Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P < 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI)-31.103 in women; leptin = 0.534 (BMI)-8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat)-24.817 in women; leptin = 0.402 (% body fat)-3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = -0.57; P < 0.0001) and high waist to hip ratio (r = 0.75; P < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.

Adipose Tissue↗

PubMed1997

The effect of changing the inertia of a trans-tibial dynamic elastic response prosthesis on the kinematics and ground reaction force patterns.

The aim of this study was to assess, by means of gait analysis, the effect on the gait of a trans-tibial amputee of altering the mass and the moment of inertia of a dynamic elastic response prosthesis. One male amputee was analysed for four to five walking trials at normal and fast cadences, using the VICON system of motion analysis and an AMTI force plate. The kinematic variables of cadence, swing time, single support time and joint angles for the knee and hip on the affected and intact sides were analysed. The ground reaction force was also analysed. The sample size was limited to one as an example to indicate the changes which are possible through simply changing the inertial characteristics. Descriptive statistics are used to demonstrate these changes. Three mass conditions for the prosthesis were analysed m1: 1080g; m2: 1080 + 530g; m3: 1080 + 1460g. The m1 condition is the mass of the prosthesis with no added weight while m2 and m3 were attachments of the same geometrical shape but were made from different materials. It was felt that the large mass range would highlight biomechanical adjustments as a result of its alteration. The effect on selected temporal characteristics were that as the speed increased the cadence changed and the affected side single support times as a percentage of the gait cycle were altered. The effect on the joint angles was also apparent at the hip and knee of both sides. The ground reaction force patterns were similar for all three mass conditions, though the impact peak which was evident in the intact limb was missing, indicating a shock absorbing property in the prosthesis. Clearly, changing the mass and moment of inertia has an effect on the kinematic variables of gait and should be considered when designing a prosthesis.

Artificial Limbs↗

PubMed1997

Dynamics of hip joint remodeling after Chiari osteotomy. 10 patients with neuromuscular disease followed for 8 years.

We analyzed the development of 10 hips in 10 consecutive patients with neuromuscular disease (9 with spasticity, 1 with Charcot-Marie-Tooth disease) who had undergone Chiari osteotomy for painful hip subluxation or dislocation. The patients were 11 (5-19) years old at surgery and follow-up time was 8 (6-11) years. The Chiari osteotomy particularly improved and maintained femoral head coverage. These parameters did not show the postoperative deterioration noted in some other studies. The osteotomy did not improve femoral head lateral displacement. Throughout the postoperative period, the configuration of the proximal femur and the height of the joint cartilage were unchanged and undisturbed, indicating that osteotomy did not place excessive or uneven pressure on the femoral head. The ambulatory status of the patients was dependent on the severity of the underlying disease, and was not improved by osteotomy. However, pain associated with subluxation or dislocation was reduced in 9 of the patients.

Activities of Daily Living↗

PubMed1997

Comparing two formats for clinical "pearls" at morning report.

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Humans↗

PubMed1997

Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.

We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.

Adaptor Proteins, Signal Transducing↗

PubMed1996

The microbiology of chronic otitis media with effusion in a group of Auckland children.

AIMS: To determine the microbiology of chronic otitis media with effusion in a group of Auckland children. To determine the antimicrobial sensitivities of isolated bacterial pathogens to commonly used antibiotics for this condition. METHODS: A descriptive study recruiting subjects from otherwise well children with chronic otitis media with effusion having insertion of ventilation tubes at Starship Children's Health, Auckland. Tympanocentesis was performed, the middle ear aspirate cultured and antimicrobial sensitivities obtained. RESULTS: Sixty seven children (11mo to 8yr) with chronic otitis media with effusion had tympanocentesis of 105 ears. 38/105 (36%) of the middle ear aspirate cultures were positive. Forty nine organisms were isolated with 10 ears having two or more different bacteria identified. Isolated were 17 Haemophilus influenzae (16 nontype b and 1 type b), 13 Moraxella catarrhalis, nine Streptococcus pneumoniae and 10 'others'. All S pneumoniae(9/9), most H influenzae(14/17) and no M catarrhalis(0/13) were sensitive to amoxycillin. More than 80% of subjects had either a sterile effusion or an organism sensitive to amoxycillin or cotrimoxazole. CONCLUSIONS: Middle ear effusions were culture positive in a third of cases of chronic otitis media with effusion. The commonest organisms were H influenzae nontype b, M catarrhalis and S pneumoniae. This is similar to reports from other countries. Sensitivity data obtained supports the continued recommendation of amoxycillin or cotrimoxazole as first line therapy for the antimicrobial treatment of this condition.

Amoxicillin↗

PubMed1996

Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome.

BACKGROUND: The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is an autosomal dominant genetic disorder caused by the inheritance of a mutation in one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC manifests as genetic instability in linked tumors. Clinically, the syndrome is characterized by early onset malignancies, primarily of the colon and endometrium, with an increased incidence of tumors at other gastrointestinal sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion of breast cancer as an integral tumor of this syndrome is controversial. METHODS: Mutation screening of MMR genes was carried out by single strand conformation polymorphism (SSCP) and sequencing analyses of genomic DNA prepared from normal lymphocytes. Expression analysis was performed by SSCP. Sequence analyses of cDNA was prepared from breast tumor tissue and normal lymphocytes. Genetic instability was assessed by comparing the electrophoretic mobility of polymerase chain reaction (PCR) products using multiple microsatellite markers. RESULTS: A 4-bp frameshift mutation in the hMLH1 gene was found to segregate with disease in the germlines of the affected members of a large kindred HNPCC. Expression of only the mutant allele was observed in the breast cancer tissue of one family member, however both alleles were observed in her normal tissue. This breast cancer exhibited widespread microsatellite instability, as did breast cancers obtained from several other HNPCC kindreds. CONCLUSIONS: These data indicate that breast cancer may result from the inheritance of a mutant MMR gene, and that breast cancer may occur as an integral tumor in the HNPCC syndrome.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Assessing services. Knowing the score.

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Health Priorities↗

PubMed1996

Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage.

BACKGROUND: The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1-related and BRCA2-related hereditary breast cancer (HBC) and non-HBC. METHODS: On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either "BRCA1-related" (26 families, 90 breast cancer pathology cases) or "Other" (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained. RESULTS: BRCA1-related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P = 0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P= 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR]= 4.42; P= 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2- linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age- and stage-dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS: BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1-related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the "Other" HBC group may be associated with BRCA2 linkage.

Adult↗

PubMed1996

Latanoprost, a prostaglandin analog, for glaucoma therapy. Efficacy and safety after 1 year of treatment in 198 patients. Latanoprost Study Groups.

PURPOSE: To determine efficacy and safety of latanoprost, a prostaglandin analog for glaucoma, during 1 year of treatment. METHODS: After baseline measurements, 0.005% latanoprost was topically applied once daily for 12 months in patients from Scandinavia, the United Kingdom, and the United States who had elevated intraocular pressure (IOP). Diagnoses included ocular hypertension, chronic open-angle glaucoma, exfoliation syndrome, and pigment dispersion syndrome. Treatment was masked for the first 6 months and open-label during the second 6 months. RESULTS: Of the 272 patients initially enrolled, withdrawals were due to inadequate IOP control (1%), increased iris pigmentation (5%), other ocular problems (3%), systemic medical problems (3%), and nonmedical reasons (14%). Latanoprost significantly (P < 0.0001) reduced diumal IOP from 25.3 +/- 3.0 mmHg (mean +/- standard deviation) at baseline to 17.4 +/- 2.7 mmHg (32% reduction) at 12 months in the 198 patients who completed 1 year of treatment. The IOP reduction was maintained at a consistent level throughout the 12 months without evidence of drift, and was not affected by sex, age, race, or eye color. Overall, latanoprost caused a possible or definite increase in iris pigmentation in 12% of the 272 patients, all of whom had multicolored irides at baseline. One half of these patients with increased pigmentation withdrew before completing 1 year of therapy. Visual field, optic disc cupping, visual acuity, refractive error, conjunctival hyperemia, aqueous flare, anterior chamber cellular response, lens examination, blood pressure, heart rate, blood tests, and urinalysis were not appreciably altered. CONCLUSION: Latanoprost safely and effectively reduces IOP for 1 year in patients of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma therapy.

Administration, Topical↗

PubMed1996

A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. The Latanoprost Study Group.

PURPOSE: To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost administered once daily with 0.5% timolol administered twice daily in patients with open-angle glaucoma or ocular hypertension. METHODS: This was a randomized, double-masked study with two parallel groups and a treatment period of 6 months. The primary objective of the study is to compare the IOP-reducing effect of lantanoprost with that of timolol at the end of the 6-month treatment period. A total of 294 patients were included: 149 were in the latanoprost group and 145 were in timolol group. Latanoprost was administered in the evening. RESULTS: Diurnal IOP (9:00 am, 1:00 pm, 5:00 pm) was reduced from 25.2 to 16.7 mmHg (33.7%) with lantanoprost and from 25.4 to 17.1 mmHg (32.7%) with timolol as determined at the end of the 6-month treatment period. No upward drift in IOP occurred with either drug during the treatment period. Latanoprost caused a somewhat more conjunctival hyperemia than timolol and more corneal punctuate epithelial erosions. However, both drugs were generally well tolerated. The most significant side effect of latanoprost was increased pigmentation of the iris which was observed in 15 patients (10.1%). Timolol caused more systemic side effects than latanoprost. CONCLUSIONS: Latanoprost 0.005% administered once daily in the evening reduced IOP at least as well as timolol 0.5% administered twice daily. Latanoprost was generally well tolerated systemically and in the eye. However, the drug has an unusual side effect of increasing the pigmentation of the iris, particularly in individuals with green-brown or blue-brown eyes.

Adrenergic beta-Antagonists↗

PubMed1996

Two infant vision screening programmes: prediction and prevention of strabismus and amblyopia from photo- and videorefractive screening.

Two infant vision screening programmes on total populations in the Cambridge Health District have been designed to identify manifest strabismus and strabismogenic and amblyogenic refractive errors at 7-9 months of age. The first, completed, programme used the isotropic photorefractor with cycloplegia together with a standard orthoptic examination. The second, current, programme uses the VRP-1 isotropic videorefractor to identify infants with accommodative lags which are followed up by refraction under cycloplegia. Both programmes show good agreement between infants identified at screening and retinoscopic refractions at follow-up, showing that photo- and videorefraction (with or without cycloplegia) can be effective methods for screening for ametropia in infants and young children. In each programme 5-6% of infants showed abnormal levels of hyperopia (> or = 3.5 D in any meridian), less than 1% showed anisometropia > or = 1.5 D; very few infants (0.25%) showed -3D myopia or greater. Less than 1% showed manifest strabismus. Hyperopic and anisometropic children entered a randomised controlled trial of partial refractive correction. All children identified at screening, alongside appropriate control groups, are extensively followed up to age 4 years. The first programme has found that children who were hyperopic in infancy were 13 times more likely to become strabismic, and 6 times more likely to show measurable acuity deficits by 4 years, compared with controls. Wearing a partial spectacle correction reduced these risk ratios to 4:1 and 2.5:1 respectively. The impaired acuity can be attributed, in part, to meridional amblyopia resulting from persisting astigmatism. Both hyperopic and myopic infants showed refractive changes in the direction of emmetropia between 9 months and 4 years. Wearing a partial spectacle correction did not affect this process of emmetropisation, but does provide the possibility of reducing the incidence of common pre-school vision problems.

Aging↗