Association of IGF-I and IGF-II with myofiber regeneration in vivo

This study examined expression of insulinlike growth factor (IGF) in the myofibers and nonmyofibrillar structures of murine soleus muscle following contraction-induced damage. Identifying the cellular sources of this myogenic growth factor could improve muscle rehabilitation strategies. Immunohistochemical analysis of muscle sections indicated that the number of myofibers expressing both IGF-I and IGF-II increased significantly at 4, 7, and 10 days following injury, compared with control. Muscle spindles and vascular tissue expressed only IGF-II, and staining intensity did not change following injury. The number of fibers expressing developmental myosin heavy chain increased significantly at 7 and 10 days postinjury, and these usually coexpressed IGF. No IGF-specific staining of interstitial/inflammatory cells was observed. Therefore, expression of IGF after mechanically induced fiber damage occurs exclusively within regenerating fibers without supplemental delivery of IGF to the tissue by inflammatory cells or changes in constitutive expression of IGF-II in vascular tissue.     

MRI findings in Hirayama’s disease: flexion-induced cervical myelopathy or intrinsic motor neuron disease?

Hirayama’s disease is a benign juvenile form of focal amyotrophy affecting the upper limbs. Previous studies have suggested that the disorder is a neck flexion induced cervical myelopathy. We report clinical and magnetic resonance imaging findings in nine patients with Hirayama’s disease. Cervical imaging of seven patients revealed spinal cord changes consisting of focal atrophy and foci of signal alterations. On neck flexion a forward movement and mild reduction in the anteroposterior diameter of the lower cervical cord against the vertebral bodies was noted in affected individuals as well as in five normal controls. In contrast to earlier reports, none of our patients showed complete obliteration of the posterior subarachnoid space. Measurement of the anteroposterior spinal cord diameter in each vertebral segment (C4–C7) revealed no significant differences in the degree of spinal cord flattening between the two groups. Furthermore, two of our patients had significant degenerative changes in the cervical spine (disc herniation, retrospondylosis) contralateral to the clinically affected side. These degenerative changes resulted in a marked cord compression on neck flexion but were not associated with ipsilateral clinical abnormalities or spinal cord alterations. Our results argue against a flexion-induced cervical myelopathy and support the view that Hirayama’s disease is an intrinsic motor neuron disease. Received: 15 March 1999 Received in revised form: 25 May 1999 Accepted: 1 June 1999     

Individualized drug dosage in patients treated with continuous hemofiltration

BACKGROUND: Subtherapeutic drug dosing may be even more dangerous than overdosage, especially for intensive care patients requiring hemofiltration. PROPOSAL: According to Dettli's fundamental equation, body clearance of any drug (Cl) is a linear function of creatinine clearance (Cl = Cl anur + a x C(Cr)), with [a = (Cl norm - Cl anur)/C(Cr), norm]. We propose to individualize drug dosage during high-flux hemofiltration by basing it on Dettli's equation and on total C(Cr) (C(Cr) tot = C(Cr) ren + C(Cr) filt). Using this approach, drug clearance will eventually be overestimated for drugs with substantial tubular secretion and for high-efficiency hemofiltration (C(Cr) tot > 30 ml/min). CONCLUSION: In patients undergoing hemofiltration, the total C(Cr) approach might be a practical alternative to standardized dosing schemes for deriving an individualized dosage from published pharmacokinetic data and functions.     

The "point of no return" and the rate of progression in the natural history of IgA nephritis

BACKGROUND: Based on the observation of 7 patients with chronic IgA nephritis and on a course to end-stage renal failure after several years, D'Amico et al. [1993] reported on a "point of no return" at 2.5 to 3 mg/dl serum creatinine. After exceeding this limit all 7 patients exhibited an irreversible progressive renal failure. PATIENTS AND METHODS: Therefore, 115 patients with IgA nephritis from the "German Glomerulonephritis Therapy Study" were examined in order to look for the existence of such a "point of no return". RESULTS: Three different courses could be distinguished: a stable chronic course with constantly normal or only minor elevated serum creatinine lasting for years (91 patients), a progressive course with continuously increasing serum creatinine (22 patients), and a rare (only 2 patients) early acute course with a short-term increase of serum creatinine followed by a rapid return to the normal range. After exceeding 3 mg/dl serum creatinine no remissions were observed in the progressive cases. Sixteen patients showed a rapid, continuously progressive course until end-stage renal failure with exactly the same progression as the 7 patients of D'Amico et al. Six patients of the 22 progressors were not observed long enough. The serum creatinine level doubled on average from 3 to 6 mg/dl within 10 months. CONCLUSION: Our study confirmed the existence of a "point of no return" at 3 mg/dl (265 micromol/l) during the natural course of chronic IgA nephritis.     

An update of antidote availability in veterinary medicine.

Lack of commercially available antidotes for animals is an issue of significant concern to the American Board of Veterinary Toxicology. A few antidotes are available for food animals through extra-label use, regulatory discretion and compounding. However, regulatory restrictions arising from human food, safety concerns have limited the availability of food animal antidotes. Use of some antidotes in food animals requires establishment of an investigational new animal drug application. Antidotes are generally more available for non-food animals from several sources: approved animal drugs, extra-label use of approved animal and human drugs, regulatory discretion and compounding. Present alternatives are discussed as well as the need for legislation to increase antidote availability. Human food safety will always be an issue for food animal antidotes. Future availability of non-food animal and food animal antidotes will depend on several mechanisms and may include the establishment of veterinary antidote depots. Stakeholders are encouraged to participate in identifying and implementing these mechanisms.     

Cerebrovascular doppler examination and cerebral angiography-alternative or complementary?

Summary Obstructions in the extracranial cerebral arteries can be detected noninvasively by directional Doppler ultrasound technique using indirect and direct criteria. The indirect criteria are based on measurement of flow in the common carotid and in the terminal branches of the ophthalmic artery before and after the common carotid artery and branches of the external carotid artery are compressed. With the direct criteria, internal and external carotid artery are differentiated by diastolic flow, and local inhomogeneities of flow (turbulence) are detected. Flow in the vertebral artery is picked up transorally in the oropharynx. The Doppler examination was used in 2230 patients of whom 436 underwent angiography. The results of Doppler and angiography correlated in more than 90% of the cases.     

Unaltered insulin sensitivity during calcium channel blockade with amlodipine

Summary The sensitivity of peripheral tissues to insulin is of pathophysiological, therapeutic and possibly also of prognostic relevance. Calcium channel blockers are widely used in the treatment of cardiovascular disorders that are commonly associated with decreased insulin sensitivity (S_I). To evaluate the effects of calcium channel blokkade on S_I, glucose homoeostasis and lipid profiles, studies were made of S_I (determined by the Minimal Model Method of Bergman), basal glucose and insulin levels, serum total triglyceride (Tg) and lipoprotein cholesterol (C) fractions and certain other variables in 38 healthy young men (24 y) during placebo and after 3 weeks of calcium channel blockade with amlodipine 5 mg once daily. Measurements were made after 3 days on a standard diet (2200 kcal · day^–1, 45% carbohydrates, 40% fat and 15% proteins) and after an overnight fast. Compared to placebo, amlodipine decreased supine systolic blood pressure (P<0.01). Heart rate, body weight and 24 h urinary sodium excretion were unaltered, and so were fasting plasma glucose (placebo vs amlodipine: 4.86 vs 4.83 mmol·1^–1, respectively) and insulin levels (7.7 vs 7.9 U·ml^–1), S_I (10.5 vs 9.6·10^–4 × min^–1 pro U·ml^–1), serum total Tg, C and lipoprotein C fractions.The findings demonstrate unchanged insulin sensitivity and secretion, as well as lipoprotein regulation, during maintenance administration of 5 mg amlodipine daily to healthy young men.This work was supported in part by the Swiss National Science Foundation     

Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses

Summary. Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6–8 g per day are often associated with severe adverse effects.This paper reports the results of much lower doses of o,p'-DDD (0.5–2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE.It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot.Steady state plasma levels of o,p'-DDD between 5–10 g/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 g/ml for several weeks may lead to relapses, whereas DDD-levels over 10 g/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 g/ml in plasma.