In vivo gene therapy for pyridoxine-induced neuropathy by herpes simplex virus-mediated gene transfer of neurotrophin-3.

Neurotrophic factors have been demonstrated to prevent the development of peripheral neuropathy in animal models, but the therapeutic use of these factors in human disease has been limited by the short serum half-life and dose-limiting side effects of these potent peptides. We used peripheral subcutaneous inoculation with a replication-incompetent, genomic herpes simplex virus-based vector containing the coding sequence for neurotrophin-3 to transduce sensory neurons of the rat dorsal root ganglion in vivo, and found that expression of neurotrophin-3 from the vector protected peripheral sensory axons from neuropathy induced by intoxication with pyridoxine assessed by electrophysiological (foot sensory response amplitude, and conduction velocity, and H-wave), histological (nerve morphology and morphometry), and behavioral measures of proprioceptive function. In vivo gene transfer using herpes simplex virus vectors provides a unique option for treatment of diseases of the sensory peripheral nervous system.     

Desmethylimipramine promotes recovery of self-stimulation from the prefrontal cortex following footshock.

Intracranial self-stimulation (ICSS) was assessed from the prefrontal cortex in CD-1 mice immediately (0 h), 24 h and 168 h following exposure to uncontrollable footshock. Marked reductions in ICSS rates were observed in all mice immediately following the stressor. Although the ICSS alterations were transient in some animals, ICSS rates were reduced in the majority of animals 24-h and 168-h poststressor. Mice of either the shock or no shock treatment groups were administered either saline or desmethylimipramine (DMI, 5 mg/kg x 2) for 20 consecutive days. Chronic DMI ameliorated the stressor-induced ICSS deficits from the prefrontal cortex. Potential explanations for the stressor-provoked variations in ICSS and the effects of DMI are discussed.     

Zollinger-Ellison syndrome

As clinical experience with patients with ZES has grown, increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy, including a thorough examination of the duodenum and perhaps intraoperative ultrasound, should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach, it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole, excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.     

Mammographic parenchymal patterns and quantitative evaluation of mammographic densities: a case-control study

The classification of breast parenchymal patterns (N1, P1, P2, DY) and the percentage of the breast containing radiographic densities are two highly correlated radiographic measures proposed as predictors of the risk of breast cancer. In this case-control study, 160 cases of breast cancer and 160 matched controls from a mammography referral practice were compared to determine the risk of breast cancer associated with each of these two radiographic measures. The mammographic densities were quantified on caudal projections by means of a compensating polar planimeter. A relative risk estimate of 3.3 (p less than .05) was associated with the P2 + DY patterns compared with the N1 + P1 patterns. Significantly elevated risks of 4.3 to 5.5 also were observed among women whose breasts contained at least 25% mammographic densities, compared with women with less than 25% involvement. These radiographic measures tended to be more predictive of the risk of breast cancer in black women than in white women. Although the precise clinical roles of breast parenchymal patterns and densities have not been defined fully, the results of this study suggest that they are useful in the recognition of women at high risk of breast cancer. We make no claims that the findings of this study are sufficiently developed to be used as a basis for screening strategies.     

Determinations of glucose turnover and oxidation in normal volunteers and septic patients using stable and radio-isotopes: the response to glucose infusion and total parenteral feeding

Rates of glucose turnover and oxidation were isotopically determined in normal volunteers (n = 16) and in severely septic patients (n = 10). Glucose turnover was determined using primed constant infusions of either 6-3H- or 6,6-d-glucose and glucose oxidation with either U-14C-glucose or U-13C-glucose after appropriate priming of the bicarbonate pool. Basal rates of glucose turnover, oxidation, and plasma clearance were significantly higher in the septic patients than in the volunteers. During glucose infusion (4 mg/kg.min) endogenous glucose production was virtually abolished in the volunteers (94 +/- 4% suppression). There was significantly less suppression in the septic patients (39 +/- 7%); (P less than 0.01). In addition, the percentage of available glucose oxidized (i.e. the percentage of glucose uptake oxidized) was significantly less in the septic patients. When the patients were studied during total parenteral nutrition (at a similar rate of glucose infusion) there was no further suppression of endogenous glucose production compared with that seen during 2 h of glucose infusion. However, the percentage of available glucose oxidized increased significantly. From these studies it is concluded that septic patients continue to have ongoing consumption of host tissue despite receiving either glucose infusion or total parenteral nutrition, and septic patients are less able to oxidize glucose than normal volunteers when infused for only 2 h. However, adaptation occurs with the longer infusion time used in total parenteral nutrition (TPN).     

Regulation of the acid-labile subunit of the insulin-like growth factor ternary complex in patients with insulin-dependent diabetes mellitus and severe burns

OBJECTIVE Little information is available regarding the regulation of serum acid-labile subunit (ALS) in human disease. We have studied alterations in serum ALS of the insulin-like growth factor (IGF) ternary complex in children with untreated insulin-dependent diabetes mellitus (IDDM) and subjects with severe burns before and after insulin therapy. In addition, we have investigated the effect of insulin plus GH on serum ALS in burn patients. DESIGN Serum samples were obtained from children with newly diagnosed and untreated IDDM before the initiation of insulin therapy and 1 month thereafter. Serum samples were also obtained from adult patients with severe burns who were on a continuous infusion of a carbohydrate-rich enteral diet via nasogastric and duodenal catheters under basal conditions, after a 1-week period of continuous insulin infusion, and after an additional week of insulin plus recombinant GH. PATIENTS Twenty children and adolescents with untreated IDDM, aged 1.2–16 years, and 6 young adult patients with severe burns aged 17–28 years were studied longitudinally. Control sera were obtained from age, sex and pubertal status matched subjects (for children with IDDM) and from fed healthy adults. MEASUREMENTS Serum insulin, GH, cortisol and IGF-I were measured by radioimmunoassay, and serum ALS levels were assessed by Western immunoblot before and after treatment periods. RESULTS Serum ALS levels were lower in untreated children with IDDM (69 ± 6% of control children). Insulin therapy significantly increased serum ALS (79 ± 5%, P<0.05) in these children. Patients with severe burns also had lower serum ALS levels (79 ± 10% of control adults). After one week of insulin therapy serum ALS levels increased to 90 ± 15% of control values (P<0.05). Addition of GH to insulin therapy for another week did not significantly further increase serum ALS levels (95 ± 27%). Serum IGF-I concentrations increased nearly 2.5-fold in diabetic subjects and fourfold in burn subjects at the end of the study periods. There were no proteolytic fragments of ALS in the sera studied. The deglycosylation pattern of ALS did not differ between diabetic and control sera. CONCLUSION Serum ALS levels were diminished in children with untreated IDDM and were partially restored after the initiation of insulin therapy. Serum ALS levels were also diminished in patients with severe burn injury and restored by insulin treatment. Addition of GH to insulin therapy did not significantly increase serum ALS levels over levels obtained during insulin therapy alone. These decreases in serum ALS were smaller than the decrease in serum IGF-I concentrations in both conditions, suggesting that IGF-I is the limiting factor for the ternary complex formation in the catabolic states. Insulin may regulate circulating ALS levels in catabolic states and helps to restore the IGF system.     

Periodontal disease in adolescents: some clinical and microbiologic correlates of attachment loss

The influence of several clinical and microbiological variables on the site-specific risk of attachment loss was studied in Navajo Indian adolescents aged 14-19. Diagnoses were made at mesio-buccal sites of the four first permanent molars. Case-control analytical methods were used, with A. actinomycetemcomitans, B. gingivalis, and B. intermedius considered the "risk" variables, and with calculus, gingival bleeding, age, and gender treated as possible confounders. The presence of B. intermedius significantly increased the likelihood that attachment loss would be diagnosed at a site (odds ratio = 2.86). However, this association was confounded by calculus and gingival bleeding; when either or both were present, the effect of B. intermedius was markedly weaker. Step-wise multiple logistic regression analyses showed that, of the variables considered, the combination of calculus, gingival bleeding, and B. intermedius gave the most parsimonious explanation of the presence of attachment loss. The chance that attachment loss would be diagnosed was increased five times when calculus was present, 16.5 times in the presence of both calculus and gingival bleeding, and 37 times when these variables plus B. intermedius were observed at a particular site.     

Hyper and hypodynamic models of sepsis in guinea pigs

The acute metabolic response following experimentally induced sepsis can generally be classified as either hypodynamic ("low flow") or hyperdynamic ("high flow"). We have found that in conscious guinea pigs the bolus infusion of 10(10) live Escherichia coli bacteria can elicit either response, depending on the route of administration of the bacteria. Intravenous infusion results in the hypodynamic condition of septic shock in which oxygen consumption (VO2) is reduced to approximately 60% of the control level, plasma glucose is elevated 4 hr after infusion with a reversal to extreme hypoglycemia 12 hr after infusion, and body temperature is reduced by approximately 5 degrees C in 12 hr. In contrast, subcutaneous injection results in increased VO2, body temperature, and plasma glucose. In both models the concentration of cortisol, catecholamines and glucagon were elevated, but the responses were more pronounced in the hypodynamic model. In both cases, insulin concentration was decreased. These models of sepsis are useful because many aspects of response are comparable to man, they are simple to create, and they are consistent and reproducible.