[Responses to "A Review of the Book 'Minamata Disease and the Responsibility of Medical Authorities'"].

Drs. Futatsuka, Eto, and Uchino expressed their opinions in the Journal of the Japanese Society for Hygiene in the form of a review of my book, "Minamata Disease and the Responsibility of Medicine." (The reviewers translated it as "Responsibility of Medical Authorities," but for my purposes in writing this book, I believe it should be translated as "Responsibility of Medicine.") The nine major comments of the three reviewers described in this book review were reviewed from the basic perspective of toxicology, epidemiology, and neuroscience. This book review is fraught with either medical, logical, or ethical problems in all the nine points as follows: (1) the inadequate way in which exposure and health hazards are considered from the toxicological perspective, (2) problems in interpreting epidemiological information, (3) the failure to consider recent achievements in methylmercury toxicosis studies, (4) presenting the reviewers' own theories without regard to the content of my book while calling it a "book review," (5) presenting and criticizing what Takaoka does not claim as if he does, and (6) making claims that are inconsistent with the three reviewers' own views. The problems with this book review will become even clearer when you read "Minamata Disease and the Responsibility of Medicine" itself.

Characteristics of Abnormalities in Somatosensory Submodalities Observed in Residents Exposed to Methylmercury.

Hundreds of thousands of people living along the Yatsushiro Sea coast have been exposed to methylmercury from the contaminated water of the Chisso factory in Minamata. The most common neurological disorder caused by methylmercury is somatosensory disturbance, but very few studies have been conducted in the world to determine its pathophysiology and origin, including the Japanese cases, which have produced numerous intoxicated individuals. We have already shown in previous studies the body part where the disorder occurs and that its cause is not peripheral nerve damage but damage to the parietal lobes of the cerebrum. We reanalyzed the results of subjective symptoms, neurological findings, and quantitative sensory measurements in 197 residents (63.2 ± 10.7 years old) from contaminated areas exposed to methylmercury from seafood and 130 residents (63.7 ± 9.3 years old) from control areas, the same subjects as in previous studies, to determine the characteristics of somatosensory disturbance in detail. The most commonly affected sensory modalities were superficial peripheral touch and pain in the extremities, followed by two-point discrimination and deep senses, and in the most severe cases, full-body sensory dysfunction and impairment of all sensory submodalities. The severity of sensory submodalities correlated with each other but not with peripheral nerve conduction test indices, further confirming the correctness of our assertion about the responsible foci of sensory disturbance. The health effects of chronic methylmercury toxicosis can be elucidated by a detailed examination of sensory deficits.

Correction: Takaoka, S., et al. Survey of the Extent of the Persisting Effects of Methylmercury Pollution on the Inhabitants around the Shiranui Sea, Japan. Toxics 2018, 6, 39.

The authors wish to make the following corrections to this paper [...].

Accelerated functional losses in ageing congenital Minamata disease patients.

Severe methylmercury poisoning occurred in Minamata and neighboring communities in Japan during the 1950s and 1960s. A considerable number of children were born with conditions resembling cerebral palsy, later known as congenital Minamata disease. Although surviving patients are now in their 50s or 60s, few assessments of functional capacities in daily living have been performed. We assessed the changes in Activities of Daily Living (ADL) status of 11 patients over a 10-year period. For assessment of ADL, we applied the Barthel Index (BI) and the Functional Independence Measure (FIM). We obtained the patients' current and previous status information by interview of their caregivers or from medical records and then compared them using the Wilcoxon signed-rank test. Both ADL measures, including the status related with cognition, had significantly declined during the 10 years. The same was true for the overall BI score (p = 0.01). Similarly, all functions of the FIM scores declined (i.e., self-care, sphincter control, mobility, locomotion, communication, and social cognition), and for FIM physical and cognition subscores as well as FIM total score, the declines were statistically significant. The present study indicates that the ADL status of congenital Minamata disease patients, now in their 50s or 60s, has substantially declined during the last 10 years; a decline that was much steeper in comparison with expectation in subjects of similar ages, but in agreement with accelerated ageing also reported in subjects with cerebral palsy, past polio infection, or epilepsy. While already incapacitated due to the prenatal methylmercury poisoning, their accelerated ageing may suggest that patients with developmental neurotoxicity have less reserve capacity to compensate for normal ageing. These patients will need continuous and increasing medical and welfare support in the community.

Survey of the Extent of the Persisting Effects of Methylmercury Pollution on the Inhabitants around the Shiranui Sea, Japan.

In 1956 methylmercury poisoning, known as Minamata disease, was discovered among the inhabitants around the Shiranui Sea, Kyushu, Japan. Although about five hundred thousand people living in the area had supposedly been exposed to methylmercury, administrative agencies and research institutes had not performed any subsequent large scale, continuous health examination, so the actual extent of the negative health effects was not clearly documented. In 2009, we performed health surveys in order to examine residents in the polluted area and to research the extent of the polluted area and period of pollution. We analyzed data collected on 973 people (age = 62.3 ± 11.7) who had lived in the polluted area and had eaten the fish there and a control group, consisting of 142 persons (age = 62.0 ± 10.5), most of whom had not lived in the polluted area. Symptoms and neurological signs were statistically more prevalent in the four groups than in the control group and were more prevalent and severe in those who had eaten most fish. The patterns of positive findings of symptoms and neurological findings in the four groups were similar. Our data indicates that Minamata disease had spread outside of the central area and could still be observed recently, almost 50 years after the Chisso Company's factory had halted the dumping of mercury polluted waste water back in 1968.

Characteristics of hand tremor and postural sway in patients with fetal-type Minamata disease.

About forty certified patients aged around 50 years old existed as living witnesses to fetal-type Minamata disease (methylmercury poisoning due to in utero exposure) in Minamata, Japan in 2006. Computerized hand tremor and postural sway tests with spectral analysis were conducted for 24 of them and in matched control subjects to examine the pathophysiological feature of neuromotor function. The tremor intensities of the patients with fetal-type Minamata disease were significantly larger than those of the 67 controls at every frequency band for both hands. In the patients, proportions for intensity at 1-6 Hz of both hands were larger, but those of the intensity at 6-10 Hz were smaller compared with the controls. The center frequency of a tremor was significantly lower in the patients than in the controls. Only eight males of the 24 patients were examined to evaluate postural sway because of extremely low scores in activities of daily living in the remaining. Most of the postural sway parameters obtained with eyes open and closed were significantly larger in the patients than in the male controls. Likewise, Romberg quotients of postural sway in anterior-posterior direction were significantly higher in the patients. In conclusion, the patients with fetal-type Minamata disease of our study showed a larger tremor of low frequency at less than 6 Hz and postural instability. Spectral analyses of computerized hand tremor and postural sway are suggested to be useful for assessing the pathophysiological change, related to a lesion of the cerebellum, resulting from prenatal methylmercury exposure.

Acute effects of traditional Japanese alcohol beverages on blood glucose and polysomnography levels in healthy subjects.

Background. Alcohol consumption is a lifestyle factor associated with type 2 diabetes. This relationship is reportedly different depending on the type of alcohol beverage. The purpose of this study was to examine the acute effects of traditional Japanese alcohol beverages on biochemical parameters, physical and emotional state, and sleep patterns. Methods. Six healthy subjects (three men and three women; age, 28.8 ± 9.5 years; body mass index, 21.4 ± 1.6 kg/m(2)) consumed three different types of alcohol beverages (beer, shochu, and sake, each with 40 g ethanol) or mineral water with dinner on different days in the hospital. Blood samples were collected before and 1, 2, and 12 h after drinking each beverage, and assessments of physical and emotional state were administered at the same time. In addition, sleep patterns and brain waves were examined using polysomnography. Results. Blood glucose levels at 1 h and the 12-h area under the curve (AUC) value after drinking shochu were significantly lower than that with water and beer. The 12-h blood insulin AUC value after drinking shochu was significantly lower than that with beer. Blood glucose × insulin level at 1 h and the 2-h blood glucose × insulin AUC value with shochu were significantly lower than that with beer. The insulinogenic indexes at 2 h with beer and sake, but not shochu, were significantly higher than that with water. The visual analogue scale scores of physical and emotional state showed that the tipsiness levels with beer, shochu, and sake at 1 h were significantly higher than that with water. These tipsiness levels were maintained at 2 h. The polysomnography showed that the rapid eye movement (REM) sleep latency with shochu and sake were shorter than that with water and beer. Conclusions. Acute consumption of alcohol beverages with a meal resulted in different responses in postprandial glucose and insulin levels as well as REM sleep latency. Alcohol beverage type should be taken into consideration for people with impaired glucose tolerance.

Signs and symptoms of methylmercury contamination in a First Nations community in Northwestern Ontario, Canada.

In 1970, fish caught in the English-Wabigoon River system in northwestern Ontario, Canada, were found to be contaminated with mercury coming from a chlor-alkali plant in the province. In the 1970s, patients exhibiting some of the symptoms of the Hunter-Russell syndrome (e.g. paresthesias, visual field constriction, ataxia, impaired hearing, and speech impairment) were reported by some researchers. However attempts to diagnose the patients as suffering from methylmercury poisoning proved to be controversial. In order to research the presence of methylmercury contamination, and show that the patients, through eating contaminated fish, were suffering from methylmercury poisoning, we studied the results of subjective complaints, neurological findings, and quantitative somatosensory measurements gathered in Grassy Narrows Indian Reservation, Ontario, in March, 2010. At that time, the population of the Grassy Narrows settlement was around 900. Ninety-one residents volunteered to be examined. From them, we selected 80 people who were older than 15 years old, and divided them into two groups. Canadian Younger (CY): 36 residents who were from 16 to 45 years old. Canadian Older (CO): 44 residents who were from 46 to 76 years old. We compared them to Japanese Exposed (JE): 88 methylmercury exposed residents from the Minamata district in Japan, and Japanese Control (JC): 164 control residents from non-polluted areas in Japan. Complaints and abnormal neurological findings were more prevalent and quantitative sensory measurements were worse in the two Canadian groups and the Japanese Exposed group than in the Japanese Control group. Complaints, neurological findings and quantitative sensory measurements were similar in Canadian Older and Japanese Exposed. The results for Canadian Younger fell between those of Canadian Older and Japanese Control. These findings indicate that the clinical signs and symptoms of the residents of Grassy Narrows are almost the same as those recorded for Minamata disease in Japan.

Synthesis of a key intermediate, 10-acetyl-7-(t-butyldiphenylsilyloxymethyl)-4-methylbicyclo[5.3.0]dec-4-en-1-ol, in the synthesis of pseudolaric acid A.

10-Acetyl-7-(t-butyldiphenylsilyloxymethyl)-4-methylbicyclo[5.3.0]dec-4-en-1-ol was synthesized by aldol cyclization to a five-membered ring, epoxidation, samarium diiodide-induced ring opening, and the RCM reaction to the seven-membered carbocycle. This method has succeeded in constructing the desired stereochemistry in the synthesis of pseudolaric acid A.

Somatosensory disturbance by methylmercury exposure.

Minamata disease is methylmercury poisoning from consuming fish and shellfish contaminated by industrial waste. The polluted seafood was widely consumed in the area around Minamata, but many individuals were never examined for or classified as having Minamata disease. Following the determination of the Supreme Court of Japan in October 2004 that the Japanese Government was responsible for spreading Minamata disease, over 13,000 residents came forward to be examined for Minamata disease. We studied 197 residents from the Minamata area who had a history of fish consumption during the polluted period to determine the importance of sensory symptoms and findings in making a diagnosis of Minamata disease. We divided the exposed subjects into non-complicated (E) and complicated (E+N) groups based on the absence or presence of other neurological or neurologically related disorders and compared them to residents in control area (C) after matching for age and sex. We quantitatively measured four somatosensory modalities (minimal tactile sense by Semmes-Weinstein monofilaments, vibration sense, position sense, and two-point discrimination) and did psychophysical tests of fine-surface-texture discrimination. Subjective complaints were higher in groups E and E+N than C. Over 90% of E+N and E subjects displayed a sensory disturbance on conventional neurological examination and 28% had visual constriction. About 50% of the E and E +N groups had upper and lower extremity ataxia and about 70% had truncal ataxia. The prevalence of these neurological findings was significantly higher in exposed subjects than controls. All sensory modalities were impaired in the E and E+N groups. All four quantitatively measured sensory modalities were correlated. The prevalence of complaints, neurological findings, and sensory impairment was similar or a little worse in group E+N than in group E. We conclude that sensory symptoms and findings are important in making the diagnosis of Minamata disease and that they can be determined even in the presence of neurological or neurologically related diseases.

Chemical constituents of Malagasy liverworts: cyclomyltaylanoids from Bazzania madagassa.

Five cyclomyltaylanoids (2-6), together with 1R,5R-diacetoxycyclomyltaylan-10-one (1), (+)-globulol, and ent-4beta,10alpha-dihydroxyaromadendrane have been isolated from the diethyl ether fraction of the Malagasy liverwort, Bazzania madagassa. The structure of 1 was confirmed by X-ray analysis, while those of the compounds were established on the basis of one- and two-dimensional NMR spectroscopic evidence, and comparison with data reported in the literature. The chemosystematics of B. madagassa are discussed.

Cinnafragrins A-C, dimeric and trimeric drimane sesquiterpenoids from Cinnamosma fragrans, and structure revision of capsicodendrin.

Two new dimeric sesquiterpenoids and a new trimeric drimane sesquiterpenoid named cinnafragrins A-C (1-3), together with cinnamodial (4), D-mannitol, capsicodendrin (5), and a vitamin E analogue, delta-tocotrienol, were isolated from Cinnamosma fragrans, a Malagasy medicinal plant. The structures of the new compounds were determined on the basis of physical, chemical, and spectroscopic evidence. Capsicodendrin, previously isolated from Capsicodendron dinisii and tentatively suggested to be a tetramer of cinnamodial, was revised structurally as a mixture of C-12'-epimers of 12'-hydroxycinnafragrin B by extensive 2D NMR analysis and X-ray crystallography of the lactone derivative, cinnafragrolide (6). The chemosystematics of the family Canellaceae are discussed.

Momordica charantia constituents and antidiabetic screening of the isolated major compounds.

Bioguided fractionation of the methanol extract of Momordica charantia dried gourds led to the isolation of three new cucurbitane triterpenoids (1-3), together with eight known compounds (4-11). The aglycone of momordicoside I was isolated from the ether soluble fraction in a high amount. The structures of the metabolites were established on the basis of one and two dimensional NMR spectroscopic evidence, X-ray analysis, and comparison with the reported data in the literature. A number of phytochemicals have been isolated from Momordica charantia but the constituents responsible for the hypoglycaemic/antihyperglycaemic activities have not been determined. Therefore, in order to evaluate the contribution of the cucurbitane triterpenoids of the ether fraction of M. charantia methanol extract to in vivo anti-diabetic effects, the major compounds, 5beta,19-epoxy-3beta,25-dihydroxycucurbita-6,23(E)-diene (4), and 3beta,7beta,25-trihydroxycucurbita-5,23(E)-dien-19-al (5) have been tested and have shown blood hypoglycaemic effects in the diabetes-induced male ddY mice strain at 400 mg/kg. The two aglycones of charantin did not show any hypoglycaemic effects. Our finding is the first demonstration that major pure cucurbutanoid compounds of M. charantia have in vivo hypoglycaemic effects.

ent-Verticillane-type diterpenoids from the Japanese liverwort Jackiella javanica.

Three ent-verticillane diterpenoids and two ent-sesquiterpenoids were isolated from the Japanese liverwort Jackiella javanica Schiffn. together with five known ent-verticillane and three ent-kaurane diterpenoids, and three sesquiterpenoids. Five ent-verticillane epoxides were synthetically prepared from ent-verticillols action to clarify the absolute configuration of natural ent-9,10-epoxyverticillol. Their structures were established by extensive NMR spectroscopic and X-ray crystallographic analyses.

New sesquiterpenoids from the New Zealand liverwort Chiloscyphus subporosus.

A new aromadendrane-type sesquiterpenoid, 4(15)-aromadendren-12,5alpha-olide and an aromadendrane-guaianolide dimer have been isolated from the New Zealand liverwort Chiloscyphus subporosus. Their structures were established by extensive NMR techniques and X-ray crystallographic analysis.

Psychophysical sensory examination in individuals with a history of methylmercury exposure.

Paresthesias are the first symptom that people report following toxic doses of methylmercury. The authors conducted a psychophysical study of tactile sensation to evaluate the somatosensory abilities of subjects living in a methylmercury-polluted area around Minamata City, Japan. The authors examined control subjects and methylmercury-exposed subjects with and without numbness. A history of methylmercury exposure was taken and a neurological examination performed. Aluminum-oxide abrasive papers were used as stimuli in a psychophysical sensory examination of fine-surface-texture discrimination. Difference thresholds from 3 microm were calculated by the two-alternative, forced-choice technique. Difference thresholds in control subjects were also calculated for comparison. The difference threshold was 6.3 microm in exposed subjects with sensory symptoms, 4.9 microm in exposed subjects without sensory symptoms, and 2.7 microm in control subjects. Acuity of fine-surface-texture discrimination was disturbed not only in subjects with clinical complaints of hand numbness, but also in subjects without hand numbness who lived in the district where methylmercury exposure occurred. Sensory testing using a psychophysical test of fine-surface-texture discrimination in this population suggests that the number of individuals affected by methylmercury exposure in the polluted area was greater than previously reported.

Terpenoids and aromatic compounds from the New Zealand liverworts Plagiochila, Schistochila, and Heteroscyphus species.

A new clerodane- and two new ent-rosane-type diterpenoids have been isolated from the New Zealand liverworts Heteroscyphus billardierii and Plagiochila deltoidea, respectively. The known bisbibenzyl compounds and acetophenones have also been isolated from Schistochila glaucescens and Plagiochila fasciculata. Their structures were established by extensive NMR techniques. Chemosystematics of the Plagiochila species have been discussed.

Tyromycic acids B-E, new lanostane triterpenoids from the mushroom Tyromyces fissilis.

Four new triterpenoids, tyromycic acids B-E (1-4), were isolated from a methanol-soluble extract of the fruit bodies of the Japanese inedible mushroom Tyromyces fissilis. Tyromycic acids B-D possess a lanostane skeleton, while tyromycic acid E is based on a rare 14(13-->12)abeo-lanostane skeleton. Their structures were determined by spectral data analysis and by single-crystal X-ray crystallography.

ent-Isopimarane-type diterpenoids from the New Zealand liverwort Trichocolea mollissima.

Two ent-isopimarane-type diterpenoids were isolated from the New Zealand liverwort Trichocolea mollissima (Hook. f. and Tayl.) Gott., together with a known 1alpha-hydroxy-ent-sandaracopimara-8(14),15-diene. Their absolute structures have been established by modified Mosher's method, X-ray crystallography and by analyses of their CD spectra.