GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.

Second primary tumors in mycosis fungoides patients: experience at the Northern Israel Oncology Center (1979-2002).

PURPOSE: Mycosis fungoides (MF) patients enjoy longstanding remissions following total skin electron irradiation (TSEI) but run the risk of developing secondary malignancies. Our purpose was to report our experience with the phenomenon of secondary malignancies in MF patients. PATIENTS AND METHODS: From 1979 to 2002, 84 patients with biopsy-proven MF were referred to our department for TSEI, using the modified Christie Hospital translational technique until 1992 and the Stanford technique after 1992. Median total dose was 32 Gy (range 16-44) Christie; 30 Gy (range 15-36) Stanford. Underdosed areas were boosted with a median total dose of 10-20 Gy. RESULTS: During a median follow-up of 73 months (range 2-191) from the end of the TSEI, 12 (15%) patients developed 17 second primary tumors within the irradiated areas and 6 patients developed 7 second primary tumors, either simultaneously with the newly diagnosed MF or prior to introduction of radiation therapy. CONCLUSION: The long-term prognosis was related solely to the second primary. Due to excellent long-lasting response rates following TSEI coupled with long-term survival, and the prognosis mainly associated to the stage and histology of the second malignancy, physicians should be aware of the possibility of second primary tumors.

Long-standing complete remission following mitomycin-C/vinblastine chemotherapy for cutaneous and lymph node metastases from breast cancer resistant to multiple chemotherapy and hormonal lines and extensive radiotherapy: an unusual case.

Widespread cutaneous and lymph nodes recurrence in breast cancer is regarded as therapy-resistant disease. We describe a 50-year-old patient who presented with treatment-refractory disease following multiple lines of chemo- and hormonotherapy, photodynamic therapy and radiotherapy, including re-irradiation to extended volumes of her chest, upper abdomen, back and regional lymph nodes. Following treatment with mitomycin-C (MMC)/vinblastine (VLB) alone, she entered sustained complete remission of 1-year duration without any side effects. A brief review of the current literature is also presented. The MMC/VLB combination might achieve reasonable response and improvement of quality life even in patients with advanced breast cancer.

Vinorelbine/VP-16 (etoposide) in metastatic breast cancer: a phase II study.

PURPOSE: This phase II study was conducted to evaluate the efficacy and tolerability of vinorelbine (navelbine) and oral VP-16 (etoposide) in pretreated metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Twenty-two female patients with therapy-resistant metastatic breast cancer were treated with vinorelbine 25 mg/m(2) i.v. on days 1 and 8 and oral VP-16 50 mg/m(2)/day for 14 days. Cycles were repeated every 28 days. Treatment was given until clear evidence of disease progression. RESULTS: Complete remission was observed in 3 (14%) patients, and partial remission or stable disease in 10 (45%) patients. Median duration of response was 4 months (range 2-8). Symptomatic improvement, irrespective of imaging methods results, as evaluated through improved performance status (PS), the lack of requirement for urgent palliative radiotherapy, and a decrease in steroids and analgesics doses was demonstrated in 10 (45%) patients through a special questionnaire completed by all patients. Side effects were manageable. Dose modification due to leucopenic fever were necessary in only 3 patients. Previous radiation therapy did not mitigate the application of full doses of chemotherapy. CONCLUSION: Vinorelbine/VP-16 combination is active and tolerable in relapsed and heavily pretreated MBC patients.

Trauma as an etiologic factor of primary bone lymphoma: a report of 4 cases.

Primary bone lymphoma (PBL) is a rare entity. Nevertheless, very high long-term complete remission and survival rates following adriamycin-based chemotherapy alone or combined with involved-field radiation therapy have been reported. While the etiology is unknown, factors comprising local or general immunocompromised states have been suggested. Sporadic cases of local trauma followed by the emergence of primary bone lymphoma have been described. We describe 4 patients who developed primary bone lymphoma following direct trauma to a specific bone area. All 4 are alive with no evidence of disease after being treated with a combined chemo-radiotherapy regimen.

Effect of thiopental on neurologic outcome following coronary artery bypass grafting.

To determine if thiopental reduces the incidence of neurologic sequelae after coronary artery surgery, we prospectively studied 300 patients undergoing coronary artery bypass grafting. Patients who had no history of neurologic or psychiatric illness were randomly assigned to receive either a thiopental infusion or a saline placebo infusion beginning with the administration of heparin and ending just after aortic decannulation. The patients received an opioid-relaxant anesthetic administered by an anesthesiologist who was not involved in this investigation and who was blinded to the test infusion. One of the investigators infused either saline or thiopental to produce an isoelectric electroencephalogram with 30-45 s between bursts. Standardized neurologic examinations were performed preoperatively and on the 2nd and 5th postoperative days by one of the blinded investigators. The group of patients receiving thiopental required a longer time for awakening (6.4 +/- 3.9 vs. 4.0 +/- 2.4 h, mean +/- SD, P less than 0.05) and for tracheal extubation (22.4 +/- 18.4 vs. 17.4 +/- 9.6 h, P less than 0.05), and a greater number of these patients were lethargic on the 2nd postoperative day. More patients receiving thiopental required vasoconstrictors during the thiopental loading and cardiopulmonary bypass (CPB) periods, while a greater number of patients receiving placebo required vasodilators. A greater number of patients receiving thiopental required inotropic drugs during separation from CPB. Despite the above differences, only 2 of the 151 patients in the placebo group (1.3%) and 5 of the 149 patients in the thiopental group (3.3%) experienced strokes (P = 0.2535).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of protamine on histamine release from human lung.

Animal mast cell models demonstrate direct histamine release by protamine. Investigators have proposed that protamine also releases histamine in man. We studied the effects of protamine alone and heparin-protamine mixtures on minced lung tissue for evidence of histamine release. We were unable to demonstrate the release of histamine despite positive anti-IgE controls. Nonimmunologic histamine release from human lung appears unlikely as a mechanism for protamine reactions in man.

Evaluation of patients at risk for protamine reactions.

Patients with neutral protamine Hagedorn and protamine-zinc insulin-dependent diabetes, a history of fish allergy, or prior vasectomy have been reported to be at an increased risk for protamine reactions after cardiopulmonary bypass because of prior sensitization. We prospectively evaluated cardiac surgical patients with prior vasectomies and fish allergies and retrospectively evaluated a cohort of 3245 consecutive cardiac surgical patients requiring cardiopulmonary bypass over a 2-year period for protamine-containing insulin use and clinical evidence of adverse reactions after protamine administration for heparin reversal after cardiopulmonary bypass. Clinical reactions to protamine did not occur in six patients with fish allergies or 16 patients with prior vasectomies. There was one reaction (0.6%) in 160 patients with neutral protamine Hagedorn insulin-dependent diabetes. The incidence of clinical reactions in the other patients was 2/3085 (0.06%). The incidence of clinical reactions in the patients with neutral protamine Hagedorn insulin-dependent diabetes is not significantly different from that in other patients. We conclude that prior neutral protamine Hagedorn insulin use, a history of fish allergy, or prior vasectomy does not represent a contraindication to protamine administration after cardiopulmonary bypass.

Use of the pacing pulmonary arterial catheter to detect endocardial electrical activity during hypothermic cardioplegic arrest.

The pacing Swan-Ganz catheter was evaluated for its ability to monitor atrial and ventricular electrical activity during cardioplegic arrest on cardiopulmonary bypass. This endocardial electrical activity was compared with the activity found on the standard electrocardiogram (ECG). The atrial electrodes detected activity that was noted also by visual inspection. The ventricular electrodes detected recurring electrical activity in 7 of 18 patients. Three of these 7 patients did not have simultaneous standard ECG activity, indicating that, in the usual monitoring circumstances, this ventricular electrical activity would not have been treated with repeat cardioplegia. If the pacing Swan-Ganz catheter is used for clinical care, it can be used also to monitor myocardial electrical activity during cardioplegic arrest.

Prospective evaluation of risk of protamine reactions in patients with NPH insulin-dependent diabetes.

Patients with NPH (neutral protamine Hagedorn) insulin-dependent diabetes may have an increased risk for protamine reactions because of prior sensitization. During one year, we prospectively evaluated 50 at-risk cardiac surgery patients for clinical reactions and determined in vitro histamine release when protamine was added to a preoperative blood sample. We speculated that in vitro histamine release would predict a reaction to protamine given clinically for neutralization of heparin. Twenty-five patients randomly received prophylactic corticosteroid and/or antihistamine pretreatment for allergic reactions. The incidence of clinical reactions to protamine was 1/50 (2%) in NPH insulin-dependent diabetic patients (1/25 in pretreated patients vs 0/25 in patients not receiving pretreatment). One pretreated NPH diabetic patient released histamine in vitro but did not demonstrate clinical signs of a reaction following protamine administration. One other NPH diabetic patient pretreated with corticosteroids developed severe pulmonary hypertension despite the absence of in vitro histamine release. Therefore, in vitro histamine release does not predict protamine reactions.

Rate of protamine administration: its effect on heparin reversal and antithrombin recovery after coronary artery surgery.

Patients received a calculated dose of protamine at two different rates (5 min and 30 min) after coronary artery surgery to determine the relationship of the rate of protamine administration with the adequacy of heparin reversal and the rate of return of antithrombin III (AT III) activity. Plasma heparin concentrations and AT III activities were measured at specific times both during and for 3 days after cardiac surgery. Both rates of protamine administration resulted in clinically acceptable clotting, return of the activated coagulation time to normal, and zero heparin concentration after 24 hr. Two hours after protamine administration, patients who received rapidly administered protamine had prolonged coagulation compared to the other group. Normal AT III activity returned the second postoperative day. These results imply that normal postoperative coagulation occurs when protamine is administered over 30 min without a bolus, and that blood is potentially hypercoagulable immediately after heparin reversal because of depressed AT III activity.

Effect of enflurane, isoflurane, and halothane on pacing stimulation thresholds in man.

Volatile anesthetic agents are often used in patients who require temporary epicardial pacing after cardiopulmonary bypass (CPB). However, the effect of anesthetic agents on energy stimulation thresholds is unknown. After CPB, 24 patients under diazepam-narcotic-pancuronium anesthesia ventilated with an FIO2 = 1.0 received equipotent concentrations of either enflurane, isoflurane, or halothane. Using temporary epicardial electrodes, energy stimulation thresholds were calculated using the data derived from a pacing systems analyzer. Volatile anesthetics do not change energy stimulation thresholds from those already present under diazepam-narcotic-pancuronium anesthesia.

Hemodynamics of pacing after aortic valve replacement and coronary artery surgery.

The cardiovascular effects of atrial, ventricular, and sequential pacing at PR intervals of 175, 150, 125, and 100 msec were studied immediately following cardiopulmonary bypass in patients with aortic stenosis, aortic insufficiency, or coronary artery disease. Atrial pacing increased the cardiac output and mean arterial blood pressure only in the patients with coronary artery disease. Ventricular pacing consistently was associated with the lowest cardiac output and mean arterial blood pressure. Hemodynamic response to changing PR intervals was variable. Our results suggest that if augmentation of heart rate is required in the period immediately after bypass, atrial pacing should be used in preference to ventricular pacing. In the presence of second- or third-degree heart block when atrial stimulation is ineffective, sequential pacing with an individualized PR interval becomes the therapeutic choice.

Use of a pacing pulmonary artery catheter during cardiac surgery.

The Swan-Ganz Pacing TD Catheter with cardiac pacing capabilities was evaluated in 65 patients who underwent a cardiac operation. The catheter was inserted quickly and easily with minimal patient discomfort. Before initiation of cardiopulmonary bypass, atrial pacing was achieved in 89.2% of the patients, ventricular pacing in 93.8%, and sequential pacing in 87.7%. After termination of bypass, atrial pacing was achieved in 84.6% of the patients, ventricular pacing in 93.8%, and sequential pacing in 81.5%. Pacing thresholds were well within the current outputs of commercially available external pulse generators. No complications that could be attributed to the Swan-Ganz Pacing TD Catheter occurred in this series of patients.

Hemodynamics of intravenous nitroglycerin during aortic clamping.

Anesthetic management and dosage schedules of vasodilators have not been standardized in many studies of aortic cross clamping (CCL). For this reason, 25 consecutive patients with arteriosclerotic disease of the aorta were studied, all having received the same anesthetic management. Six patients who received nitroglycerin during the cross clamp period, at a dosage of 0.25 micrograms/kg/min, were compared with 19 who underwent CCL without the drug. Contractility was maintained in the nitroglycerin group, but not in the other group. Despite a low cardiac index in both groups, peripheral blood flow was adequate only in the nitroglycerin group. Intrapulmonary shunt was higher in the nitroglycerin group, but it did not significantly decrease the Pao2. Nitroglycerin infusion seems to be helpful in maintaining pre-CCL contractility and adequacy of peripheral blood flow.

Esophageal lead for intraoperative electrocardiographic monitoring.

The use and safety of the esophageal electrocardiogram for detection and diagnosis of dysrhythmias or ischemia during anesthesia was compared with the conventional electrocardiogram using leads II and V5 in 20 patients undergoing coronary artery bypass graft surgery. Using an intra-atrial electrocardiogram as the standard to provide detection and definitive diagnosis of dysrhythmias, the correct diagnosis from leads II and V5 was made in 53.8% and 42.3% of cases, respectively, whereas 100% of the dysrhythmias were properly diagnosed from the esophageal electrocardiogram (p less than 0.05). In two patients, the presence of a significant dysrhythmia was not detected using standard leads II and V5 alone. Large, distinct P waves, resulting from the proximity of the esophageal lead to the left atrium, clearly established the temporal relationship between atrial and ventricular depolarization. Posterior myocardial ischemia was diagnosed in one patient by ST-segment elevation in the esophageal electrocardiogram, whereas leads II and V5 did not demonstrate ischemic changes. No complications were encountered during the study. The esophageal lead is safe, simple to use, and provides valuable information for detection or diagnosis of dysrhythmias and myocardial ischemia during anesthesia.