height. The lower molars were intruded about 3 to 5 mm, and open-bite was significantly improved with little if any extrusion of the lower incisors. No serious side-effects were observed during the orthodontic treatment. The system was also very effective for controlling the cant and level of the occlusal plane during orthodontic open-bite correction.

[The effects of sevoflurane, isoflurane or enflurane on the pattern of phrenic nerve discharge in rabbits].

In order to estimate primary action of anesthetic agents on the central neural mechanisms of respiratory control and the ventilatory response to an acute increased ETCO2, the effect of sevoflurane (SEV), isoflurane (ISO) or enflurane (ENF) on the pattern of phrenic nerve discharge (Phr.N.A.) was studied in adult rabbits which had been vagotomized, paralyzed and ventilated artificially with 100% oxygen. Throughout the course of experiment, ETCO2 and the rectal temperature of animals were maintained around physiological values. Depressant effects of these anesthetics on Phr. N.A. which consisted of inspiratory slope (SLO), peak amplitude (AMP), inspiratory (Ti) and expiratory (Te) time, I/E ratio (I/E) and respiratory cycle (Tc) were evaluated and compared with each anesthetic. At 0.5 MAC administration, SEV and ISO reduced SLO and AMP without a remarkable change in Tc, but ENF did with a prolongation in Tc. Inhalation of each anesthetic with 1 MAC caused a marked respiratory slowing with a more reduction of SLO and AMP than those occurred at 0.5 MAC; SEV increased Te more than Ti, but ENF prolonged Ti more than Te, while ISO enhanced both Ti and Te without any change of I/E. An acutely increased ETCO2 after the respiratory arrest (RA test) induced the change of Phr.N.A which was characterized by a marked prolongation in Tc with a prolonged Te, an increased SLO and an augmented AMP. The prolonged Tc induced by RA test was diminished by the inhalation of anesthetics, and a new response, shortening in Ti was produced by ENF and ISO. Based on these results, it might be concluded that there are both quantitative and qualitative differences in these anesthetic effects on the central pattern generator of respiration and the mechanism of CO2 responses at equipotent anesthetic concentrations.

X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency.

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. It is X-linked and hemizygous new-born males usually suffer fatal hyperammonemia. In contrast, carrier females manifest variable phenotypes, ranging from asymptomatic carriers to those with severe hyperammonemia. In order to understand the correlation between X-inactivation status and the clinical phenotype of carrier females with this disorder, we analyzed the X-inactivation pattern of peripheral blood leukocytes in a family consisting of a clinically normal mother and two daughters with severe manifestation. In addition, we obtained tissue samples from various parts of the liver of one of these daughters and analyzed X-inactivation patterns and the residual OTC activities. The X-inactivation of peripheral blood leukocytes was nearly random in these carrier females and showed no correlation with the disease phenotype. However, the X-inactivation of the liver was much more skewed and correlated well with the OTC activity of all samples. Interestingly, the degree of X-inactivation varied considerably, even within the same liver.

[The effects of isoflurane on the formalin-induced activity in the spinal dorsal horn of transected cat].

Although the formalin test is widely used in rodents, the electrical response to this stimulus and the effect of isoflurane on this response, has not been well understood in cats. We have therefore examined the effect of isoflurane on spinal wide-dynamic-range neuronal activity evoked by a subcutaneous (s.c.) formalin injection in cats. In decerebrate, spinal cord-transected cats (L 1-2), a s.c. injection of formaldehyde solution (0.05 ml; 5%) was performed in the receptive fields of spinal wide-dynamic-range neurons at the hind paw. Isoflurane (1.5%) inhalation was given 20 mins prior to formalin injection or 5 mins after the formalin injection. The formalin injection elicited an immediate and continuous discharge or burst activity in the neurons that lasted at least 90 min. Inhaled isoflurane was found to markedly inhibit this neuronal discharge. At 30 mins after discontinuing of isoflurane, the neuronal activity in both groups recovered to approximately 55% of the control value. These results suggest that formalin injection will reliably produce a continuous burst of neuronal activity in the spinal dorsal horn of cats, and that this activity can be markedly reduced by isoflurane. The ability of isoflurane to inhibit this neuronal response was not temporally related to the formalin injection.