Paternal age at childbirth and eating disorders in offspring.

BACKGROUND: Advanced paternal age at childbirth is associated with psychiatric disorders in offspring, including schizophrenia, bipolar disorder and autism. However, few studies have investigated paternal age's relationship with eating disorders in offspring. In a large, population-based cohort, we examined the association between paternal age and offspring eating disorders, and whether that association remains after adjustment for potential confounders (e.g. parental education level) that may be related to late/early selection into fatherhood and to eating disorder incidence. METHOD: Data for 2 276 809 individuals born in Sweden 1979-2001 were extracted from Swedish population and healthcare registers. The authors used Cox proportional hazards models to examine the effect of paternal age on the first incidence of healthcare-recorded anorexia nervosa (AN) and all eating disorders (AED) occurring 1987-2009. Models were adjusted for sex, birth order, maternal age at childbirth, and maternal and paternal covariates including country of birth, highest education level, and lifetime psychiatric and criminal history. RESULTS: Even after adjustment for covariates including maternal age, advanced paternal age was associated with increased risk, and younger paternal age with decreased risk, of AN and AED. For example, the fully adjusted hazard ratio for the 45+ years (v. the 25-29 years) paternal age category was 1.32 [95% confidence interval (CI) 1.14-1.53] for AN and 1.26 (95% CI 1.13-1.40) for AED. CONCLUSIONS: In this large, population-based cohort, paternal age at childbirth was positively associated with eating disorders in offspring, even after adjustment for potential confounders. Future research should further explore potential explanations for the association, including de novo mutations in the paternal germline.

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood.

BACKGROUND: Genetic and environmental factors are important in the etiology of substance use. However, little is known about the stability of these factors across development. We aimed to answer three crucial questions about this etiology that have never been addressed in a single study: (1) Is there a general vulnerability to substance consumption from early adolescence to young adulthood? (2) If so, do the genetic and environmental influences on this vulnerability change across development? (3) Do these developmental processes differ in males and females? METHOD: Subjects included 1480 twin pairs from the Swedish Twin Study of Child and Adolescent Development who have been followed since 1994. Prospective, self-reported regular smoking, alcohol intoxication and illicit drug use were assessed at ages 13-14, 16-17 and 19-20 years. Structural modeling was performed with the program Mx. RESULTS: An underlying common factor accounted for the association between smoking, alcohol and illicit drug consumption for the three age groups. Common genetic and shared environmental effects showed substantial continuity. In general, as participants aged, the influence of the shared environment decreased, and genetic effects became more substance specific in their effect. CONCLUSIONS: The current report answers three important questions in the etiology of substance use. The genetic and environmental risk for substance consumption is partly mediated through a common factor and is partly substance specific. Developmentally, evidence was strongest for stability of common genetic effects, with less evidence for genetic innovation. These processes seem to be the same in males and females.

Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.

BACKGROUND: The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects. METHODS: Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients. RESULTS: Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, K(trans) values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1alpha, IL-8, ICAM-1, and VCAM-1. CONCLUSION: Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.

Prospective randomized comparison of 50%/50% versus 65%/65% tilt biphasic waveform on defibrillation in humans.

It is unknown if there is a single optimal biphasic waveform for defibrillation. Biphasic waveform tilt may be an important determinant of defibrillation efficacy. The purpose of this study was to compare acute defibrillation success with a three-electrode configuration in humans using 50%/50% versus 65%/65% tilt truncated exponential, biphasic waveforms delivered through a 110-microF capacitor. Acute DFTs for biphasic waveforms with 50%/50% versus 65%/65% tilt were measured in random order in 60 patients using a binary search method. The electrode configuration consisted of a RV coil as the cathode, and a SVC coil plus a pectoral active can emulator (CAN) as the anode. The waveforms were derived from an external voltage source with 110-microF capacitance, and the leading edge voltage of phase 2 was equal to the trailing edge voltage of phase 1. Stored energy DFT (9.2 +/- 5.7 [50%/50%] vs 10.8 +/- 6.4 [65%/65%] J, P = 0.007), current DFT (10.9 +/- 4.0 [50%/50%] vs 12.0 +/- 4.4 [65%/65%] A, P = 0.002) and voltage DFT (391 +/- 118 [50%/50%] vs 424 +/- 128 [65%/65%] V, P = 0.004) were significantly lower for the 50%/50% tilt waveform versus the 65%/65% tilt waveform using this three-electrode configuration and a 110-microF capacitor. For an RV(-)/SVC plus CAN(+) electrode configuration and a 110-microF capacitor, a 50%/50% tilt biphasic waveform results in a 15% reduction in energy DFT, 9% reduction in current DFT, and 8% reduction in voltage DFT versus a 65%/65% tilt biphasic waveform.

The brain response to 2-deoxy glucose is blocked by a glial drug.

Two brain regions - the basomedial hypothalamus and area postrema (AP) - react to changes in circulating glucose levels by altering feeding behavior and the secretion of pituitary and non-pituitary hormones. The precise identity of cells responding to glucose in these regions is uncertain. The recent detection of high-capacity glucose transporter proteins in astrocytes in these areas has suggested that astrocytes may play a role in glucose sensing by the brain. To test this hypothesis, rats were injected with either saline or methionine sulfoximine (MS), a compound that produces alterations in carbohydrate and glutamate metabolism in astrocytes. Eighteen hours later, rats were injected with either saline or 2-deoxy glucose (2-DG) and brain sections were stained to demonstrate 2-DG-activated neurons immunoreactive for Fos protein. MS-treated rats showed a 70% reduction in numbers of Fos+ neurons in the AP region (p<0.05). Also, specialized, Gomori+ astrocytes were particularly abundant in both glucose sensitive regions and showed a distribution identical to that reported for high-capacity glucose transporter proteins. These data suggest that specialized astrocytes influence the glucose-sensing function of the brain.

Evidence for polar cytoplasm/nuage in rat oocytes.

In many organisms oocytes contain dark-staining material, termed nuage, that is concentrated at one pole of the oocyte cytoplasm and that influences the further development of the oocyte after fertilization. In mammalian oocytes, ultrastructural studies have detected small patches of nuage-like material, but thus far no nuage-rich zone of polar cytoplasm has been reported. Here, we report that when large sections of rat ovary embedded in methacrylate resin are stained with toluidine blue and surveyed, many oocytes contain a narrow, sharply defined, basophilic zone of polar cytoplasm that appears analogous to the polar cytoplasm of Xenopus and other non-mammalian species. This basophilic polar cytoplasm was common in multilaminar follicles and was not visible in smaller, primordial follicles. In one out of five oocytes stimulated with hCG to complete the first meiotic division, a relatively faint region of cortical basophilia was detectable. Further studies will be needed to ascertain if this nuage-like material has an influence upon the development of oocytes similar to that seen in non-mammalian species.

Duodenal motor responses in preterm infants fed formula with varying concentrations and rates of infusion.

Feeding intolerance is frequently reflected in preterm infants by delayed gastric emptying. Gastric emptying is delayed by the physical characteristics of ingested nutrient as well as the rate of feeding. Because gastric emptying is dependent upon duodenal function, the present studies were undertaken to assess duodenal motor responses to feeding of differing nutrient content and rate of feeding. Using a Latin square design we recorded duodenal motor responses in 14 preterm infants given four test feedings in random order over 18 h. Three were given as a 120-min infusion containing no nutrient, a 10 cal/oz formula, and a 20 cal/oz formula. The fourth test feeding consisted of a 20 cal/oz formula given as a bolus over 15 min. Although caloric density was altered, osmotic load and nutrient proportions of the formulas were not. Motor responses were recorded using a low compliance continuous perfusion manometric system. When infants were fed "water" and half-strength formula as a slow infusion, they demonstrated little or no duodenal motor response to feeding. When these infants were fed full-strength formula as a slow infusion, they displayed a brisk increase in motor activity (p < 0.05), but profound motor quiescence when fed the same volume by bolus over 15 min (p < 0.05). Of the four test feedings, only full-strength formula given as a slow infusion triggered adult-like duodenal motor responses to feeding. We speculate that feedings of full-strength formula given slowly by infusion will improve feeding tolerance.

A prospective, randomized evaluation of a nonthoracotomy implantable cardioverter defibrillator lead system. Endotak/PRX Investigator Group.

Nonthoractomy lead systems for ICDs have been developed that obviate the need for a thoracotomy and reduce the morbidity and mortality associated with implantation. However, an adequate DFT cannot be achieved in some patients using transvenous electrodes alone. Thus, a new subcutaneous "array" electrode was designed and tested in a prospective, randomized trial that compared the DFT obtained using monophasic shock waveforms with a single transvenous lead alone that has two defibrillating electrodes, the transvenous lead linked to a subcutaneous/submuscular patch electrode, and the transvenous lead linked to the investigational array electrode. There were 267 patients randomized to one of the three nonthoracotomy ICD lead systems. All had DFTs that met the implantation criterion of < or = 25 J. The resultant study population was 82% male and 18% female, mean age of 63 +/- 11 years. The indication for ICD implantation was monomorphic VT in 70%, VF in 19%, monomorphic VT/VF in 6%, and polymorphic VT in 4% of the patients, respectively. The mean LVEF was 0.33 +/- 0.13. The mean DFT obtained with the transvenous lead alone was 17.5 +/- 4.9 J as compared to 16.9 +/- 5.5 J with the lead linked to a patch electrode (P = NS), and 14.9 +/- 5.6 with the lead linked to the array electrode (array versus lead alone, P = 0.0001; array versus lead/patch, P = 0.007). The results of this investigation suggest that the subcutaneous array may be superior to the standard patch as a subcutaneous electrode to lower the DFT and increase the margin of safety for successful nonthoracotomy defibrillation.

Posterior left thoracic cardiac sympathectomy by surgical division of the sympathetic chain: an alternative approach to treatment of the long QT syndrome.

Although high thoracic left sympathectomy via an anterior surgical approach is a highly efficacious treatment for refractory ventricular arrhythmias in patients with the long QT syndrome, the degree of sympathetic denervation has been variable, success of the operation is influenced by anatomical differences between patients, and Horner's syndrome may result. We hypothesized that interruption of sympathetic input to the heart could be accomplished using a posterior thoracic approach to this variable and often complex anatomy by division of the sympathetic chain rather than by direct destruction of the stellate and superior thoracic ganglia with the more conventional anterior, supraclavicular approach. In addition, the posterior approach should decrease the risk of Horner's syndrome by avoiding the ocular sympathetic efferent nerves. This posterior approach is described in five patients with the long QT syndrome and recurrent ventricular arrhythmias. After a mean follow-up of 18 +/- 12 months, all are alive without Horner's syndrome.

PR/RR interval ratio during rapid atrial pacing: a simple method for confirming the presence of slow AV nodal pathway conduction.

INTRODUCTION: Although the AV conduction curve in patients with AV nodal reentrant tachycardia (AVNRT) is usually discontinuous, many patients with this arrhythmia do not demonstrate criteria for dual AV nodal pathways. During rapid atrial pacing, the PR interval often exceeds the pacing cycle length when there is anterograde conduction over the slow pathway and AVNRT is induced. The purpose of this prospective study was to determine the diagnostic value of the ratio of the PR interval to the RR interval during rapid atrial pacing as an indicator of anterograde slow pathway conduction in patients undergoing electrophysiologic testing. METHODS AND RESULTS: The PR and RR intervals were measured during rapid atrial pacing at the maximum rate with consistent 1:1 AV conduction in four study groups: (1) patients with inducible AV nodal reentry and the classical criterion for dual AV nodal pathways during atrial extrastimulus testing (AVNRT Group 1); (2) patients with inducible AV nodal reentry without dual AV nodal pathways (AVNRT Group 2); (3) control subjects < or = 60 years of age without inducible AV nodal reentry; and (4) control subjects > 60 years of age without inducible AV nodal reentry. For both groups of patients with inducible AV nodal reentry, AV conduction was assessed before and after radiofrequency ablation of the slow AV nodal pathway. Before slow pathway ablation, the PR/RR ratio exceeded 1.0 in 12 of 13 AVNRT Group 1 patients (mean 1.27 +/- 0.21) and 16 of 17 AVNRT Group 2 patients (mean 1.18 +/- 0.15, P = NS Group 1 vs Group 2). After slow pathway ablation, the maximum PR/RR ratio was < 1.0 in all AVNRT patients (Group 1 = 0.59 +/- 0.08, P < 0.00001 vs before ablation; Group 2 = 0.67 +/- 0.11; P < 0.00001 vs before ablation). Among both groups of control subjects, the PR/RR ratio was > 1.0 in only 3 of 27 patients with no relation to patient age. CONCLUSION: The ratio of the PR interval to the RR interval during rapid atrial pacing at the maximum rate with consistent 1:1 AV conduction provides a simple and clinically useful method for determining the presence of slow AV nodal pathway conduction. This finding may be particularly useful in patients with inducible AV nodal reentry without dual AV nodal physiology on atrial extrastimulus testing.

Immunoreactivity for brain-fatty acid binding protein in gomori-positive astrocytes.

Gomori-positive (GP) astrocytes are a subset of brain astrocytes with highly stained cytoplasmic granules that arise from the degradation of mitochondria. The GP granules of these astrocytes are most prominent in the arcuate nucleus of the hypothalamus, but can also be detected in the olfactory bulbs, hippocampus, habenula, and other selected brain regions. The cause and functional effects of this mitochondrial pathology in these glia are not yet known with certainty. In other tissues, mitochondrial dysfunction is associated with elevations in cytoplasmic lipids and lipid-binding proteins, due to impaired mitochondrial oxidation of lipids. To see if GP astrocytic mitochondrial pathology is also associated with an elevation in lipid binding proteins, rat brain sections were stained for brain fatty acid binding protein (B-FABP), using immunocytochemistry. Astrocytes immunoreactive for B-FABP were much more abundant in brain regions enriched in GP astrocytes than in other brain regions. Semi-thin sections revealed that astrocytic B-FABP immunoreactivity was often, but not always, associated with GP cytoplasmic granules. These data suggest that GP astrocytes have an unusual lipid metabolism, which may relate to degenerative processes occurring in the selected brain regions that contain GP astrocytes.

Predictors of recurrent atrioventricular nodal reentry after selective slow pathway ablation.

Although radiofrequency catheter ablation of the slow atrioventricular (AV) nodal pathway is highly effective for the management of AV nodal reentrant tachycardia (AVNRT), this arrhythmia may recur in some patients after an ablation procedure that initially renders AVNRT noninducible. A retrospective study examined the factors that are associated with the recurrence of AVNRT after selective radiofrequency catheter ablation of the slow pathway. Patients were included in the study if they had initially inducible, typical slow-fast AVNRT that was noninducible at the end of the ablation session. Selective ablation of the slow pathway was performed using radiofrequency energy applied along the tricuspid annulus near the coronary sinus ostium. AVNRT recurred after initially successful slow pathway ablation in 10 of 136 patients (7.4%) over a mean follow-up period of 20.1 +/- 5.0 months; the time to recurrence ranged from 1 to 411 days. Despite the absence of inducible AVNRT, dual anterograde AV nodal conduction properties persisted after slow pathway ablation in 10 patients. AVNRT recurred in 4 of 10 patients who had evidence of residual slow pathway conduction compared with only 6 of 126 who had no residual slow pathway conduction (p = 0.003). All patients with persistent slow pathway conduction and recurrent AVNRT also had residual AV nodal echo beats. AVNRT recurred in 3 of 6 patients without accelerated junctional tachycardia during radiofrequency application compared with only 7 of 109 with accelerated junctional tachycardia (p = 0.003). Thus, AVNRT infrequently recurs after successful selective radiofrequency ablation of the slow pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Paraplegia and traumatic rupture of the aorta: a disease process or surgical complication?

Surgical repair of traumatic rupture of the aorta results in an excellent survival rate especially among the young, although paraplegia continues to be a serious postoperative complication. The authors present nine cases admitted to Stoke Mandeville Hospital, England, including detailed post-mortem findings on one of the cases. Although it was difficult to be certain of the patients' general and neurological status prior to surgery, as it was not well documented in the patients' case notes, it was evident that systemic hypotension and poor distal aortic perfusion were responsible for the disabling complication. A review of the initial medical management of these patients and the surgical techniques employed in repairing such injuries is urgently needed.

An experimental investigation of interactions in snail-macrophyte-epiphyte systems.

An experimental investigation under field conditions of enclosures containing freshwater pulmonate snails, the macrophyteCeratophyllum demersum and epiphytes, produced evidence of beneficial interactions.Ceratophyllum growth, measured in terms of stem length, numbers of leaf-nodes and growing tips and leaf survival was significantly enhanced in the presence of snails. This effect was attributed to the increased availability of plant nutrients of snail origin, such as phosphates and ammonia, as well as to the snails' action as "cleaning symbionts" in reducing the density of bacterial and algal epiphyton potentially deleterious to macrophytes. Principal component analysis revealed both seasonal and treatment effects of snail grazing on algal epiphyton. Small adnate algal species (e.g.Cocconeis placentula) survived grazing and benefited from the removal of larger, competitor, species. Snail densities increased in all treatments, despite high (86%) juvenile mortality. It is concluded that freshwater pulmonate snails are strong interactors in lentic habitats, enhancing the growth ofCeratophyllum and producing characterisic epiphyte communities. This benefits not only the snails, but also the plants and epiphytes that are associated with them. Thus the interactions between these component parts of the community can be considered as mutualistic.

Muscle regeneration following segmental necrosis in tenotomized muscle fibers.

The aim of this study was to determine how the new myotendinous junctions were re-established at the proximal and distal ends of the soleus muscle after tenotomy. Both proximal and distal tendons of the soleus muscle in mature female rats were severed. The animals were killed and the soleus muscles were removed and prepared for light and electron microscopic examination 1, 3, 5, 7, 14, 21, 28, and 42 days after the operation. It was found that segmental fiber destruction followed by removal by macrophages occurred at the ends of the soleus muscle fibers. This resulted in the liberation and myogenic activation of satellite cells. By 3 days after tenotomy the fusion of myoblasts to form myotubes could be seen. The myotubes developed within the original basal lamina and reattached to the surviving non-necrotic segments and grew in both length and width so that by 6 weeks postoperation, normal myotendinous junctions had been reformed. This study is the first to show that re-establishment of the myotendinous junction following tenotomy is accomplished by regeneration of the necrotic ends of the tenotomized fibers.

Association of iron-containing astrocytes with dopaminergic neurons of the arcuate nucleus.

Specialized astrocytes, identified by cytoplasmic granules that are electron-dense and vividly stained by toluidine blue due to the presence in the granules of SH molecules and molecules of iron, have long been known to be present within the arcuate nucleus of the hypothalamus. Their function, however, is obscure. To determine whether or not these specialized astrocytes are in contact with dopaminergic neurons, rat brain sections were stained to detect tyrosine hydroxylase (TH) immunoreactive neurons by immunocytochemistry and were examined by both light and electron microscopy. Iron-rich astrocytes were located in the same general portion of the arcuate nucleus as were TH+ neurons, and most appeared closely associated with TH+ structures (somas, dendrites, and fibers) at the light-microscopic level. At the ultrastructural level, close contact between TH + neurons and processes of iron-rich glia was confirmed. This unique anatomical association suggests a functional relationship between the two cell types that may be related to unusual histochemical features of both cell types and/or to the location of these cells in an area with a highly permeable blood-brain barrier.

Elevated serum IgE, eosinophilia, and lung function in rubber workers.

We previously reported an outbreak of acute respiratory illness associated with eosinophilia in a group of rubber workers who performed a thermoinjection process in which synthetic rubber was heated and then injected onto metal molds. This study was conducted to determine if persistent respiratory health effects were associated with this work area and to explore the possible allergic etiology of this syndrome. A survey was performed 1 mo after a major improvement in area ventilation and consisted of baseline, cross-shift, and cross-week spirometry; diffusing capacity; serum immunoglobulin E (IgE), total eosinophil count; and skin patch testing. Baseline lung function, cross-shift, and cross-week spirometry were not significantly worse in the exposed group as compared to the control group. However, either eosinophilia (greater than 450/mm3) or elevated serum IgE (greater than 470 ng/ml) were present in 44% of exposed workers vs. 11% of the control group (p = .003). Nine months later, neither eosinophilia nor elevated IgE were associated with employment in this work area. We conclude that employment in the thermoinjection process was associated with eosinophilia and elevated IgE, which suggests sensitization to one of the components of the rubber, although no effect on pulmonary function could be demonstrated.

Fungemia caused by an amphotericin B-resistant isolate of Sporothrix schenckii. Successful treatment with itraconazole.

A 58-year-old, alcoholic, diabetic man presented with multiple, ulcerated skin lesions and polymicrobial septicemia. Sporothrix schenckii was recovered from blood cultures and was resistant to amphotericin B by in vitro testing. Amphotericin B therapy failed, but the patient responded dramatically to itraconazole therapy, only to relapse 3 months after therapy was stopped. Reinstitution of itraconazole therapy has produced another dramatic response. This report is noteworthy for three reasons. First, to our knowledge, it represents only the second reported instance of fungemia with S schenckii that responded to medical therapy. Second, it illustrates that in vitro antifungal susceptibility tests may predict clinical infection response to drug therapy. Third, it suggests that itraconazole has significant promise in treating systemic sporotrichosis.

Adaptation of skeletal muscle to immobilization in a shortened position.

This study determined the morphological changes and adaptations that occur following immobilization of rat soleus and gastrocnemius muscles when the ankle joint is placed in complete plantar flexion for 2, 5, 7, 14, 21, and 28 days by means of plaster casts. Previous studies of such shortened muscles have shown that the number of sarcomeres in series is reduced, but how the sarcomeres are reduced has not been determined. We observed that the fibers in the mid-belly region of the muscles demonstrated a progressive degenerative process over the first few weeks. Myofibrils across the entire width of the affected fibers underwent dissolution. However, by 4 weeks new myofibrils were being formed, and sarcomere lengths appeared normal. Portions of the fibers near the tendon underwent segmental necrosis. These findings are similar to the response of the soleus and gastrocnemius muscles to tenotomy and are clinically relevant to orthopedic procedures that maintain muscles in shortened conditions for prolonged periods.