William A. Bauman

An association between hyperinsulinemia and hypertension during the third trimester of pregnancy

We studied 43 women in their third trimester of pregnancy whose fetuses were at significant risk of intrauterine growth retardation. To define metabolic subtypes for intrauterine growth retardation, a 100 gm glucose load was administered after an overnight fast. Twenty-seven women were normotensive and 16 had hypertension. The glucose tolerance of the hypertensive group was essentially the same as that of the normotensive group. However, 8 of the 16 women with hypertension had marked hyperinsulinemia in response to an oral glucose load. Of the five women with hypertension who gave birth to offspring of low birth weight, three had hyperinsulinemia.

A Small-Scale Clinical Trial to Determine the Safety and Efficacy of Testosterone Replacement Therapy in Hypogonadal Men with Spinal Cord Injury

Men with spinal cord injury are at an increased risk for secondary medical conditions, including metabolic disorders, accelerated musculoskeletal atrophy, and, for some, hypogonadism, a deficiency, which may further adversely affect metabolism and body composition. A prospective, open label, controlled drug intervention trial was performed to determine whether 12 months of testosterone replacement therapy increases lean tissue mass and resting energy expenditure in hypogonadal males with spinal cord injury. Healthy eugonadal (nu2009=u200911) and hypogonadal (nu2009=u200911) outpatients with chronic spinal cord injury were enrolled. Hypogonadal subjects received transdermal testosterone (5 or 10u2009mg) daily for 12 months. Measurements of body composition and resting energy expenditure were obtained at baseline and 12 months. The testosterone replacement therapy group increased lean tissue mass for total body (49.6u2009±u20097.6 vs. 53.1u2009±u20096.9u2009kg; pu2009<u20090.0005), trunk (24.1u2009±u20094.1 vs. 25.8u2009±u20093.8u2009kg; pu2009<u20090.005), leg (14.5u2009±u20092.7 vs. 15.8u2009±2.6u2009u2009kg; pu2009=u20090.005), and arm (7.6u2009±u20092.3 vs. 8.0u2009±u20092.2u2009kg; pu2009<u20090.005) from baseline to month 12. After testosterone replacement therapy, resting energy expenditure (1328u2009±u2009262 vs. 1440u2009±u2009262u2009kcal/d; pu2009<u20090.01) and percent predicted basal energy expenditure (73u2009±u20099 vs. 79u2009±u200910%; pu2009<u20090.05) were significantly increased. In conclusion, testosterone replacement therapy significantly improved lean tissue mass and energy expenditure in hypogonadal men with spinal cord injury, findings that would be expected to influence the practice of clinical care, if confirmed. Larger, randomized, controlled clinical trials should be performed to confirm and extend our preliminary findings.

Early and Long-Term Effects of Acute Caloric Deprivation in Obese Diabetic Patients

PURPOSEnIt is generally assumed that diet therapy can ameliorate the metabolic derangements experienced by obese type 2 diabetic patients, thereby leading to discontinuation of insulin or oral sulfonylurea drug therapy. We decided to retrospectively investigate which clinical and biochemical parameters affect therapeutic responses.nnnPATIENTS AND METHODSnSixty-four poorly controlled obese diabetic patients were hospitalized and placed on a precisely defined, hypocaloric diet. Known duration of diabetes, type of pharmacologic therapy, body weight, weight loss, fasting plasma glucose concentrations, C-peptide levels, hemoglobin A1C, and plasma lipid levels were assessed, as were nitrogen and electrolyte balances.nnnRESULTSnAverage weight loss was 13 pounds in a mean of 23 days. During hospitalization, the mean fasting plasma glucose value for the group fell from 221 +/- 10 to 122 +/- 5 mg/dl. In 45 patients (73 percent), the final fasting plasma glucose level was less than 125 mg/dl (mean: 102 +/- 2 mg/dl). Oral glucose tolerance even in those patients in whom fasting plasma glucose levels normalized was still grossly diabetic at the end of the hospital stay, deteriorating further after three days of liberalized caloric intake. In part this may have been due to decreased insulin secretory reserve as reflected by blunted plasma C-peptide response. Forty of 42 patients who entered the study taking insulin were able to discontinue the drug within one to seven days of hospitalization. After a mean follow-up period of 19 months, only 10 of 50 patients continued to maintain fasting euglycemia; five were on diet alone, and five were receiving oral hypoglycemic agents. Thirteen patients were receiving insulin therapy.nnnCONCLUSIONnDiet therapy in these patients resulted in short-term improvement of glycemic control and, in the majority, normalization of fasting plasma glucose levels. However, long-term outpatient follow-up revealed that relapse occurred in most patients.

Cerebral cortical concentrations of bioamines and their metabolites during arousal and after feeding in the little brown bat (Myotis lucifugus)

The concentrations of bioamines and their metabolites have been determined in March and April during arousal from hibernation in the cerebral cortex of the little brown bat (Myotis lucifugus). The patterns during arousal for dopamine and serotonin (5-HT) were similar with a significant fall in concentrations by 1 h of arousal, and an inverse relationship with their respective metabolites, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolacetic acid (5-HIAA). This suggests an acute release and metabolism of these bioamines with onset of arousal. During arousal, cerebral cortical concentrations of norepinephrine (NE) were not significantly changed. Levels of homovanillic acid were markedly depressed during hibernation and rose acutely with arousal. After arousal and 4 days of feeding in April, there was an increase in all bioamines and their metabolites studied except for NE. Of note is the marked decrease in the hibernating level of 5-HT and increase in its metabolite 5-HIAA from March to April, which may herald the natural termination of hibernation. Our results suggest that the brain of hibernators undergoes complex changes in the modulation of neurotransmitter systems which are consistent with both down- and up-regulation of neuronal activity in the maintenance of hibernation and the initiation of the arousal process.

Provocative stimulation of the hypothalamic–pituitary–testicular axis in men with spinal cord injury

Study design:Prospective study.Objective:To determine the integrity of the hypothalamic-pituitary-testicular axis in healthy men with spinal cord injury (SCI).Methods:Thirty healthy men with chronic SCI (37±10 years) and thirty-eight able-bodied (AB) controls (36±10 years) participated. Gonadotropin-releasing hormone (GnRH; 100u2009μg IV) was administered to determine gonadotropin release, and human chorionic gonadotropin (hCG; 4000 IU IM) was administered to determine testosterone (T) secretion. Responses to stimulation were categorized as ‘responder’ or ‘non-responder’ by clinical criteria. Single factor ANOVA with repeated measures was performed to identify group differences.Results:The proportion of responders to pituitary GnRH stimulation was similar in the SCI group (22 subjects (73%) for the follicular-stimulating hormone (FSH) and 23 subjects (76%) for the luteinizing hormone (LH) to that of the AB group. The SCI-responder group had an increased FSH response after stimulation compared with the AB-responder group (P<0.05). The SCI-responder group had a greater LH area under the curve to GnRH stimulation than the AB-responder group (P=0.06). The peak FSH response was at 60u2009min and the peak LH response at 30u2009min, regardless of group designation. All groups had similar increases in serum T concentration to hCG stimulation.Conclusions:The pituitary response to stimulation in healthy men with SCI revealed an augmented FSH response; LH response only trended higher. The testicular response to provocative stimulation was similar in hypogonadal and eugondal subjects and in GnRH responders and non-responders. These findings suggest a lack of hypothalamic drive of pituitary gonadotropin release in healthy people with chronic SCI.

Testicular responses to hCG stimulation at varying doses in men with spinal cord injury

Study design:Prospective.Objectives:To test whether provocative stimulation of the testes identifies men with chronic spinal cord injury (SCI), a population in which serum testosterone concentrations are often depressed, possibly due to gonadal dysfunction. To accomplish this objective, conventional and lower than the conventional doses of human chorionic gonadotropin (hCG) were administered.Methods:Thirty men with chronic SCI (duration of injury >1 year; 18 and 65 years old; 16 eugonadal (>12.1u2009nmolu2009l−1) and 14 hypogonadal (⩽12.1u2009nmolu2009l−1)) or able-bodied (AB) men (11 eugonadal and 27 hypogonadal) were recruited for the study. Stimulation tests were performed to quantify testicular responses to the intramuscular administration of hCG at three dose concentrations (ithat is, 400, 2000 and 4000u2009IU). The hCG was administered on two consecutive days, and blood was collected for serum testosterone in the early morning prior to each of the two injections; subjects returned on day 3 for a final blood sample collection.Results:The average gonadal response in the SCI and AB groups to each dose of hCG was not significantly different in the hypogonadal or eugonadal subjects, with the mean serum testosterone concentrations in all groups demonstrating an adequate response.Conclusions:This work confirmed the absence of primary testicular dysfunction without additional benefit demonstrated of provocative stimulation of the testes with lower than conventional doses of hCG. Our findings support prior work that suggested a secondary testicular dysfunction that occurs in a majority of those with SCI and depressed serum testosterone concentrations.

Difficulty in Identifying Factors Responsible for Pressure Ulcer Healing in Veterans With Spinal Cord Injury

OBJECTIVEnTo identify characteristics associated with pressure ulcer (PrU) healing for individuals with spinal cord injury (SCI).nnnDESIGNnSecondary analysis of a large clinical trials data for healing PrUs in individuals with SCI; prospective Delphi process was conducted with SCI and/or PrU experts.nnnSETTINGnSpinal cord injury centers.nnnPARTICIPANTSnThere were 629 screening and 162 treatment participants (N=791); 185 SCI clinicians/national PrU/wound care experts participated in the Delphi process.nnnINTERVENTIONSnNone.nnnMAIN OUTCOME MEASUREnPrU healing of 50% and 100% at weeks 4 andxa012.nnnRESULTSnPoisson regression models using the top Delphi-recommended factors found that only ulcer stage consistently predicted 50% and 100% healing at weeks 4 and 12. Additionally, ischial/perineal location was associated with 33% higher likelihood of 50% healing at week 4. Patient noncompliance with treatment recommendations, the top-ranked Delphi factor, did not predict healing at week 4 or 12. Expanded models found that at week 4, baseline PrU size, PrU stage IV, PrU pain, and American Spinal Injury Association grade A significantly predicted 100% healing, while at week 12, only PrU stage (IV) significantly predicted 100% healing. Significant predictors of 50% healing at week 4 included baseline PrU size, stage, ischial/perianal location body mass index >30kg/m2, foul odor, and signs of infection. At week 12, PrU duration, paraplegia predicted 50% healing. SCI center identifiers consistently showed 2- to 5-fold variation in predicting 50% PrU healing at weeks 4 and 12.nnnCONCLUSIONSnDelphi panel-recommended factors (eg, patient compliance) did not predict PrU healing. Reducing center-level variability in wound healing by learning from best practices should be a health system goal. PrU healing in SCI is still poorly understood, and future studies should focus on as yet unidentified or underappreciated factors.

Greatly increased prevalence of esophageal dysmotility observed in persons with spinal cord injury

The effects of spinal cord injury (SCI) on esophageal motility are largely unknown. Furthermore, due to the complete or partial loss of sensory innervation to the upper gastrointestinal tract, a symptom-based diagnosis of esophageal dysmotility is problematic in the SCI population. To determine the prevalence and characterize the type of motility disorders observed in persons with chronic SCI compared with that of able-bodied (AB) controls based on esophageal pressure topography isometrics acquired by high-resolution manometry and categorized by application of the Chicago Classification. High-resolution manometry of the esophagus was performed in 39 individuals: 14 AB, 12 with paraplegia (level of injury between T4-T12) and 13 with tetraplegia (level of injury between C5-C7). A catheter containing multiple pressure sensors arranged at 360° was introduced into the esophagi of subjects at a distance that allowed visualization of both the upper esophageal sphincters (UES) and lower esophageal sphincters (LES). After a period to acquire pressures at baseline, subjects were asked to perform 10 wet swallows with 5-mL boluses of isotonic saline while esophageal pressure and impedance were being recorded. No significant differences were noted for gender, age, or body mass index between AB and SCI groups. Twenty-one of 25 (84%) subjects with SCI had at least one motility abnormality: 12% with Type II achalasia, 4% with Type III achalasia, 20% with esophagogastric junction outflow obstruction, 4% with the hypercontractile esophagus, and 48% with peristaltic abnormalities (weak peristalsis with small or large defects or frequent failed peristalsis). In contrast, only 7% (1 out of 14) of the AB subjects had any type of esophageal motility disorder. Despite the lack of subjective complaints and clinical awareness, esophageal dysmotility appears to be a highly prevalent condition in persons with SCI. The use of new and improved techniques, as well as a more stringent classification system, permitted the identification of the presence of nonspecific motility disorders in almost all SCI subjects, including four individuals who were previously undiagnosed with achalasia. Future work in persons with SCI is required to clarify the clinical impact of this observation and to study potential associations between esophageal dysmotility, gastroesophageal reflux disease, and pulmonary function. An increased awareness of esophageal dysfunction in the SCI population may lead to the development of new clinical guidelines for the diagnosis, prevention, and treatment of these largely unrecognized disorders.

Chapter 47 – Immobilization Osteoporosis

Immobilization osteoporosis represents a wide spectrum of conditions and disorders. Bone loss due to immobilizing conditions is a consequence of reduction in mechanical load. The etiology and severity of the immobilizing condition, anatomical region, age, gender, genetic factors, and duration are a few considerations that determine the location, magnitude, and characteristics of the observed accelerated skeletal deterioration. After severe immobilization-related bone loss, risk of fracture is increased in the short-term, or if less severe, increased when associated with age-related bony changes. Currently, the interventions intended to maintain bone during immobilization are often not efficacious. Animal models of immobilization, including those of limb casting, tenotomy, hindlimb unweighting, peripheral nerve transection, and spinal cord injury, have afforded knowledge and insight into the cellular, biochemical, and molecular changes that occur with immobilization/disuse, and have provided potential strategies to implement in an attempt to reduce the bone loss related to reduction in load.

A high molecular weight form of pancreatic polypeptide was present in USP insulin and is absent in a more recent insulin preparation

The concentrations and molecular forms of pancreatic polypeptide (PP) and glucagon were determined in USP XX and single‐peak insulin preparations. In USP insulin the concentration of PP was 7 ng mg−1 insulin; on gel chromatography the PP immunoreactivity fractionated into two peaks of about equal size. One of the PP peaks was in the region of 4200 dalton PP, and the other PP peak eluted earlier in the region of a 7000‐10***000 dalton peptide. The concentration of PP in single‐peak insulin was 0ṁ8 ng mg−1 insulin; the immunoreactivity eluted in a single peak in the region of [125I]PP. The concentration of glucagon in each preparation was 55 ng mg−1 insulin. On gel chromatography the immunoreactive glucagon in each insulin preparation eluted in the region of [125I]glucagon.