Pancreatic α-cell hyperplasia and hyperglucagonemia due to a glucagon receptor splice mutation.

Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3' mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato-pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells. LEARNING POINTS: Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.A hepato-pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

Differences in the Treatment Response to Antithyroid Drugs versus Electroconvulsive Therapy in a Case of Recurrent Catatonia due to Graves' Disease.

We reported a case which presented recurrent episodes of catatonia as a result of Graves' disease with hyperthyroidism. The patient showed different treatment response in each episodes; in the first episode, psychiatric and physical symptoms were resolved by a combination of antithyroid and anxiolytic therapies, while in the second episode, the combination therapy did not ameliorate her symptoms and ECT was indicated. We postulated that decreased CSF level of TTR and the resulting susceptibility to the derangement of peripheral thyroid function might be involved in this different treatment response.

Losartan potassium/hydrochlorothiazide (Preminent®) and hyponatremia: case series of 40 patients.

The clinical course of losartan potassium/hydrochlorothiazide (Preminent(®))-induced hyponatremia has not been described. We summarized 40 patients with Preminent-induced hyponatremia. The study involved 15 (37.5%) men and 25 (62.5%) women (mean age [SD], 76.4 [8.3] years; range, 55-95). Their sodium levels before Preminent administration were 139.5 (4.9) mEq/L (range, 131-145; reference range, 135-147). The duration from the day of Preminent administration to the day with the lowest sodium level was 59.3 (64.9) days (range, 2-207; median, 24). Most patients for whom this duration was <50 days exhibited progressive symptoms, whereas most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss. The lowest sodium value was 114.4 (8.2) mEq/L (range, 99-133). The duration from the time of Preminent discontinuation to (1) the time of early recovery and (2) the time of final recovery was 6.8 (5.5) days (range, 1-20; median, 5) and 11.6 (7.6) days (range, 2-29; median, 7.5), respectively. Of the 40 patients, 36 (90.0%) achieved full recovery, 1 (2.5%) suffered from after-effects due to central pontine myelinolysis, 1 (2.5%) died, and 2 (5.0%) were unknown. In the analysis of other adverse effects of Preminent and the same adverse effects of other three angiotensin II receptor blocker (ARB)/thiazide combinations, hyponatremia was observed as a primary adverse effect of all ARB/thiazide combinations. However, hyperesthesia dermatitis was reported as an adverse effect of Preminent only.

Severe hypothyroidism associated with the degree of edema in a patient with nephrosis.

We report the pleural fluid values of thyroid hormones and their carrier proteins in a patient who suffered from nephrotic syndrome with renal insufficiency and transient hypothyroidism. The pleural effusion was transudate. The concentrations of thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 30-50% of the plasma. Hypothyroidism was associated with the degree of edema. After improving systemic edema, proteinuria remained unchanged but the patient did not require levothyroxine. We speculate that the large amount of transudation of thyroid hormones with their carrier proteins from the blood vessels to the third space (edema and pleural effusion), thereby reducing thyroid hormones in the plasma, was associated with hypothyroidism.

Thyroid hormones, their carrier proteins, and thyroid antibodies in the pleural effusion of two patients with graves' disease-induced thyrotoxicosis.

INTRODUCTION: Concentrations of thyroid hormones, their carrier proteins, and thyroid antibodies in plasma have been extensively investigated, but those in pleural effusion have not. PATIENTS AND MEDTHODS: In the present study, we report, for the first time, the concentrations of thyroid hormones, their carrier proteins, and thyroid antibodies in the pleural effusion of two thyrotoxicosis patients with Graves' disease. RESULTS: The pleural effusions were transudates. The concentrations of thyroid hormone carrier proteins, such as thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 15-40%, 45-55%, 45-75%, and 80-85% of the plasma, respectively. The concentration of thyroid stimulating hormone receptor antibody (TRAb) (equal to TSH-binding inhibitory immunoglobulins%; TBII%) was approximately 90% of the plasma. CONCLUSION: If the pleural effusions were treated with diuretics, substantial quantity of thyroid hormones and thyroid antibodies in the pleural effusion may have returned to the plasma, and might exacerbate thyrotoxicosis. For patients with thyrotoxicosis and pleural effusion, thoracentesis should be considered. The present findings will contribute to the understanding and treatment of hyperthyroidism-induced pleural effusion.

A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizure and epilepsy.

DiGeorge syndrome - a component of the 22q11 deletion syndrome - causes a disturbance in cervical neural crest migration that results in parathyroid hypoplasia. Patients can develop hypocalcemia-induced seizures. Spina bifida is caused by failure of neurulation, including a disturbance in the adhesion processes at the neurula stage. Spina bifida has been reported as a risk factor for epilepsy. We report, for the first time, the case of a patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizures and epilepsy. The patient had spina bifida and sacral myelomeningocele at birth. At the age of 13 years, he experienced a seizure for the first time. At this time, the calcium concentration was normal. An electroencephalogram (EEG) proved that the seizure was due to epilepsy. Antiepileptic medications controlled the seizure. At the age of 29, the patient's calcium concentration began to reduce. At the age of 40, hypocalcemia-induced seizure occurred. At this time, the calcium concentration was 5.5mg/dL (reference range, 8.7-10.1mg/dL). The level of intact parathyroid hormone (PTH) was 6 pg/mL (reference range, 10-65 pg/mL). Chromosomal and genetic examinations revealed a deletion of TUP-like enhancer of split gene 1 (tuple1)-the diagnostic marker of DiGeorge syndrome. Many patients with DiGeorge syndrome have cardiac anomalies; however, our patient had none. We propose that the association among DiGeorge syndrome, spina bifida, epilepsy, cardiac anomaly, 22q11, tuple1, and microdeletion inheritance should be clarified for appropriate diagnosis and treatment.

Severe duodenal hemorrhage induced by Lugol's solution administered for thyroid crisis treatment.

Lugol's solution is an iodinated agent used for treating thyroid crisis. It is primarily used in diagnostic tests for esophageal diseases. However, Lugol's solution can cause local mucosal injury and hemorrhage. We report, for the first time, a case of 34-year-old man who exhibited severe duodenal hemorrhage induced by Lugol's solution that was used to treat thyroid crisis. The quantity of Lugol's solution used for treating thyroid crisis is much higher than that used for mucosal disease investigation. Clinical practitioners should be aware of gastrointestinal hemorrhage when using Lugol's solution for the treatment of thyroid crisis.

The best insulin injection pen device for caregivers: results of injection trials using five insulin injection devices.

BACKGROUND: Insulin injection pens have been primarily developed for self-injection among individuals with diabetes. However, an increased elderly population with diabetes has caused an increase in the number of patients who cannot self-inject insulin. Consequently, caregivers inject insulin to the patients ("other-injection"); however, insulin injection devices have not yet been developed for other-injection use. METHODS: We evaluated five devices-OptiClik (Sanofi-aventis, Paris, France), SoloStar (Sanofi-aventis), MirioPen without an antiskid tool (Eli Lilly and Co., Indianapolis, IN), MirioPen with an antiskid tool (Eli Lilly, Hyogo, Japan), and FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark). In all, 22 respondents (mean +/- SD age, 42.6 +/- 9.3 years [range, 26-57 years]), including 11 men (50.0%) and 11 women (50.0%), injected themselves (self-injection) and others (other-injection). Thereafter, respondents evaluated the ease of use and feel of the pen devices via questionnaires. As a result, we evaluated 220 procedures of insulin injections [22 (respondents) x 5 (devices) x 2 (self and other)] in this study. RESULTS: FlexPen was selected as the best device for self-injection but as the worst device for other-injection. OptiClik was selected as the second worst device for self-injection but as the best device for other-injection. Moreover, for other-injection, FlexPen was too long and less stable, had poor dial visibility, was difficult to recap, and was comprehensively inferior. CONCLUSIONS: We identified problems that were not apparent during studies evaluating conventional self-injection. We conclude that devices meant for other-injection should have different features from those designed for self-injection and that consideration of caregivers' viewpoints is necessary for developing an insulin device specifically meant for other-injection.

Primary sellar lymphoma: intravascular large B-cell lymphoma diagnosed as a double cancer and improved with chemotherapy, and literature review of primary parasellar lymphoma.

Lymphoma is one of the causative factors of hypothalamus-pituitary dysfunction, and intravascular large B-cell lymphoma (IVLBCL) is a subtype of primary extranodal neoplasm. A 69-year-old woman visited our hospital because of general fatigue. We diagnosed her with presumable non-functional primary pituitary adenoma and subsequent dysfunction. Eight months after, the patient revisited our hospital because of dyspnea. Though we conducted systemic investigations including chest and abdomen enhanced computer tomography, transbronchial lung biopsy, and bone marrow biopsy, the diagnosis was not confirmed. Inadvertently, a breast cancer was found, and the surgical specimen proved that the patient had double cancer-adenocarcinoma and IVLBCL. Rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone regimen was initiated, and complete remission was achieved. Notably, the sellar mass returned to normal size with improved function. We reviewed 32 patients with primary parasellar lymphoma. In affected sites, both sellar and pituitary stalk (6.7%), both hypothalamus and pituitary stalk (6.7%), only sellar (63.3%), only pituitary stalk (6.7%), only hypothalamus (13.3%), and only clivus (3.3%) were observed. In hypothalamus-pituitary dysfunction, both anterior and posterior dysfunction (20.7%), only anterior dysfunction (58.6%), only posterior dysfunction (3.4%), and no dysfunction (17.2%) were observed. It seemed that hypothalamic lesion is related to both anterior and posterior dysfunction, while sellar lesion is related to mainly anterior dysfunction. In cranial nerve dysfunction, 2nd nerve dysfunction (45.2%) and 6th nerve dysfunction (35.5%) were frequently observed. It seemed that sellar lesion is related to both 2nd and 6th nerve dysfunction, while hypothalamic lesion is related to mainly 2nd nerve dysfunction.

Tremor in Klinefelter's syndrome improved by testosterone administration.

Tremor in Klinefelter's syndrome is believed to be essential tremor since the publication of "Klinefelter's syndrome and essential tremor" in 1969. However, the author also stated that tremor in Klinefelter's syndrome might differ from essential tremor. A 71-year-old man with Klinefelter's syndrome who suffers from postural hand tremor is described. The electromyogram indicated lower motor neuron disturbance and chronic neurogenic change. The muscle biopsy indicated neurogenic muscle atrophy. Upon testosterone administration, the amplitude of tremor was reduced and a gradual improvement in handwriting was observed. The tremor in this patient was different from essential tremor. The foresight by Baughman in 1969 proved to be true in this patient. This case report provides new insights into the pathogenesis and treatment of tremor in Klinefelter's syndrome, which would benefit patients who suffer from the tremor.

Glutest Neo Super--a new handheld blood glucose meter-corrects for the effects of the hematocrit values in both hematocrit-adjusted samples and samples obtained from anemic patients.

BACKGROUND: Handheld blood glucose (BG) meters are convenient tools that are widely used to measure the BG levels. However, the hematocrit (Hct) value has been identified as a confounding factor for accurate BG measurement. Some BG meters are equipped with an Hct-correcting feature, whose effectiveness has been tested previously. Nevertheless, the measurements yielded by many BG meters are confounded by the Hct values. Recently, a new BG meter equipped with an Hct-correcting feature has been developed; however, its effectiveness has not yet been confirmed. STUDY DESIGN: Venous blood samples were collected from two healthy volunteers, and the Hct values in the samples were adjusted to approximately 0%, 10%, 20%, 30%, 40%, 50%, and 60%. Further, venous blood samples were collected from 10 anemic patients (Hct <40%). The whole BG (WBG) levels in the samples were measured using two devices-the new BG meter (Glutest Neo Super [Sanwa Kagaku Kenkyusho Co. Ltd., Nagoya, Japan]) and a standard BG meter (OneTouch Ultra [Life Scan Inc., Milpitas, CA]). For reference, plasma glucose (PG) levels were measured using a machine at our hospital laboratory (GA08 [A&T Co., Kanagawa, Japan]). The bias in the measurements was calculated as follows: bias = ([WBG - PG]/PG) x 100. Further, the correlation between the Hct values and the bias was assessed by performing linear regression analysis. RESULTS: In both the Hct-adjusted samples and the samples obtained from anemic patients, the WBG levels measured using Glutest Neo Super were minimally affected by the Hct values, while those measured using OneTouch Ultra were affected by the Hct values to a statistically significant extent. CONCLUSIONS: The Hct-correcting feature of the new BG meter Glutest Neo Super was effective. The use of this new device for BG measurements may lead to more appropriate treatment selection.

Shakuyaku-kanzo-to induces pseudoaldosteronism characterized by hypokalemia, rhabdomyolysis, metabolic alkalosis with respiratory compensation, and increased urinary cortisol levels.

BACKGROUND: Licorice, the primary ingredient of the Japanese herbal medicine shakuyaku-kanzo-to, can cause pseudoaldosteronism. Thus, shakuyaku-kanzo-to can cause this condition. CASE DESCRIPTION: A 79-year-old woman was brought to the emergency room. She had been experiencing general fatigue, numbness in the hands, and weakness in the lower limbs and could not stand up without assistance. She presented with hypokalemia (potassium level, 1.7 mEq/L), increased urinary excretion of potassium (fractional excretion of K, 21.2%), abnormalities on an electrocardiogram (flat T waves in II, III, AVF, and V1-6), rhabdomyolysis (creatine kinase level, 28,376 U/L), myopathy, metabolic alkalosis with respiratory compensation (O(2) flow rate, 2 L/min; pH, 7.473; pco(2), 61.0 mm Hg; po(2), 78.0 mm Hg; HCO(3), 44.1 mmol/L), hypertension (174/93 mm Hg), hyperglycemia (blood glucose level, 200-300 mg/dL), frequent urination, suppressed plasma renin activity (0.1 ng/mL/hour), decreased aldosterone levels (2.6 ng/dL), and increased urinary cortisol levels (600.6 microg/day; reference range, 26.0-187.0 microg/day). CONCLUSIONS: In this case, the observed reduction in the urinary cortisol levels, from 600.6 to 37.8 microg/day, led to a definitive diagnosis of pseudoaldosteronism instead of the apparent mineralocorticoid excess syndrome. Discontinuing shakuyaku-kanzo-to treatment and administering spironolactone and potassium proved effective in improving the patient's condition. Medical practitioners prescribing shakuyaku-kanzo-to should take into account the association between licorice, which is its main ingredient, and pseudoaldosteronism.

IL-12 and IL-18 induction and subsequent NKT activation effects of the Japanese botanical medicine Juzentaihoto.

In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT). Of the cytokines measured interleukin (IL) -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT) cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM) observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours) induction of interferon (IFN)-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects.

Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus.

OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.