Effect of alendronate on bone metabolic indices and bone mineral density in patients treated with high-dose glucocorticoid: a prospective study.

SUMMARY: This prospective study, in the very early phase after initiation of glucocorticoid (GC) treatment, showed that alendronate was effective in suppressing accelerated bone resorption and subsequent decrease in bone mineral density (BMD) at the lumbar spine of patients with high-dose GC treatment. INTRODUCTION: How bisphosphonates affect bone metabolism and BMD of patients with high-dose GC in the early phase, especially within 1 month is unclear. METHODS: We examined the prospective effects of daily 5 mg alendronate on bone metabolism and BMD in 20 patients with high-dose GC (at least 40 mg prednisolone/day) and compared them to 34 high-dose GC-treated patients without alendronate. RESULTS: Serum levels of calcium decreased at day 28 in the alendronate group. Urinary calcium excretion significantly increased after day 7 in both groups. The increase in serum parathyroid hormone (PTH) level at day 7 in the control group was not observed in the alendronate group, but PTH levels increased at day 28 and month 3 in the alendronate group. As for the bone turnover markers, the serum osteocalcin level decreased in both alendronate and control groups, but serum bone-type alkaline phosphatase levels did not show significant changes. Although the urinary type I collagen cross-linked N-telopeptide (NTX) level showed significant increases on days 7 and 28 in the control group; such early increases in urinary NTX were not observed in the alendronate group. Thereafter, the urinary NTX levels fell slowly in the alendronate group significantly. BMD at the lumbar spine significantly decreased from month 1 in the control group, whereas in the alendronate group, BMD at the lumbar spine maintained almost the same level at all time points observed. CONCLUSION: Alendronate was effective in suppressing bone resorption and subsequent BMD decrease at the lumbar spine in patients with high-dose GC treatment.

"Dropped head syndrome" caused by Lambert-Eaton myasthenic syndrome.

A 67-year-old man was admitted with a 2-year history of dropped head. Neurological examination revealed ptosis, dysarthria, neck weakness, hyporeflexia of all limbs, and autonomic failure. Electrophysiologic study showed a 400% increment response to high-rate repetitive nerve stimulation. Serum anti-P/Q-voltage-gated calcium channel antibody was positive, confirming the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS). His symptoms and electrophysiological abnormalities improved with oral prednisolone following plasmapheresis. This is the first report of LEMS as a cause of dropped head syndrome.

Nodular-type muscle sarcoidosis developing after a dog bite.

We report a 46-year-old woman who experienced swelling of the right thigh around the wound caused by a dog bite. Physical findings, laboratory findings, imaging studies, and muscle biopsy showed that this was nodular-type muscle sarcoidosis. This is an unusual case of sarcoidosis, and the possibility is discussed that a dog bite may serve as a trauma to trigger sarcoidosis in genetically predisposed individuals.

Clinical features and skewed X-chromosome inactivation in female carriers of X-linked recessive spinal and bulbar muscular atrophy.

In X-linked recessive disorders, a few female gene carriers become symptomatic. Recent evidence implicates skewed X-chromosome inactivation in such female carriers. We studied the clinical features of eight female gene carriers of X-linked recessive spinal and bulbar muscular atrophy (SBMA), and evaluated the relationship between phenotype and genotype from the viewpoint of X-chromosome inactivation. Seven of eight cases were symptomatic, showing mild muscle weakness, frequent muscle cramps, slight elevation of the serum creatinine kinase level, or neurogenic changes on the electromyogram. Only one carrier was asymptomatic clinically. For the estimation of X-chromosome inactivation, the methylation status of the androgen receptor (AR) gene was determined by polymerase chain reaction-based assay. Highly skewed inactivation of the affected AR gene was found in the asymptomatic carrier, while symptomatic carriers had a random or lower inactivation pattern of the affected AR gene. These findings suggest that most female carriers of SBMA show some clinical abnormalities, and highly skewed inactivation of the affected X-chromosome seems to closely relate with escape of the manifestation in female carriers of SBMA.

[A case of cephalic tetanus presenting with opisthotonus].

We report a case of cephalic tetanus presenting with opisthotonus. A 49-year-old man was admitted because of repeated convulsions. The patient was a garbage truck driver known to be alcoholic, who fell down to suffer an injury of the left face two days before the onset of convulsion. Intravenous administration of diazepam and phenytoin partially relieved the convulsions. Anti-tetanus human immuno-globulin was also administered despite absence of typical clinical sign. Six hours later, however, the patient became unable to open the mouth, i.e. lockjaw developed, and the diagnosis of tetanus was made. Additional anti-tetanus human immunoglobulin of 3,000 units and 4,500 units on the next day rapidly relieved the lockjaw, convulsion, and general muscle rigidity without sequalae. The patient showed transient bilateral facial palsy and rotatory nystagmus during the course. Cephalic tetaus is characterized by a history of an injury of the head and a short latency before developing generalized tonic convulsion or opisthotonus. While a typical case presents with lockjaw, our case presented with opisthotonus, presumably because of early systemic lymphatic spreading of tetanus toxin. Early diagnosis and treatment is important to prevent generalized convulsions which are more frequent and sometimes lethal in cephalic tetanus than the common form.

Decrease of neurons in the medullary arcuate nucleus in myotonic dystrophy.

Respiratory insufficiency has been reported frequently in patients with myotonic dystrophy (MyD). Recent data support the hypothesis that this respiratory failure results from a primary dysfunction of the central nervous system. The medullary arcuate nucleus (ARC) has been shown to be involved in the regulation of respiration. We performed a quantitative study of neurons in the ARC in eight MyD patients, ten control subjects with other neurological diseases (control group A) and eight control subjects without neurological diseases (control group B). Alveolar hypoventilation of the central type occurred in three of the MyD patients but not in the remaining MyD patients or controls. The density of neurons in the ARC in MyD patients with hypoventilation was significantly lower than in MyD patients without hypoventilation and control groups A and B. There was no significant difference in the neuronal density of the ARC between MyD patients without hypoventilation and control groups A and B. These data suggest that the neuronal loss of the ARC is associated with the presence of hypoventilation in MyD.

Insulin-like growth factor 1 inhibits glucocorticoid-induced glutamine synthetase activity in cultured L6 rat skeletal muscle cells.

We previously demonstrated the preventive effect of insulin-like growth factor 1 (IGF-1) on steroid myopathy in rats. However, the mechanism by which IGF-1 inhibits steroid myopathy remains unclear. Recent studies have revealed that glutamine synthetase (GS) is induced by glucocorticoid and may be related to the development of steroid myopathy. In this study, we examined whether IGF-1 affected steroid-induced enhancement of GS activity in L6 rat skeletal muscle cells. Dexamethasone (10(-6) M) significantly increased GS activity in L6 cells (P < 0.01). IGF-1 dose-dependently inhibited dexamethasone-induced GS activity. Addition of IGF-1 (750 ng/ml) decreased GS activity to approximately 50% of that with dexamethasone alone (P < 0.01). These results suggest that a decrease in GS activity may be involved in the preventive effect of IGF-1 on steroid myopathy.

[A survey of radical surgery without neoadjuvant therapy for patients with stage B and C prostatic carcinoma].

There has been much controversy regarding radical surgery for both localized and locally extensive carcinoma of the prostate. We analyzed the outcome of radical prostatectomy and the preoperative evaluation in order to assess the indication of radical prostatectomy. Fifty-six patients with clinical stage B or C prostate cancer were treated by radical prostatectomy without neoadjuvant therapy. Endocrine therapy was added to the non-curative cases postoperatively. Preoperative evaluation was compared with pathological results and survival, and furthermore the usefulness of the preoperative PSA and PSA half-life were investigated. The mean follow-up period was 44.5 months. The accuracy of the grade and the clinical stage were 58.9% and 23.2%, respectively. Organ-confined disease was seen in patients with an initial PSA level less than 30 ng/ml. Postoperative PSA half-life is significantly prolonged in cases with poorly differentiated adenocarcinoma or lymph node involvement and may be a predictor of PSA failure. The cause-specific 5-year survival rates were 92.7% on the whole, 92.9% for well differentiated, 96.7% for moderately differentiated, 85.7% for poorly differentiated, 100% for stage B1, 95.0% for stage B2 and 86.8% for stage C. These results indicated that patients with an initial PSA level of less than 30 ng/ml will benefit from radical prostatectomy.

A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1.

A novel mutation (Arg381Cys) in the second zinc-finger domain of early growth response 2 (EGR2) was identified in a late-onset Charcot--Marie--Tooth disease type 1 (CMT1) patient. This patient had initial symptoms of numbness and weakness in the leg at age 59, and a median nerve motor conduction velocity of 27 m/s. A sural nerve biopsy showed a severe loss of myelinated fibers with numerous onion bulbs. This is the first report of the EGR2 mutation presenting a late onset of CMT1 phenotype. Its mutation was a different amino acid substitution at codon 381 (Arg381His) which demonstrated congenital hypomyelinating neuropathy or early-onset CMT1. This report suggests that the EGR2 mutation represents divergent phenotypes at codon 381, which may be a mutation hotspot.

Sonographically detected malignant transformation of a simple renal cyst.

The clinical course is reported of a simple renal cyst which developed into a septated renal cyst, and finally to a cystic renal cell carcinoma. A 49-year-old man, who had been diagnosed as having a renal cyst, was found by repeated ultrasonography over 6 years to have solid components developing within the cyst. Radical nephrectomy was performed, and pathological examination confirmed cystic renal cell carcinoma (RCC). This case clearly shows a natural history of malignant transformation from a simple renal cyst, and emphasizes that careful follow-up of renal cysts, especially of complicated renal cysts, is mandatory for successful treatment of RCC.

[A case of bladder tumor producing granulocyte-colony stimulation factor and parathyroid hormone-related protein].

A 68-year-old woman presented with urinary pain and frequency. Cystoscopy, intravenous pyelography and magnetic resonance imaging showed a huge bladder mass and hydronephrosis of the left kidney. Transurethral resection of bladder tumor (TUR-Bt) was done. Histopathological findings of TUR-biopsy was high grade transitional cell carcinoma. Post operatively, the laboratory examination showed marked leukocytosis with a maximum of 99,600/mm3 in the peripheral blood and a high level of granulocyte colony stimulating factor (G-CSF), 70 pg/ml in the serum (normal: less than 9.8 pg/ml). Serum calcium level increased gradually and parathyroid hormone-related protein (PTH-rP) revealed high, 8.4 pMol/l (normal: less than 0.6 pMol/l). The tumor cells were positive for G-CSF and PTH-rP immunohistochemical staining. She died of the disease 46 days after the operation. This is the third case of G-CSF and PTH-rP producing bladder tumor in the literature.

Steroid myopathy: pathogenesis and effects of growth hormone and insulin-like growth factor-I administration.

Glucocorticoids have been widely used in the treatment of autoimmune and other diseases. Chronic steroid use, however, could cause proximal muscle weakness and atrophy, termed steroid myopathy. The onset of steroid myopathy is usually insidious and there are no specific laboratory findings except for elevated urinary creatine excretion. Muscle biopsy reveals non-specific type II fiber atrophy. There are many reports showing preventive effects of either growth hormone (GH) or insulin-like growth factor (IGF)-I on steroid myopathy. The pathogenesis of steroid myopathy is not fully understood. Recently, glutamine synthetase has been reported to play a key role in steroid myopathy. GH as well as IGF-I decreased the steroid-induced glutamine synthetase activity in skeletal muscle.

Multifocal fibrosclerosis as a possible cause of panhypopituitarism with central diabetes insipidus.

Multifocal fibrosclerosis denotes a combination of similar fibrous disorders occurring at different anatomical sites. We encountered a 53-year-old male patient with orbital pseudotumor, chronic paranasal sinusitis, fibrous nodules of the lungs, intracranial pachymeningitis, and panhypopituitarism with central diabetes insipidus (DI) as a possible manifestation of multifocal fibrosclerosis. It has been reported that intracranial pachymeningitis or orbital pseudotumor associated with multifocal fibrosclerosis could invade the sella turcica causing a variety of anterior and/or posterior pituitary dysfunctions. In our case, intracranial pachymeningitis apparently involved the pituitary stalk and gland. Isolated gonadotropin deficiency, in addition to central DI, preceded panhypopituitarism. Although panhypopituitarism with central DI due to multifocal fibrosclerosis is quite rare and only one case has ever been reported, this systemic fibrotic disorder can be a possible cause of panhypopituitarism with central DI.

Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448R) of the glycogen debranching enzyme gene found in a homozygous patient.

Several different mutations in the glycogen-debranching enzyme gene AGL have been found in patients with glycogen storage disease type III (GSD III) to date, but no missense mutations have been reported for GSD III, only nonsense, splicing, and deletion/insertion lesions. Here we describe a novel G1448R missense mutation in a Japanese GSD IIIa patient from a consanguineous family. Sequence analysis of cDNA from the patient' liver specimen revealed two separate nucleotide changes: a G-to-A transition at nucleotide 3737 in exon 26 (3737G>A) and a G-to-C transversion at nucleotide 4742 in exon 33 (4742G>C), both of which result in substitution of glycine by arginine (G1115R and G1448R). Because homo-zygotes for G1115R were found in healthy controls, G1115R seems to be a polymorphism. Restriction fragment length polymorphism analysis with Bsa JI showed that the patient was homozygous for G1448R and that none of the normal controls had the mutation. This missense mutation is located at a putative glycogen-binding site that is indispensable for enzyme activity. Thus, G1448R is likely to be the causative mutation in this patient. This is the first report of a missense mutation associated with GSD III.

Alteration in amino acids in motor neurons of the spinal cord in amyotrophic lateral sclerosis.

Little is known concerning the changes of amino acid composition in different regions of the spinal cord in patients with amyotrophic lateral sclerosis (ALS). We performed quantitative amino acid analyses in the posterior funiculus, the lateral corticospinal tract, and the anterior horn of cervical enlargement of the spinal cord from seven ALS patients, and the results were compared with those of seven patients with other neurologic diseases (control A) and seven patients without neurologic diseases (control B). The levels of collagen-associated amino acids, hydroxyproline, proline, glycine, and hydroxylysine, were markedly lower in the lateral corticospinal tract and the anterior horn of ALS patients than in controls A and B. The contents of the acidic amino acids glutamate and aspartate were also significantly decreased in the lateral corticospinal tract and the anterior horn of ALS patients as compared with those of controls A and B. These data suggest that decreased contents of collagen-associated amino acids and excitatory amino acids are related to the degeneration of the upper and lower motor neurons in the spinal cord in ALS.

Preventive effects of insulinlike growth factor-I on steroid-induced muscle atrophy.

We examined the effects of simultaneous administration of recombinant insulinlike growth factor-I (IGF-I) and glucocorticoid on the diameter of muscle fibers in rats. The steroid group received subcutaneous injection of triamcinolone, the IGF-treated group received IGF-I alone, and the steroid plus IGF group received both triamcinolone and IGF-I. After 14 days, each rat was subjected to muscle biopsy of the extensor digitorum longus and soleus. Glucocorticoid treatment caused significant reduction in diameter of muscle fibers, compared to controls. Simultaneous administration of IGF-I significantly attenuated glucocorticoid-induced muscle atrophy. Glucocorticoid increased both urinary concentration of 3-methylhistidine and urinary creatine/creatinine ratio. IGF-I reduced those changes in the urine. We conclude that IGF-I administration prevents, at least partially, the development of steroid myopathy.