Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group.

OBJECTIVE: To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone. RESEARCH DESIGN AND METHODS: A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed postprandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G). RESULTS: At end point, HbA1c was significantly lower with all therapies (P = 0.001) and was significantly lower for L+G (7.68+/-0.88%) compared with either NPH+G (8.51+/-1.38%, P = 0.003) or M+G (8.31+/-1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49+/-2.36 mmol/l) compared with either L+G (10.57+/-1.97 mmol/l, P = 0.001) or M+G (9.69+/-2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87+/-2.88 mmol/l) versus NPH+G (12.21+/-3.12 mmol/, P = 0.052) or versus M+G (12.72+/-3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups (P = 0.156). CONCLUSIONS: Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes.

Stability of U-10 and U-50 dilutions of insulin lispro.

BACKGROUND: Insulin lispro, a rapid acting analog of human insulin, has been shown to be useful in the treatment of children with diabetes. However, lower concentrations of this insulin may be needed to facilitate optimal clinical use. Therefore, the stability of insulin lispro when diluted with an appropriate diluent was evaluated. METHODS: Insulin lispro (U-100, 100 U/mL) was diluted with sterile Neutral Protamine Hagedorn (NPH) diluent to U-10 and U-50. After storage for 7, 14, 21, 28, and 32 days at 5 degrees C and 30 degrees C, the diluted insulins were analyzed by high-performance liquid chromatography (HPLC) to determine potency, purity, polymer, and preservative (metacresol or phenol) content in addition to physical appearance and pH determinations. Microbiological testing for preservative effectiveness was performed on the U-10 and U-50 solutions after 32 days at both temperatures. RESULTS: U-10 and U-50 dilutions of insulin lispro stored at 5 degrees C and 30 degrees C maintained potency and purity throughout the 32-day testing period. Additionally, both control and diluted vials maintained antimicrobial effectiveness. CONCLUSION: Insulin lispro when diluted with the appropriate diluent demonstrates acceptable stability when stored at 5 degrees C and 30 degrees C for a period of 32 days.

Pharmacokinetic and glucodynamic comparisons of recombinant and animal-source glucagon after IV, IM, and SC injection in healthy volunteers.

The structure of the hormone glucagon is identical among humans and several species of other mammals. Equivalence of recombinant glucagon (rG) to animal-source glucagon (aG) was assessed in this two-part, open-label, randomized study. Part I was a four-way crossover intravenous dose-ranging study of rG (pH 2.8) involving 12 subjects. Part II was a six-way crossover study of 29 subjects comparing rG (diluent pH 2.0 and 2.8) with aG administered subcutaneously (sc) and intramuscularly (im). Maximum glucagon plasma concentrations (C(max)) and area under the glucagon concentration curve (AUC) were calculated. Additionally, maximum blood glucose concentrations (BG(max)), maximum absolute BG excursion (MAE), and area under the glucose concentration curve from time of dosing to return to baseline (AUC(rtb)) were calculated. The primary focus was equivalence of the formulation intended for marketing (rG pH 2.0) to aG. Administration of rG pH 2.0 through the im route demonstrated equivalence to aG for all pharmacokinetic and glucodynamic comparisons. Subcutaneous administration of rG pH 2.0 demonstrated standard bioequivalence for AUC (5.87 versus 6.63 ng x h/mL; NS) and near equivalence for C(max) (7.94 versus 9.12 ng/mL; p < 0.05). rG pH 2.0 showed glucodynamic equivalence to aG (BG(max), 136 versus 133 mg/dL; MAE, 50.0 versus 47.4 mg/dL, respectively) and statistically greater AUC(rtb) values (151 versus 126 mg x h/dL, p < 0. 05). rG and aG were equally safe and well tolerated. In conclusion, rG provides equivalent safety and efficacy to aG.

Detection of intensity decrements by the chinchilla.

Three monaural chinchillas were trained to detect intensity decrements in broadband noise (20 kHz) using a shock-avoidance conditioning procedure. The intensity decrements were presented at one of nine different durations between 2 and 35 ms at noise levels of 25, 45, and 65 dB SPL. At each intensity-duration combination, the level of the decrement was varied to obtain a decrement threshold. The minimal detectable decrement decreased from approximately 20 dB at the shortest duration to an asymptote of roughly 4 dB at approximately 30 ms. The data were modeled by a low-pass filter with an 11-ms time constant. The decrement detection function of the chinchilla is similar to that of humans. However, long-duration decrement thresholds are larger in the chinchilla, as would be predicted from the large intensity difference limen of the chinchilla. In general, there was little change in the decrement function across background intensities except that 2-ms decrements were not detected at the 25-dB SPL background intensity.

Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a long-term prognostic study. II. Ruptured intracranial aneurysms managed conservatively.

The late natural history of ruptured intracranial aneurysms was studied in 568 cases reported to the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage from 1958 to 1965. The patients had been selected for conservative management of their aneurysms at the time of diagnosis. A follow-up search in 1981 and 1982 revealed 378 known deaths; 40% had occurred within six months of hemorrhage. During the next two decades, the patients' survival probabilities were significantly worse than those of a matched US population. Multiple aneurysms did not differ prognostically from single aneurysms, but posterior circle aneurysms carried a better prognosis after ten-year survival. The rate of probable recurrent bleeding after six months was 2.2% per year for the first 9 1/2 years and 0.86% per year for the second decade. Reported rebleeding episodes were fatal in 78%.

Cooperative study of intracranial aneurysms and subarachnoid hemorrhage: a long-term prognostic study. III. Subarachnoid hemorrhage of undetermined etiology.

Among 6,638 cases reported to the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage were 477 cases in which the cause of hemorrhage could not be determined after carotid and vertebral angiography. These patients were followed up for up to 24 years after hemorrhage. Twenty patients were subsequently found to have an aneurysm or arteriovenous malformation missed by the first angiographic survey. After six-month survival, the rate of recurrent hemorrhage was a maximum 0.86% per year. Survival was significantly better than that of patients with verified ruptured aneurysms managed conservatively in this cooperative study. For normotensive patients who survived the first six months, the life expectancy for the next 20 years equaled that of an age- and sex-matched US population. Hypertensive patients had a higher mortality than normotensive patients.

Management and outcome of pineal region tumors.

The management and outcome of 45 patients with tumors in the pineal region are reviewed. The overall male to female ratio was 2:1, and over one-half of the patients presented during the 2nd decade of life. Sixteen of the 21 survivors are presently gainfully employed and suffer only minor deficits. Two of 3 survivors in whom the lesion was biopsied harbored germinomas, while the third had an epidermoid. Among the 18 nonsurvivors, all of whom died of their tumors, 15 succumbed within 2 1/2 years of hospital admission. Twelve of the 13 nonsurvivors in whom histological confirmation was obtained by operation or autopsy had malignant tumors. Computed axial tomography was helpful in making the diagnosis of tumor type in 7 of the 11 cases with confirmed pathology. Cerebrospinal fluid cytology disclosed malignant cells in 4 of 11 patients with proven pineal malignancy. Irradiation and shunting were performed in nearly all survivors and in a little over one-half of the nonsurvivors. Where noninvasive studies are equivocal for malignancy, biopsy may be indicated.

Bleeding from cerebral arteriovenous malformations as part of their natural history.

The case records of 191 patients with a cerebral arteriovenous malformation (AVM) were reviewed to determine bleeding characteristics of these lesions. Possible influences of age, sex, the location and size of the AVM, type of initial hemorrhage, and condition of the patients were analyzed. Of these 191 patients, 102 had a single hemorrhage, 32 had a recurrent hemorrhage, and 57 never bled. The follow-up period for patients with an unruptured AVM was a mean of 4.8 years and a maximum of 31 years; for those with a ruptured AVM, the mean was 2 years, and the maximum 37 years. Size of the AVM was significantly related to the risk of first hemorrhage. The average yearly risk for first hemorrhage was between 2% and 3%. Bleeding occurred most frequently in the 11- to 35-year-old age group. The risk of rebleeding increased with advancing age. Among 93 patients followed after their AVM had ruptured, the risk of rebleeding was 6% in 1 year. After the first year, the average rebleeding rate was about 2% per year up to 20 years.

Management of vein of Galen aneurysms. Report of two cases.

Aneurysms of the great vein of Galen are rare and potentially lethal lesions, especially in early infancy. Sectioning of the feeding arteries and excision of the lesions have been proposed for the best long-term results. An alternative approach was utilized in the two children discussed here. The computerized tomography (CT) scan established the precise diagnosis and demonstrated hydrocephalus and cortical atrophy preoperatively. Parieto-occipital craniotomy with an interhemispheric approach was performed to clip the numerous feeders. The procedure was terminated when the sac collapsed and blood aspirated from the lesion was venous in oxygen saturation. A Doppler probe over the aneurysm then revealed a venous flow. Serial postoperative CT scans demonstrated that the mass had shrunk in size. Follow-up angiography was not thought necessary.

Overall management of ruptured aneurysm: comparison of early and late operation.

The overall management results with 61 consecutive patients admitted within 3 days of subarachnoid hemorrhage from a ruptured intracranial aneurysm were analyzed. During the course of this study, the preferred method of management shifted from late surgery (planned at least 7 days after the last hemorrhage) to early surgery (within 4 days of the last hemorrhage). Ten moribund patients were excluded from analysis, leaving 24 in the late group and 27 in the early group. Both groups had comparable patient demographic characteristics and neurological conditions, and their care was supervised by one neurosurgeon (N.F.K.). A microsurgical intracranial operation was performed on all patients who survived long enough to have surgery. The intraoperative conditions and complications were similar for the two groups. The average length of follow-up was 11 months in the late and 9 months in the early group. The overall management results for the late group showed a 42% favorable outcome, a 17% unfavorable outcome, and a 42% mortality. The early group had an 81% favorable outcome, a 7% unfavorable outcome, and an 11% mortality. Patients in both good and poor conditions fared better in the early group. Seven late group patients rebled, compared to none in the early group. The number of medical complications, the length of hospitalization, and the occurrence of symptomatic vasospasm were all greater in the late group. Vasospasm in the early group occurred only postoperatively and, with the aneurysms secured, was treated more aggressively and successfully with hypertensive/hypervolemic therapy than the predominantly operative vasospasm in the late group.

Complications of spinal drainage in the management of cerebrospinal fluid fistula.

Continuous cerebrospinal fluid (CSF) drainage may be used in the treatment CSF fistula. The procedure, however, is not without risk. Marked gradients between the intracranial and intraspinal CSF pressures and intravasation of air through an unsealed fistula may produce serious neurological problems. The use of continuous CSF drainage requires an alert, informed nursing staff to avert catastrophe.

Craniocervical abnormalities. A comprehensive surgical approach.

Guidelines are proposed for surgical management of symptomatic abnormalities of the craniocervical junction. Experience with 17 recent cases is described. Gas or metrizamide (Amipaque) myelograms with pluridirectional tomograms revealed the etiology and mechanisms of compression of the cervicomedullary junction, as well as its reducibility. Stabilization was the goal in treatment of reducible lesions. Decompression of the cervicomedullary junction was paramount in irreducible cases. Ventral compression was treated in nine patients by transoral transpalatine resection of the odontoid-clivus complex, and all nine improved. A posterior decompression was carried out when bone impingement was present from the dorsal aspect. Fusion was performed in cases in which stability was not achieved by either procedure.

Abnormalities of the cranio-vertebral junction with cervico-medullary compression. A rational approach to surgical treatment in children.

8 children with cranio-vertebral abnormalities and neurological deficits are reviewed. The specific treatment is dependent on etiology, mechanisms of compression, and whether the bony abnormality can be reduced to its normal position. Irreducible ventral compression of the cervico-medullary junction was relieved by transoral removal of the odontoid-clivus complex in 3 patients. Primary posterior decompression was done in 4 children with dorsal encroachment. A reducible C1-C2 dislocation in 1 child with juvenile rheumatoid arthritis underwent primary posterior fusion. A detailed surgical physiological approach is described.

Trigeminal neurilemmoma presenting as a sphenoid sinus mass.

Trigeminal neurilemmomas have been known to invade the posterior fossa. Infratemporal fossa, encroach upon the lateral wall of the sphenoid sinus and extend along the three divisions of the trigeminal nerve. Herein described, is a patient with a trigeminal neurilemmoma that extended into the sphenoid sinus, necessitating transphenoidal excision.

The complementary nature of computed tomography and angiography in the diagnosis of cerebellar hemangioblastoma.

Cerebellar hemangioblastomas were seen in seven persons, five being members of the same family. All were studied with constrast enhanced CT scans and vertebral angiograms. The CT scans were superior for demonstrating the cystic component of the tumors and associated hydrocephalus, features not usually evident on the angiograms. The angiograms were superior for revealing the vascular nature, supply and drainage of the tumors. In several patients the angiograms revealed more tumors than could be seen by CT. Both CT and angiography contribute important information in the diagnosis of these neoplasms.

Catecholamine response to intracranial hypertension.

Pulmonary congestion, hemorrhage, and edema, produced in the experimental animal by various methods of disturbing the central nervous system, have led to the concept that such neurogenically-initiated changes are mediated through the autonomic nervous system. Blocking the sympathetic nervous mechanisms prevents these changes. Little is found concerning the expected role of catecholamines. In this study, using a standard model of increasing intracranial pressure (ICP), intense cardiovascular changes, with blood pressure rising above 320 mm Hg and heart rate of 180 beats per minute, were noted. Within seconds, plasma catecholamine levels rose as much as 1200 times the highest normal values for epinephrine, 145 times for norepinephrine, and 35 times for dopamine. These changes occurred only when raised ICP was sustained and spatial compensation of the brain was exceeded. It is not unlikely that these events are related not only to increased ICP, but also to the effects of physical distortion of the brain stem with structural, functional, and vascular alterations within it.

Spinal cord abscess: a review.

The literature on abscesses in the spinal cord has been reviewed. A total of 54 cases was reported. A digest is made of information on the subject including the diagnosis, pathology, treatment and the results to be expected. The best results have been achieved by operation plus antibiotic therapy. It is essential that the abscess be drained after aspiration. A case of ours showing the salient features and management of a subacute cervical spinal cord abscess is also reported.